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1
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Herdenberg C, Henriksson R, Hedman H, Rondahl V. Lrig3-deficient mice exhibit strain-specific alterations in liver fat accumulation, intestinal morphology, and middle ear inflammation. Gene 2025; 960:149539. [PMID: 40320098 DOI: 10.1016/j.gene.2025.149539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 04/13/2025] [Accepted: 04/30/2025] [Indexed: 05/09/2025]
Abstract
The transmembrane protein leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) regulates fat metabolism and bone morphogenetic protein (BMP) signaling. Lrig3-deficient mice exhibit impaired development of the snout and the inner ear lateral canal, neural defects, and cardiac hypertrophy in adulthood. However, no thorough and unbiased analysis of the physiological functions of Lrig3 has previously been performed. To address this knowledge gap, we performed histopathological examination of 42 tissues and organs from 1-year-old female C57BL/6JBomTac and 129S1-U mice with different Lrig3 genotypes. Among the scored pathologies, three were significantly associated with Lrig3 genotype: spontaneous macrovesicular hepatocellular degeneration (hepatocellular steatosis) was less prevalent in Lrig3-deficient C57BL/6JBomTac mice, whereas dilated or flaccid ileum and otitis media were more common in Lrig3-deficient 129S1-U mice. To further investigate hepatic steatosis phenotypes, 8-week-old C57BL/6JBomTac mice of both sexes and different Lrig3 genotypes were subjected to consuming a high-fat diet (HFD) for 8 weeks. The HFD regimen led to relatively few cases of hepatocellular steatosis, with no significant differences among the genotypes; however, female Lrig3-deficient mice presented reduced microvesicular hepatocellular degeneration compared with their wild-type littermates. This study revealed that Lrig3 regulates liver fat accumulation, intestinal morphology, and middle ear inflammation in a mouse strain-dependent manner.
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Affiliation(s)
- Carl Herdenberg
- Department of Diagnostics and Intervention, Oncology, Umeå University, SE-90187 Umeå, Sweden
| | - Roger Henriksson
- Department of Diagnostics and Intervention, Oncology, Umeå University, SE-90187 Umeå, Sweden
| | - Håkan Hedman
- Department of Diagnostics and Intervention, Oncology, Umeå University, SE-90187 Umeå, Sweden.
| | - Veronica Rondahl
- Department of Pathology and Wildlife Disease, National Veterinary Institute (SVA), SE-751 89 Uppsala, Sweden; Department of Animal Biosciences, Division for Anatomy, Physiology, Immunology, and Pathology, Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden(1)
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2
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Banjac I, Maimets M, Tsang IHC, Dioli M, Hansen SL, Krizic K, Bressan RB, Lövkvist C, Jensen KB. Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells. Dev Cell 2025; 60:1281-1289.e6. [PMID: 39793582 DOI: 10.1016/j.devcel.2024.12.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 08/10/2024] [Accepted: 12/11/2024] [Indexed: 01/13/2025]
Abstract
The intestinal epithelium has a remarkably high turnover in homeostasis. It remains unresolved how this is orchestrated at the cellular level and how the behavior of stem and progenitor cells ensures tissue maintenance. To address this, we combined quantitative fate mapping in three complementary mouse models with mathematical modeling and single-cell RNA sequencing. Our integrated approach generated a spatially and temporally defined model of crypt maintenance based on two cycling populations: stem cells at the crypt-bottom and transit-amplifying (TA) cells above them. Subsequently, we validated the predictions from the mathematical model, demonstrating that fate decisions between the secretory and absorptive lineages are made within the stem cell compartment, whereas TA cell divisions contribute specifically to the absorptive lineage. These quantitative insights provide further direct evidence for crypt-bottom stem cells as the dominant driver of the intestinal epithelium replenishment.
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Affiliation(s)
- Isidora Banjac
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Martti Maimets
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Ingrid H C Tsang
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Marius Dioli
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Stine Lind Hansen
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Kata Krizic
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Raul Bardini Bressan
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Cecilia Lövkvist
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
| | - Kim B Jensen
- Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark.
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3
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Green EH, Kotrannavar SR, Rutherford ME, Lunnemann HM, Kaur H, Heiser CN, Ding H, Simmons AJ, Liu X, Lacy DB, Washington MK, Shrubsole MJ, Liu Q, Lau KS, Sears CL, Coffey RJ, Drewes JL, Markham NO. Multiomic spatial atlas shows deleted in malignant brain tumors 1 (DMBT1) glycoprotein is lost in colonic dysplasia. J Pathol 2025; 266:51-65. [PMID: 40026233 PMCID: PMC11985286 DOI: 10.1002/path.6406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 12/03/2024] [Accepted: 01/15/2025] [Indexed: 03/05/2025]
Abstract
Colorectal cancer (CRC) is responsible for over 900,000 annual deaths worldwide. Emerging evidence supports pro-carcinogenic bacteria in the colonic microbiome are at least promotional in CRC development and may be causal. We previously showed toxigenic C. difficile from human CRC-associated bacterial biofilms accelerates tumorigenesis in ApcMin/+ mice, both in specific pathogen-free mice and in gnotobiotic mice colonized with a defined consortium of bacteria. To further understand host-microbe interactions during colonic tumorigenesis, we combined single-cell RNA-sequencing (scRNA-seq), spatial transcriptomics, and immunofluorescence to define the molecular spatial organization of colonic dysplasia in our consortium model with or without C. difficile. Our data show a striking bipartite regulation of Deleted in Malignant Brain Tumors 1 (DMBT1) in the inflamed versus dysplastic colon. From scRNA-seq, differential gene expression analysis of normal absorptive colonocytes at 2 weeks postinoculation showed DMBT1 upregulated by C. difficile compared to colonocytes from mice without C. difficile exposure. In contrast, our spatial transcriptomic analysis showed DMBT1 dramatically downregulated in dysplastic foci compared with normal-adjacent tissue. We further integrated our datasets to generate custom colonic dysplasia scores and ligand-receptor mapping. Validation with immunofluorescence showed DMBT1 protein downregulated in dysplastic foci from three mouse models of colonic tumorigenesis and in adenomatous dysplasia from human samples. Finally, we used mouse and human organoids to implicate WNT signaling in the downregulation of DMBT1 mRNA and protein. Together, our data reveal cell type-specific regulation of DMBT1, a potential mechanistic link between bacteria and colonic tumorigenesis. Published 2025. This article is a U.S. Government work and is in the public domain in the USA. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Emily H Green
- Department of Pathology, Microbiology, and ImmunologyVanderbilt University Medical CenterNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
| | | | - Megan E Rutherford
- Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | - Hannah M Lunnemann
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | - Harsimran Kaur
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Chemical and Physical Biology ProgramVanderbilt UniversityNashvilleTNUSA
| | - Cody N Heiser
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
| | - Hua Ding
- Department of Microbiology and Molecular ImmunologyBloomberg School of Public HealthBaltimoreMDUSA
| | - Alan J Simmons
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
| | - Xiao Liu
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTNUSA
| | - D Borden Lacy
- Department of Pathology, Microbiology, and ImmunologyVanderbilt University Medical CenterNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of Veterans AffairsTennessee Valley Healthcare SystemNashvilleTNUSA
| | - M Kay Washington
- Department of Pathology, Microbiology, and ImmunologyVanderbilt University Medical CenterNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Martha J Shrubsole
- Vanderbilt Epidemiology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Vanderbilt‐Ingram Cancer CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Qi Liu
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTNUSA
| | - Ken S Lau
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
- Vanderbilt‐Ingram Cancer CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Cynthia L Sears
- Department of Microbiology and Molecular ImmunologyBloomberg School of Public HealthBaltimoreMDUSA
- Department of Medicine, Division of Infectious DiseasesJohns Hopkins University School of MedicineBaltimoreMDUSA
- Department of OncologyJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Robert J Coffey
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
- Department of Cell and Developmental BiologyVanderbilt UniversityNashvilleTNUSA
- Vanderbilt‐Ingram Cancer CenterVanderbilt University Medical CenterNashvilleTNUSA
| | - Julia L Drewes
- Department of Medicine, Division of Infectious DiseasesJohns Hopkins University School of MedicineBaltimoreMDUSA
- Department of OncologyJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Nicholas O Markham
- Department of Pathology, Microbiology, and ImmunologyVanderbilt University Medical CenterNashvilleTNUSA
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTNUSA
- Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
- Department of Veterans AffairsTennessee Valley Healthcare SystemNashvilleTNUSA
- Vanderbilt‐Ingram Cancer CenterVanderbilt University Medical CenterNashvilleTNUSA
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Smith NR, Giske NR, Sengupta SK, Conley P, Swain JR, Nair A, Fowler KL, Klocke C, Yoo YJ, Anderson AN, Sanati N, Torkenczy K, Adey AC, Fischer JM, Wu G, Wong MH. Dual states of murine Bmi1-expressing intestinal stem cells drive epithelial development utilizing non-canonical Wnt signaling. Dev Cell 2025:S1534-5807(25)00177-7. [PMID: 40262610 DOI: 10.1016/j.devcel.2025.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 11/07/2024] [Accepted: 03/28/2025] [Indexed: 04/24/2025]
Abstract
Intestinal epithelial development and homeostasis critically rely upon balanced stem cell proliferation, involving slow-cycling/label-retaining and active-cycling/canonical Wnt-dependent intestinal stem cell (ISC) subtypes. ISC regulation during development remains poorly understood but has important implications for establishing key mechanisms governing tissue maintenance. Herein, we identify Bmi1+ cells as functional stem cells present in early murine intestinal development, prior to Lgr5-expressing ISCs. Lineage tracing and single-cell RNA sequencing identify that Bmi1+ ISCs can trace to Lgr5+ ISCs and other differentiated lineages. Initially highly proliferative, Bmi1+ ISCs transition to slow-cycling states as Lgr5+ ISCs emerge. Non-canonical Wnt signaling regulates the proliferative Bmi1+ cell state. These findings highlight the dynamic interplay between stem cell populations and the opposing Wnt pathways that govern proliferation-ultimately having implications for tissue development, homeostasis, regeneration, and tumorigenesis. Understanding these fundamental developmental mechanisms is critical for understanding adult intestinal maintenance.
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Affiliation(s)
- Nicholas R Smith
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Nicole R Giske
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Sidharth K Sengupta
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Patrick Conley
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA
| | - John R Swain
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Ashvin Nair
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Kathryn L Fowler
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
| | - Christopher Klocke
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Yeon Jung Yoo
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Ashley N Anderson
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA
| | - Nasim Sanati
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Kristof Torkenczy
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
| | - Andrew C Adey
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; The Knight Cancer Institute, Oregon Health & Science University, Oregon Health & Science University, Portland, OR 97201, USA
| | - Jared M Fischer
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA; Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR 97201 USA; The Knight Cancer Institute, Oregon Health & Science University, Oregon Health & Science University, Portland, OR 97201, USA
| | - Guanming Wu
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR 97239, USA; The Knight Cancer Institute, Oregon Health & Science University, Oregon Health & Science University, Portland, OR 97201, USA
| | - Melissa H Wong
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR 97201, USA; The Knight Cancer Institute, Oregon Health & Science University, Oregon Health & Science University, Portland, OR 97201, USA.
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5
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Lei X, Xu Z, Huang Y, Huang L, Lang J, Qu M, Liu D. Regulation of Mitochondrial Quality Control of Intestinal Stem Cells in Homeostasis and Diseases. Antioxid Redox Signal 2025; 42:494-511. [PMID: 39225500 DOI: 10.1089/ars.2023.0489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Significance: Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases. Recent Advances: In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological conditions and protects against intestinal injury remains to be comprehensively reviewed. Critical Issues: In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy, and proteostasis impact ISC proliferation, differentiation, and regeneration, respectively. Future Directions: We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases. Antioxid. Redox Signal. 42, 494-511.
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Affiliation(s)
- Xudan Lei
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Zhenni Xu
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yujun Huang
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Lingxiao Huang
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Jinyi Lang
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Mingyue Qu
- The PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Dengqun Liu
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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6
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Chen S, Qin Z, Zhou S, Xu Y, Zhu Y. The emerging role of intestinal stem cells in ulcerative colitis. Front Med (Lausanne) 2025; 12:1569328. [PMID: 40201327 PMCID: PMC11975877 DOI: 10.3389/fmed.2025.1569328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/14/2025] [Indexed: 04/10/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the colon and rectum. Characterized by recurrent attacks, UC is often resistant to traditional anti-inflammatory therapies, imposing significant physiological, psychological, and economic burdens on patients. In light of these challenges, innovative targeted therapies have become a new expectation for patients with UC. A crucial pathological feature of UC is the impairment of the intestinal mucosal barrier, which underlies aberrant immune responses and inflammation. Intestinal stem cells (ISCs), which differentiate into intestinal epithelial cells, play a central role in maintaining this barrier. Growing studies have proved that regulating the regeneration and differentiation of ISC is a promising approach to treating UC. Despite this progress, there is a dearth of comprehensive articles describing the role of ISCs in UC. This review focuses on the importance of ISCs in maintaining the intestinal mucosal barrier in UC and discusses the latest findings on ISC functions, markers, and their regulatory mechanisms. Key pathways involved in ISC regulation, including the Wnt, Notch, Hedgehog (HH), Hippo/Yap, and autophagy pathways, are explored in detail. Additionally, this review examines recent advances in ISC-targeted therapies for UC, such as natural or synthetic compounds, microbial preparations, traditional Chinese medicine (TCM) extracts and compounds, and transplantation therapy. This review aims to offer novel therapeutic insights and strategies for patients who have long struggled with UC.
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Affiliation(s)
- Siqing Chen
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Zhang Qin
- The Fourth Hospital of Changsha (Changsha Hospital Affiliated with Hunan Normal University), Changsha, Hunan, China
| | - Sainan Zhou
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yin Xu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ying Zhu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
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Xu Q, Zeng Y, Jiang L, Zhou Y, Wu Z, Liu S, Men R, Li S, Yang J, Huang W, Shi Y. c-Kit + cells that intercalate with crypt Lgr5 + cells are distinctively multipotent in colonic epithelium renewal and repair. Cell Death Differ 2025:10.1038/s41418-025-01471-1. [PMID: 40055578 DOI: 10.1038/s41418-025-01471-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 02/04/2025] [Accepted: 02/24/2025] [Indexed: 03/17/2025] Open
Abstract
The colonic crypts are principally composed by Lgr5+ stem cells and deep crypt secretory (DCS) cells. c-Kit-expressing cells mark DCS cells and supply Wnt3, EGF, and Notch signals to support their neighboring crypt bottom-intermingled Lgr5+ cells. However, the role of c-Kit+ cells beyond supporting Lgr5+ cells in colonic epithelium remains unexplored. Here, we identify that c-Kit+ cells are a heterogeneous entity and possess stemness potency to differentiate into the entire spectrum of epithelial cells and renew the homeostatic colon. Intriguingly, c-Kit+ cells play a pivotal role in epithelium repair in mouse models of colitis when contemporary Lgr5+ cells are insufficient or absent. Depletion of c-Kit+ cells or inhibition of SCF/c-Kit signaling worsens, while supplementation of SCF alleviates colonic epithelium injury during colitis. Our findings unravel the fate and function of c-Kit+ cells in homeostatic colon and recovery during colonic epithelium injury which has translational implications for human inflammatory bowel diseases.
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Affiliation(s)
- Qing Xu
- Department of Pathology and Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Yuting Zeng
- Department of Pathology and Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Lan Jiang
- West China Biobank, West China Hospital, Sichuan University, Chengdu, China
| | - Yongjie Zhou
- Department of General Surgery, Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenru Wu
- Department of Pathology and Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China
| | - Shiyu Liu
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China
- Institutes for Systems Genetics & Immunology and Inflammation, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Ruoting Men
- Department of Gastroenterology and Hepatology, West China Hospital, Chengdu, China
| | - Shujun Li
- West China Biobank, West China Hospital, Sichuan University, Chengdu, China
| | - Jiayin Yang
- Department of General Surgery, Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Wei Huang
- West China Biobank, West China Hospital, Sichuan University, Chengdu, China.
- West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China.
- Institutes for Systems Genetics & Immunology and Inflammation, Frontiers Science Centre for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
| | - Yujun Shi
- Department of Pathology and Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, China.
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8
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Krantz S, Bell B, Lund K, Parra NS, Ng Y, De Oliveira Rosa N, Mukhopadhyay S, Croix BS, Sarin KY, Weigert R, Raimondi F, Iglesias-Bartolome R. Dissection of Gαs and Hedgehog signaling crosstalk reveals therapeutic opportunities to target adenosine receptor 2b in Hedgehog-dependent tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.21.639530. [PMID: 40060632 PMCID: PMC11888225 DOI: 10.1101/2025.02.21.639530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Basal cell carcinoma (BCC), the most common human cancer, is driven by hyperactivation of Hedgehog Smoothened (SMO) and GLI transcription. Gαs and protein kinase A (PKA) negatively regulate Hedgehog signaling, offering an alternative BCC development and treatment pathway. Here, using histology alongside bulk and single-cell RNA sequencing, we find that mouse BCC-like tumors that originate from Gαs pathway inactivation are strikingly similar to those driven by canonical Hedgehog SMO. Interestingly, mutations that reduce Gαs and PKA activity are present in human BCC. Tumors from Gαs pathway inactivation are independent of the canonical Hedgehog regulators SMO and GPR161, establishing them as an SMO-independent oncogenic Hedgehog signaling model. Finally, we demonstrate that activation of the Gαs-coupled adenosine 2B receptor counteracts oncogenic SMO, reducing Hedgehog signaling and tumor formation and offering a potential therapeutic strategy for BCC.
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Affiliation(s)
- Sarah Krantz
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Braden Bell
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Katherine Lund
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Natalia Salinas Parra
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Yeap Ng
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
- Intravital Microscopy Core, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | | | - Saikat Mukhopadhyay
- Department of Cell Biology, University of Texas Southwestern Medical Center, Texas, United States
| | - Brad St Croix
- Tumor Angiogenesis Unit, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland, United States
| | - Kavita Y Sarin
- Department of Dermatology, Stanford University School of Medicine, Stanford, California, United States
| | - Roberto Weigert
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
- Intravital Microscopy Core, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
| | | | - Ramiro Iglesias-Bartolome
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States
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9
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Mehra L, Bhowmik S, Makharia GK, Das P. Intestinal stem cell niche: An upcoming area of immense importance in gastrointestinal disorders. Indian J Gastroenterol 2025; 44:8-23. [PMID: 39514159 DOI: 10.1007/s12664-024-01699-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/29/2024] [Indexed: 11/16/2024]
Abstract
The intestinal stem cell (ISC) niche is vital for maintaining the integrity and function of the intestinal epithelium. ISC populations, characterized by their high proliferation and multipotency, reside within a specialized microenvironment at the base of crypts. Crypt base columnar (CBC) cells at the deepest part of crypts serve as replicating ISCs, while position 4 label-retaining cells (LRCs) located higher up in the crypts are also important for ISC maintenance during experiments. The interplay between CBCs, position 4 LRCs, transient amplifying (TA) cells and other niche components, including the pericrypt stromal cells, ensures a continuous supply of differentiated epithelial cells. Recent advancements in ISC biomarker studies have provided valuable insights into their molecular signatures, regulatory pathways and roles in the pathogenesis of intestinal disorders. Understanding the ISC niche has significant therapeutic implications, as manipulating ISC behaviors and regenerating damaged or diseased intestinal tissue show promise for novel therapeutic approaches. ISC organoids have also provided a platform for studying intestinal diseases and testing personalized therapies. This comprehensive review covers the anatomical composition, physiological regulation, ISC biomarker studies, contribution to intestinal disorder pathogenesis and potential therapeutic implications of the ISC niche.
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Affiliation(s)
- Lalita Mehra
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Subham Bhowmik
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutritions, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India.
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10
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Spencer PN, Wang J, Smith EP, Spiga L, Simmons AJ, Kim T, Kim W, Brown ME, Yang Y, Kaur H, Xu Y, Kang SW, Helou MD, Lee MA, Zheng L, Arceneaux D, Tasneem N, Mueller KD, Kuddar OS, Harned MH, Ro J, Li J, Banerjee A, Markham NO, Wilson KT, Coburn LA, Goettel JA, Liu Q, Kay Washington M, Valdivia RH, Zhu W, Lau KS. Pathobiont-triggered induction of epithelial IDO1 drives regional susceptibility to Inflammatory Bowel Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.04.630951. [PMID: 39803424 PMCID: PMC11722351 DOI: 10.1101/2025.01.04.630951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/25/2025]
Abstract
The structure and function of the mammalian gut vary by region, yet why inflammatory diseases manifest in specific regions and not others remains unclear. We use a TNF-overexpressing Crohn's disease (CD) model (TnfΔARE/+), which typically presents in the terminal ileum (TI), to investigate how environmental factors interact with the host's immune susceptibility to drive region-specific disease. We identified Chlamydia muridarum, an intracellular bacterium and murine counterpart to the human sexually transmitted C. trachomatis, as necessary and sufficient to trigger disease manifestation in the ascending colon (AC), another common site of human CD. Disease manifestation in the AC depends on indoleamine 2,3-dioxygenase (IDO1) activity induced by hypersensitive surface secretory cells in genetically susceptible hosts. Single-cell and microbial analyses of human specimens also implicates this pathobiont-epithelial IDO1 pathway in patients with a history of CD in the AC. Our findings demonstrate that genetic and microbial factors can independently drive region-specific disease and provide a unique model to study CD specific to the AC.
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Affiliation(s)
- Paige N Spencer
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Jiawei Wang
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Erin P Smith
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Luisella Spiga
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alan J Simmons
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Taewoo Kim
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - William Kim
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Monica E Brown
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Yilin Yang
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Harsimran Kaur
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Yanwen Xu
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Seung Woo Kang
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Matthew D Helou
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Mason A Lee
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Lin Zheng
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Deronisha Arceneaux
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Naila Tasneem
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Katherine D Mueller
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Ozge S Kuddar
- Department of Molecular Genetics and Microbiology, Duke School of Medicine, Durham, NC 27710, USA
| | - Mariah H Harned
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - James Ro
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN, 37232, USA
| | - Amrita Banerjee
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
| | - Nicholas O Markham
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville TN, 37232, USA
| | - Keith T Wilson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Lori A Coburn
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Jeremy A Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Qi Liu
- Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN, 37232, USA
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN, 37232, USA
| | - Raphael H Valdivia
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27710, USA
| | - Wenhan Zhu
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ken S Lau
- Department of Cell and Developmental Biology and Program in Developmental Biology, Vanderbilt University, Nashville TN, 37232, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville TN, 37232, USA
- Center for Computational Systems Biology, Vanderbilt University, Nashville TN, 37232, USA
- Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville TN, 37232, USA
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11
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Liu S, Li Y, Huang D, Liu M, Zhang X, Zhao H, Liu H, Li Q, Chen Z. Single-Cell RNA-Seq and Histological Analysis Reveals Dynamic Lrig1 Expression During Salivary Gland Development. J Cell Physiol 2025; 240:e31487. [PMID: 39587709 DOI: 10.1002/jcp.31487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 09/28/2024] [Accepted: 11/05/2024] [Indexed: 11/27/2024]
Abstract
The development of the salivary gland (SG) is a complex process regulated by multiple signaling pathways in a spatiotemporal manner. Various stem/progenitor cell populations and respective cell lineages are involved in SG morphogenesis and postnatal maturation. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) has been identified as critical regulator of stem cells by virtue of its ability to restrain stem cell proliferation, indicating its potential role in the development of several maxillofacial tissues and in the regulation of the quiescence in adult tissues. This study aimed to investigate the expression pattern and functions of Lrig1 in the developing and mature murine submandibular gland (SMG). To accomplish this objective, we collected the murine SMGs at different developmental stages and examined the expression pattern and levels of Lrig1 with qRT-PCR, immunofluorescent (IF) and RNAscope staining. We observed that Lrig1 was widely distributed in both epithelial and mesenchymal cells throughout embryonic and neonatal stages, with specific localization in the more mature epithelium. Furthermore, through single-cell RNA sequencing (scRNA-Seq) and IF techniques, we confirmed that LRIG1 is highly concentrated along with SMG progenitor markers in acinar and basal cells. Additionally, transcription factors (TFs) that could regulate LRIG1 expression were predicted from JASPAR databases and their motifs were identified by the UCSC browser's BLAT tool. Gene Ontology (GO) enrichment analyses on postnatal day 5 (PN5) scRNA-Seq data also provided insights into Lrig1's functions in SG development. Finally, we also conducted in vitro experiments on a human salivary gland (HSG) cell line to assess LRIG1's impact on HSG proliferation and migration, as well as its potential upstream regulatory TFs. Taken together, our study reveals that LRIG1 plays a vital role in SG development.
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Affiliation(s)
- Shumin Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yuanyuan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Delan Huang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ming Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xinye Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Hui Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Huan Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Periodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Qiuhui Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhi Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
- Department of Cariology & Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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12
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Ahn JY, Kim S, Rok Kim C, Lee JH, Kim JM, Klompstra TM, Ha Choi Y, Jeon Y, Na Y, Kim JS, Okada Y, Lee H, Kim IS, Kim JK, Koo BK, Baek SH. Dual function of PHF16 in reinstating homeostasis of murine intestinal epithelium after crypt regeneration. Dev Cell 2024; 59:3089-3105.e7. [PMID: 39232563 DOI: 10.1016/j.devcel.2024.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 10/24/2023] [Accepted: 08/08/2024] [Indexed: 09/06/2024]
Abstract
Intestinal stem cells (ISCs) are highly vulnerable to damage, being in a constant state of proliferation. Reserve stem cells repair the intestinal epithelium following damage-induced ablation of ISCs. Here, we report that the epigenetic regulator plant homology domain (PHD) finger protein 16 (PHF16) restores homeostasis of the intestinal epithelium after initial damage-induced repair. In Phf16-/Y mice, revival stem cells (revSCs) showed defects in exiting the regenerative state, and intestinal crypt regeneration failed even though revSCs were still induced in response to tissue damage, as observed by single-cell RNA sequencing (scRNA-seq). Analysis of Phf16-/Y intestinal organoids by RNA sequencing (RNA-seq) and ATAC sequencing identified that PHF16 restores homeostasis of the intestinal epithelium by inducing retinoic acid receptor (RAR)/retinoic X receptor (RXR) target genes through HBO1-mediated histone H3K14 acetylation, while at the same time counteracting YAP/TAZ activity by ubiquitination of CDC73. Together, our findings demonstrate the importance of timely suppression of regenerative activity by PHF16 for the restoration of gut homeostasis after acute tissue injury.
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Affiliation(s)
- Jun-Yeong Ahn
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul 08826, South Korea; School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Somi Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea
| | - Chang Rok Kim
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul 08826, South Korea; School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Ji-Hyun Lee
- Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, South Korea
| | - Jong Min Kim
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul 08826, South Korea; School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Thomas M Klompstra
- Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, South Korea
| | - Yoon Ha Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea
| | - Yoon Jeon
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, South Korea
| | - Yongwoo Na
- School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Jong-Seo Kim
- School of Biological Sciences, Seoul National University, Seoul 08826, South Korea; Center for RNA Research, Institute for Basic Science, School of Biological Sciences, Seoul National University, Seoul 08826, South Korea
| | - Yuki Okada
- Laboratory of Pathology and Development, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan
| | - Ho Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, South Korea
| | - Ik Soo Kim
- Department of Microbiology, Gachon University College of Medicine, Incheon 21999, South Korea.
| | - Jong Kyoung Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea; Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul 03722, South Korea.
| | - Bon-Kyoung Koo
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea; Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, South Korea.
| | - Sung Hee Baek
- Creative Research Initiatives Center for Epigenetic Code and Diseases, Seoul National University, Seoul 08826, South Korea; School of Biological Sciences, Seoul National University, Seoul 08826, South Korea.
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13
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Feng X, Flüchter P, De Tenorio JC, Schneider C. Tuft cells in the intestine, immunity and beyond. Nat Rev Gastroenterol Hepatol 2024; 21:852-868. [PMID: 39327439 DOI: 10.1038/s41575-024-00978-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/02/2024] [Indexed: 09/28/2024]
Abstract
Tuft cells have gained substantial attention over the past 10 years due to numerous reports linking them with type 2 immunity and microorganism-sensing capacity in many mucosal tissues. This heightened interest is fuelled by their unique ability to produce an array of biological effector molecules, including IL-25, allergy-related eicosanoids, and the neurotransmitter acetylcholine, enabling downstream responses in diverse cell types. Operating through G protein-coupled receptor-mediated signalling pathways reminiscent of type II taste cells in oral taste buds, tuft cells emerge as chemosensory sentinels that integrate luminal conditions, eliciting appropriate responses in immune, epithelial and neuronal populations. How tuft cells promote tissue alterations and adaptation to the variety of stimuli at mucosal surfaces has been explored in multiple studies in the past few years. Since the initial recognition of the role of tuft cells, the discovery of diverse tuft cell effector functions and associated feedback loops have also revealed the complexity of tuft cell biology. Although earlier work largely focused on extraintestinal tissues, novel genetic tools and recent mechanistic studies on intestinal tuft cells established fundamental concepts of tuft cell activation and functions. This Review is an overview of intestinal tuft cells, providing insights into their development, signalling and interaction modules in immunity and other states.
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Affiliation(s)
- Xiaogang Feng
- Department of Physiology, University of Zurich, Zurich, Switzerland
| | - Pascal Flüchter
- Department of Physiology, University of Zurich, Zurich, Switzerland
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Su CC, Su YC, Wu CC, Lee PT. Explanatory Role of Conversion Surgery as a Mediator of the Mortality Risk Difference Between Patients With Unresectable Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR Agents Versus Bevacizumab. Clin Colorectal Cancer 2024; 23:364-371. [PMID: 38879376 DOI: 10.1016/j.clcc.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 12/01/2024]
Abstract
INTRODUCTION Bevacizumab and antiepidermal growth factor receptor-blocking (anti-EGFR) agents plus chemotherapy are first-line therapies for metastatic colorectal cancer (mCRC). Conversion surgery may improve outcomes; however, the extent to which it explains the difference in mortality rates among treatments is unclear. Herein, we aimed to assess the effects of conversion surgery on survival outcomes of patients with unresectable mCRC treated with bevacizumab and anti-EGFR agents. MATERIALS AND METHODS This retrospective cohort study included patients with mCRC treated with bevacizumab and anti-EGFR agents as first-line therapy. We estimated the direct and indirect effects of treatments by comparing the mortality risk associated with targeted therapy type. Hazard ratios (HR) and the corresponding confidence intervals (CI) were estimated. Mediation analysis was used to estimate hazard ratio differences, and the proportion mediated. RESULTS A total of 5,106 patients were included. The natural indirect effect of conversion surgery reduced mortality risk (HR: 0.95; 95% CI, 0.93-0.97), with a mediated proportion of 42% after propensity score adjustment. In subgroup analyses, KRAS wild-type (HR: 0.94; 95% CI: 0.91-0.97), left tumor sidedness (HR: 0.94; 95% CI, 0.91-0.96), and liver resection (HR: 0.95; 95% CI, 0.93-0.98) were associated with reduced risks of mortality. The controlled and total direct effects of targeted therapy were associated with reduced mortality risk in the anti-EGFR-treated group compared to those in the bevacizumab-treated group; however, this effect was not statistically significant. CONCLUSION Conversion surgery may account for the difference in survival outcomes between users of the anti-EGFR agents and bevacizumab.
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Affiliation(s)
- Chien-Chou Su
- Clinical Innovation and Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Chia Su
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Chih-Chien Wu
- Department of Surgery, Division of Colorectal Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Pei-Ting Lee
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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15
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Lee Y, Kim KH, Park J, Kang HM, Kim SH, Jeong H, Lee B, Lee N, Cho Y, Kim GD, Yu S, Gee HY, Bok J, Hamilton MS, Gewin L, Aronow BJ, Lim KM, Coffey RJ, Nam KT. Regenerative Role of Lrig1+ Cells in Kidney Repair. J Am Soc Nephrol 2024; 35:1702-1714. [PMID: 39120954 PMCID: PMC11617485 DOI: 10.1681/asn.0000000000000462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 08/05/2024] [Indexed: 08/11/2024] Open
Abstract
Key Points Lrig1 + cells exist long term during kidney homeostasis and become activated upon injury, contributing to regeneration. Lrig1 + cells and their progeny emerge during tubulogenesis and contribute to proximal tubule and inner medullary collecting duct development. Lrig1 + cells expand and differentiate into a mature nephron lineage in response to AKI to repair the proximal tubule. Background In response to severe kidney injury, the kidney epithelium displays remarkable regenerative capabilities driven by adaptable resident epithelial cells. To date, it has been widely considered that the adult kidney lacks multipotent stem cells; thus, the cellular lineages responsible for repairing proximal tubule damage are incompletely understood. Leucine-rich repeats and immunoglobulin-like domain protein 1–expressing cells (Lrig1 + cells) have been identified as a long-lived cell in various tissues that can induce epithelial tissue repair. Therefore, we hypothesized that Lrig1 + cells participate in kidney development and tissue regeneration. Methods We investigated the role of Lrig1 + cells in kidney injury using mouse models. The localization of Lrig1 + cells in the kidney was examined throughout mouse development. The function of Lrig1 + progeny cells in AKI repair was examined in vivo using a tamoxifen-inducible Lrig1 -specific Cre recombinase-based lineage tracing in three different kidney injury mouse models. In addition, we conducted single-cell RNA sequencing to characterize the transcriptional signature of Lrig1 + cells and trace their progeny. Results Lrig1 + cells were present during kidney development and contributed to formation of the proximal tubule and collecting duct structures in mature mouse kidneys. In three-dimensional culture, single Lrig1 + cells demonstrated long-lasting propagation and differentiated into the proximal tubule and collecting duct lineages. These Lrig1 + proximal tubule cells highly expressed progenitor-like and quiescence-related genes, giving rise to a novel cluster of cells with regenerative potential in adult kidneys. Moreover, these long-lived Lrig1 + cells expanded and repaired damaged proximal tubule in response to three types of AKIs in mice. Conclusions These findings highlight the critical role of Lrig1 + cells in kidney regeneration.
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Affiliation(s)
- Yura Lee
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang H. Kim
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jihwan Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Hyun Mi Kang
- Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Sung-Hee Kim
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Haengdueng Jeong
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Buhyun Lee
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Nakyum Lee
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yejin Cho
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Gyeong Dae Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Seyoung Yu
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Heon Yung Gee
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jinwoong Bok
- Department of Anatomy, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Maxwell S. Hamilton
- Epithelial Biology Center and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Leslie Gewin
- Division of Nephrology and Hypertension, Department of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Bruce J. Aronow
- Departments of Biomedical Informatics, Developmental Biology, and Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Robert J. Coffey
- Epithelial Biology Center and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Ki Taek Nam
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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16
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Llewellyn J, Baratam R, Culig L, Beerman I. Cellular stress and epigenetic regulation in adult stem cells. Life Sci Alliance 2024; 7:e202302083. [PMID: 39348938 PMCID: PMC11443024 DOI: 10.26508/lsa.202302083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 09/16/2024] [Accepted: 09/16/2024] [Indexed: 10/02/2024] Open
Abstract
Stem cells are a unique class of cells that possess the ability to differentiate and self-renew, enabling them to repair and replenish tissues. To protect and maintain the potential of stem cells, the cells and the environment surrounding these cells (stem cell niche) are highly responsive and tightly regulated. However, various stresses can affect the stem cells and their niches. These stresses are both systemic and cellular and can arise from intrinsic or extrinsic factors which would have strong implications on overall aging and certain disease states. Therefore, understanding the breadth of drivers, namely epigenetic alterations, involved in cellular stress is important for the development of interventions aimed at maintaining healthy stem cells and tissue homeostasis. In this review, we summarize published findings of epigenetic responses to replicative, oxidative, mechanical, and inflammatory stress on various types of adult stem cells.
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Affiliation(s)
- Joey Llewellyn
- Epigenetics and Stem Cell Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
| | - Rithvik Baratam
- Epigenetics and Stem Cell Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
| | - Luka Culig
- Epigenetics and Stem Cell Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
| | - Isabel Beerman
- Epigenetics and Stem Cell Unit, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA
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17
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Trubin S, Patel DB, Tian A. Regulation of the Intestinal Stem Cell Pool and Proliferation in Drosophila. Cells 2024; 13:1856. [PMID: 39594605 PMCID: PMC11592481 DOI: 10.3390/cells13221856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/07/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Understanding the regulation of somatic stem cells, both during homeostasis and in response to environmental challenges like injury, infection, chemical exposure, and nutritional changes, is critical because their dysregulation can result in tissue degeneration or tumorigenesis. The use of models such as the Drosophila and mammalian adult intestines offers valuable insights into tissue homeostasis and regeneration, advancing our knowledge of stem cell biology and cancer development. This review highlights significant findings from recent studies, unveiling the molecular mechanisms that govern self-renewal, proliferation, differentiation, and regeneration of intestinal stem cells (ISCs). These insights not only enhance our understanding of normal tissue maintenance but also provide critical perspectives on how ISC dysfunction can lead to pathological conditions such as colorectal cancer (CRC).
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Affiliation(s)
- Simona Trubin
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Dhruv B. Patel
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Aiguo Tian
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
- Tulane Aging Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
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18
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Gulino ME, Ordóñez-Morán P, Mahida YR. Establishment of a 3D organoid culture model for the investigation of adult slow-cycling putative intestinal stem cells. Histochem Cell Biol 2024; 162:351-362. [PMID: 39073425 DOI: 10.1007/s00418-024-02312-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 07/30/2024]
Abstract
The study of intestinal stem cells is a prerequisite for the development of therapies aimed at regenerating the gut. To enable investigation of adult slow-cycling H2B-GFP-retaining putative small intestinal (SI) stem cells in vitro, we have developed a three-dimensional (3D) SI organoid culture model based on the Tet-Op histone 2 B (H2B)-green fluorescent protein (GFP) fusion protein (Tet-Op-H2B-GFP) transgenic mouse. SI crypts were isolated from 6- to 12-week-old Tet-Op-H2B-GFP transgenic mice and cultured with appropriate growth factors and an animal-derived matrix (Matrigel). For in vitro transgene expression, doxycycline was added to the culture medium for 24 h. By pulse-chase experiments, H2B-GFP expression and retention were assessed through direct GFP fluorescence observations, both by confocal and fluorescence microscopy and by immunohistochemistry. The percentages of H2B-GFP-retaining putative SI stem cells and H2B-GFP-retaining Paneth cells persisting in organoids were determined by scoring relevant GFP-positive cells. Our results indicate that 24 h exposure to doxycycline (pulse) induced ubiquitous expression of H2B-GFP in the SI organoids. During subsequent culture, in the absence of doxycycline (chase), there was a gradual loss (due to cell division) of H2B-GFP. At 6-day chase, slow-cycling H2B-GFP-retaining putative SI stem cells and H2B-GFP-retaining Paneth cells were detected in the SI organoids. The developed culture model allows detection of slow-cycling H2B-GFP-retaining putative SI stem cells and will enable the study of self-renewal and regeneration for further characterization of these cells.
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Affiliation(s)
- Maria Eugenia Gulino
- Translational Medical Sciences, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK.
| | - Paloma Ordóñez-Morán
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University of Nottingham, Nottingham, NG7 2RD, UK
| | - Yashwant R Mahida
- Translational Medical Sciences, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
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19
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Zhang R, Perekatt A, Chen L. Metabolic regulation of intestinal homeostasis: molecular and cellular mechanisms and diseases. MedComm (Beijing) 2024; 5:e776. [PMID: 39465140 PMCID: PMC11502721 DOI: 10.1002/mco2.776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/21/2024] [Accepted: 09/22/2024] [Indexed: 10/29/2024] Open
Abstract
Metabolism serves not only as the organism's energy source but also yields metabolites crucial for maintaining tissue homeostasis and overall health. Intestinal stem cells (ISCs) maintain intestinal homeostasis through continuous self-renewal and differentiation divisions. The intricate relationship between metabolic pathways and intestinal homeostasis underscores their crucial interplay. Metabolic pathways have been shown to directly regulate ISC self-renewal and influence ISC fate decisions under homeostatic conditions, but the cellular and molecular mechanisms remain incompletely understood. Understanding the intricate involvement of various pathways in maintaining intestinal homeostasis holds promise for devising innovative strategies to address intestinal diseases. Here, we provide a comprehensive review of recent advances in the regulation of intestinal homeostasis. We describe the regulation of intestinal homeostasis from multiple perspectives, including the regulation of intestinal epithelial cells, the regulation of the tissue microenvironment, and the key role of nutrient metabolism. We highlight the regulation of intestinal homeostasis and ISC by nutrient metabolism. This review provides a multifaceted perspective on how intestinal homeostasis is regulated and provides ideas for intestinal diseases and repair of intestinal damage.
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Affiliation(s)
- Ruolan Zhang
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human DiseaseSoutheast UniversityNanjingChina
| | - Ansu Perekatt
- Department of Chemistry and Chemical BiologyStevens Institute of TechnologyHobokenNew JerseyUSA
| | - Lei Chen
- School of Life Science and Technology, Key Laboratory of Developmental Genes and Human DiseaseSoutheast UniversityNanjingChina
- Institute of Microphysiological SystemsSoutheast UniversityNanjingChina
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20
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Chen SM, Guo BJ, Feng AQ, Wang XL, Zhang SL, Miao CY. Pathways regulating intestinal stem cells and potential therapeutic targets for radiation enteropathy. MOLECULAR BIOMEDICINE 2024; 5:46. [PMID: 39388072 PMCID: PMC11467144 DOI: 10.1186/s43556-024-00211-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Radiotherapy is a pivotal intervention for cancer patients, significantly impacting their treatment outcomes and survival prospects. Nevertheless, in the course of treating those with abdominal, pelvic, or retroperitoneal malignant tumors, the procedure inadvertently exposes adjacent intestinal tissues to radiation, posing risks of radiation-induced enteropathy upon reaching threshold doses. Stem cells within the intestinal crypts, through their controlled proliferation and differentiation, support the critical functions of the intestinal epithelium, ensuring efficient nutrient absorption while upholding its protective barrier properties. Intestinal stem cells (ISCs) regulation is intricately orchestrated by diverse signaling pathways, among which are the WNT, BMP, NOTCH, EGF, Hippo, Hedgehog and NF-κB, each contributing to the complex control of these cells' behavior. Complementing these pathways are additional regulators such as nutrient metabolic states, and the intestinal microbiota, all of which contribute to the fine-tuning of ISCs behavior in the intestinal crypts. It is the harmonious interplay among these signaling cascades and modulating elements that preserves the homeostasis of intestinal epithelial cells (IECs), thereby ensuring the gut's overall health and function. This review delves into the molecular underpinnings of how stem cells respond in the context of radiation enteropathy, aiming to illuminate potential biological targets for therapeutic intervention. Furthermore, we have compiled a summary of several current treatment methodologies. By unraveling these mechanisms and treatment methods, we aspire to furnish a roadmap for the development of novel therapeutics, advancing our capabilities in mitigating radiation-induced intestinal damage.
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Affiliation(s)
- Si-Min Chen
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China
| | - Bing-Jie Guo
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - An-Qiang Feng
- Department of Digestive Disease, Xuzhou Central Hospital, Xuzhou, China
| | - Xue-Lian Wang
- School of Medicine, Shanghai University, Shanghai, China
| | - Sai-Long Zhang
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China.
| | - Chao-Yu Miao
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China.
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21
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Shi G, Li Y, Shen H, He Q, Zhu P. Intestinal stem cells in intestinal homeostasis and colorectal tumorigenesis. LIFE MEDICINE 2024; 3:lnae042. [PMID: 39872442 PMCID: PMC11749485 DOI: 10.1093/lifemedi/lnae042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/24/2024] [Indexed: 01/30/2025]
Abstract
Colorectal cancer (CRC), one of the most common tumors in the world, is generally proposed to be generated from intestinal stem cells (ISCs). Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive ISCs are located at the bottom of the crypt and harbor self-renewal and differentiation capacities, serving as the resource of all intestinal epithelial cells and CRC cells as well. Here we review recent progress in ISCs both in non-tumoral and tumoral contexts. We summarize the molecular mechanisms of ISC self-renewal, differentiation, and plasticity for intestinal homeostasis and regeneration. We also discuss the function of ISCs in colorectal tumorigenesis as cancer stem cells and summarize fate dynamic, competition, niche regulation, and remote environmental regulation of ISCs for CRC initiation and propagation.
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Affiliation(s)
- Gaoli Shi
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Yang Li
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Haihong Shen
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
| | - Qiankun He
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Pingping Zhu
- School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
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22
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Kumari B, Tiwari A, Meena S, Ahirwar DK. Inflammation-Associated Stem Cells in Gastrointestinal Cancers: Their Utility as Prognostic Biomarkers and Therapeutic Targets. Cancers (Basel) 2024; 16:3134. [PMID: 39335106 PMCID: PMC11429849 DOI: 10.3390/cancers16183134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Stem cells are critical for the development and homeostasis of the gastrointestinal (GI) tract. Inflammatory molecules are known to regulate the activity of stem cells. A comprehensive review specifically describing the role of inflammatory molecules in the regulation of stem cells within the GI tract and in GI cancers (GICs) is not available. This review focuses on understanding the role of inflammatory molecules and stem cells in maintaining homeostasis of the GI tract. We further discuss how inflammatory conditions contribute to the transformation of stem cells into tumor-initiating cells. We also describe the molecular mechanisms of inflammation and stem cell-driven progression and metastasis of GICs. Furthermore, we report on studies describing the prognostic value of cancer stem cells and the clinical trials evaluating their therapeutic utility. This review provides a detailed overview on the role of inflammatory molecules and stem cells in maintaining GI tract homeostasis and their implications for GI-related malignancies.
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Affiliation(s)
- Beauty Kumari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Aniket Tiwari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Sakshi Meena
- School of Life Sciences, Devi Ahilya Vishwavidyalaya Indore, Indore 452001, Madhya Pradesh, India;
| | - Dinesh Kumar Ahirwar
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
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23
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Yun CC, Han Y, McConnell B. Lysophosphatidic Acid Signaling in the Gastrointestinal System. Cell Mol Gastroenterol Hepatol 2024; 18:101398. [PMID: 39233124 PMCID: PMC11532463 DOI: 10.1016/j.jcmgh.2024.101398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/09/2024] [Accepted: 08/13/2024] [Indexed: 09/06/2024]
Abstract
The intestinal epithelium undergoes continuous homeostatic renewal to conduct the digestion and absorption of nutrients. At the same time, the intestinal epithelial barrier separates the host from the intestinal lumen, preventing systemic infection from enteric pathogens. To maintain homeostasis and epithelial functionality, stem cells, which reside in the base of intestinal crypts, generate progenitor cells that ultimately differentiate to produce an array of secretory and absorptive cells. Intestinal regeneration is regulated by niche signaling pathways, specifically, Wnt, bone morphogenetic protein, Notch, and epidermal growth factor. In addition, growth factors and other peptides have emerged as potential modulators of intestinal repair and inflammation through their roles in cellular proliferation, differentiation, migration, and survival. Lysophosphatidic acid (LPA) is such a factor that modulates the proliferation, survival, and migration of epithelial cells while also regulating trafficking of immune cells, both of which are important for tissue homeostasis. Perturbation of LPA signaling, however, has been shown to promote cancer and inflammation. This review focuses on the recent advances in LPA-mediated signaling that contribute to physiological and pathophysiological regulation of the gastrointestinal system.
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Affiliation(s)
- C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia.
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Beth McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
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24
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De Vincenti AP, Bonafina A, Ledda F, Paratcha G. Lrig1 regulates cell fate specification of glutamatergic neurons via FGF-driven Jak2/Stat3 signaling in cortical progenitors. Development 2024; 151:dev202879. [PMID: 39250533 DOI: 10.1242/dev.202879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 08/07/2024] [Indexed: 09/11/2024]
Abstract
The cell-intrinsic mechanisms underlying the decision of a stem/progenitor cell to either proliferate or differentiate remain incompletely understood. Here, we identify the transmembrane protein Lrig1 as a physiological homeostatic regulator of FGF2-driven proliferation and self-renewal of neural progenitors at early-to-mid embryonic stages of cortical development. We show that Lrig1 is expressed in cortical progenitors (CPs), and its ablation caused expansion and increased proliferation of radial/apical progenitors and of neurogenic transit-amplifying Tbr2+ intermediate progenitors. Notably, our findings identify a previously unreported EGF-independent mechanism through which Lrig1 negatively regulates neural progenitor proliferation by modulating the FGF2-induced IL6/Jak2/Stat3 pathway, a molecular cascade that plays a pivotal role in the generation and maintenance of CPs. Consistently, Lrig1 knockout mice showed a significant increase in the density of pyramidal glutamatergic neurons placed in superficial layers 2 and 3 of the postnatal neocortex. Together, these results support a model in which Lrig1 regulates cortical neurogenesis by influencing the cycling activity of a set of progenitors that are temporally specified to produce upper layer glutamatergic neurons.
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Affiliation(s)
- Ana Paula De Vincenti
- Laboratorio de Neurociencia Molecular y Celular, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina. Universidad de Buenos Aires (UBA), Buenos Aires CP1121, Argentina
| | - Antonela Bonafina
- Laboratorio de Neurociencia Molecular y Celular, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina. Universidad de Buenos Aires (UBA), Buenos Aires CP1121, Argentina
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires C1405 BWE, Argentina
| | - Fernanda Ledda
- Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, Buenos Aires C1405 BWE, Argentina
| | - Gustavo Paratcha
- Laboratorio de Neurociencia Molecular y Celular, Instituto de Biología Celular y Neurociencias (IBCN)-CONICET-UBA, Facultad de Medicina. Universidad de Buenos Aires (UBA), Buenos Aires CP1121, Argentina
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25
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Oh SJ, Seo Y, Kim HS. Navigating the Landscape of Intestinal Regeneration: A Spotlight on Quiescence Regulation and Fetal Reprogramming. Int J Stem Cells 2024; 17:213-223. [PMID: 38267367 PMCID: PMC11361849 DOI: 10.15283/ijsc23176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/20/2023] [Accepted: 01/02/2024] [Indexed: 01/26/2024] Open
Abstract
Tissue-specific adult stem cells are pivotal in maintaining tissue homeostasis, especially in the rapidly renewing intestinal epithelium. At the heart of this process are leucine-rich repeat-containing G protein-coupled receptor 5-expressing crypt base columnar cells (CBCs) that differentiate into various intestinal epithelial cells. However, while these CBCs are vital for tissue turnover, they are vulnerable to cytotoxic agents. Recent advances indicate that alternative stem cell sources drive the epithelial regeneration post-injury. Techniques like lineage tracing and single-cell RNA sequencing, combined with in vitro organoid systems, highlight the remarkable cellular adaptability of the intestinal epithelium during repair. These regenerative responses are mediated by the reactivation of conserved stem cells, predominantly quiescent stem cells and revival stem cells. With focus on these cells, this review unpacks underlying mechanisms governing intestinal regeneration and explores their potential clinical applications.
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Affiliation(s)
- Su-Jeong Oh
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Korea
| | - Yoojin Seo
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Hyung-Sik Kim
- Department of Oral Biochemistry, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
- Department of Life Science in Dentistry, School of Dentistry, Pusan National University, Yangsan, Korea
- Education and Research Team for Life Science on Dentistry, Pusan National University, Yangsan, Korea
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26
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Ford NC, Benedeck RE, Mattoon MT, Peterson JK, Mesler AL, Veniaminova NA, Gardon DJ, Tsai SY, Uchida Y, Wong SY. Hair follicles modulate skin barrier function. Cell Rep 2024; 43:114347. [PMID: 38941190 PMCID: PMC11317994 DOI: 10.1016/j.celrep.2024.114347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/23/2024] [Accepted: 05/24/2024] [Indexed: 06/30/2024] Open
Abstract
Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with the interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell-autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing IL-17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
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Affiliation(s)
- Noah C Ford
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rachel E Benedeck
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Matthew T Mattoon
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jamie K Peterson
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Arlee L Mesler
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Natalia A Veniaminova
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Danielle J Gardon
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shih-Ying Tsai
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yoshikazu Uchida
- Department of Food Science and Nutrition, and Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, Republic of Korea
| | - Sunny Y Wong
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
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27
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Ouzikov S, Edwards KM, Anandampillai T, Watanabe S, Lozano Casasbuenas D, Siu KK, Harkins D, Dou A, Jeong D, Lee JE, Yuzwa SA. LRIG1 controls proliferation of adult neural stem cells by facilitating TGFβ and BMP signalling pathways. Commun Biol 2024; 7:845. [PMID: 38987622 PMCID: PMC11237139 DOI: 10.1038/s42003-024-06524-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 06/28/2024] [Indexed: 07/12/2024] Open
Abstract
Adult Neural Stem Cells (aNSCs) in the ventricular-subventricular zone (V-SVZ) are largely quiescent. Here, we characterize the mechanism underlying the functional role of a cell-signalling inhibitory protein, LRIG1, in the control of aNSCs proliferation. Using Lrig1 knockout models, we show that Lrig1 ablation results in increased aNSCs proliferation with no change in neuronal progeny and that this hyperproliferation likely does not result solely from activation of the epidermal growth factor receptor (EGFR). Loss of LRIG1, however, also leads to impaired activation of transforming growth factor beta (TGFβ) and bone morphogenic protein (BMP) signalling. Biochemically, we show that LRIG1 binds TGFβ/BMP receptors and the TGFβ1 ligand. Finally, we show that the consequences of these interactions are to facilitate SMAD phosphorylation. Collectively, these data suggest that unlike in embryonic NSCs where EGFR may be the primary mechanism of action, in aNSCs, LRIG1 and TGFβ pathways function together to fulfill their inhibitory roles.
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Affiliation(s)
- Stephanie Ouzikov
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Kyshona M Edwards
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Tanvi Anandampillai
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Samuel Watanabe
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Daniela Lozano Casasbuenas
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Karen K Siu
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Danyon Harkins
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Aaron Dou
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Danielle Jeong
- Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
- Program in Neurosciences and Mental Health, Hospital for Sick Children, 686 Bay Street, Toronto, ON, M5G 0A4, Canada
| | - Jeffrey E Lee
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Scott A Yuzwa
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
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28
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Viragova S, Li D, Klein OD. Activation of fetal-like molecular programs during regeneration in the intestine and beyond. Cell Stem Cell 2024; 31:949-960. [PMID: 38971147 PMCID: PMC11235077 DOI: 10.1016/j.stem.2024.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/10/2024] [Accepted: 05/24/2024] [Indexed: 07/08/2024]
Abstract
Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate "fetal-like reversion" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.
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Affiliation(s)
- Sara Viragova
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Dong Li
- Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA
| | - Ophir D Klein
- Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA.
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29
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Morgan HJ, Olivero C, Shorning BY, Gibbs A, Phillips AL, Ananthan L, Lim AXH, Martuscelli L, Borgogna C, De Andrea M, Hufbauer M, Goodwin R, Akgül B, Gariglio M, Patel GK. HPV8-induced STAT3 activation led keratinocyte stem cell expansion in human actinic keratoses. JCI Insight 2024; 9:e177898. [PMID: 38916963 PMCID: PMC11383611 DOI: 10.1172/jci.insight.177898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 06/20/2024] [Indexed: 06/27/2024] Open
Abstract
Despite epidermal turnover, the skin is host to a complex array of microbes, including viruses, such as HPV, which must infect and manipulate skin keratinocyte stem cells (KSCs) to survive. This crosstalk between the virome and KSC populations remains largely unknown. Here, we investigated the effect of HPV8 on KSCs using various mouse models. We observed that the HPV8 early region gene E6 specifically caused Lrig1+ hair follicle junctional zone KSC proliferation and expansion, which would facilitate viral transmission. Within Lrig1+ KSCs specifically, HPV8 E6 bound intracellular p300 to phosphorylate the STAT3 transcriptional regulatory node. This induced ΔNp63 expression, resulting in KSC expansion into the overlying epidermis. HPV8 was associated with 70% of human actinic keratoses. Together, these results define the "hit-and-run" mechanism for HPV8 in human actinic keratosis as an expansion of KSCs, which lack melanosome protection and are thus susceptible to sun light-induced malignant transformation.
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Affiliation(s)
- Huw J Morgan
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Carlotta Olivero
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Boris Y Shorning
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Alex Gibbs
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Alexandra L Phillips
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Lokapriya Ananthan
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Annabelle Xiao Hui Lim
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Licia Martuscelli
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Cinzia Borgogna
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Marco De Andrea
- Viral Pathogenesis Unit, Department of Public Health and Pediatric Sciences, University of Turin Medical School, Turin, Italy
- Intrinsic Immunity Unit, Translational Research Centre for Autoimmune and Allergic Diseases, University of Eastern Piedmont, Novara, Italy
| | - Martin Hufbauer
- Institute of Virology, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
| | - Richard Goodwin
- Department of Dermatology, Aneurin Bevan University Health Board, Royal Gwent Hospital, Newport, United Kingdom
| | - Baki Akgül
- Institute of Virology, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
| | - Marisa Gariglio
- Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Girish K Patel
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom
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30
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Zutshi N, Mohapatra BC, Mondal P, An W, Goetz BT, Wang S, Li S, Storck MD, Mercer DF, Black AR, Thayer SP, Black JD, Lin C, Band V, Band H. Cbl and Cbl-b ubiquitin ligases are essential for intestinal epithelial stem cell maintenance. iScience 2024; 27:109912. [PMID: 38974465 PMCID: PMC11225835 DOI: 10.1016/j.isci.2024.109912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 02/29/2024] [Accepted: 05/03/2024] [Indexed: 07/09/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) control stem cell maintenance vs. differentiation decisions. Casitas B-lineage lymphoma (CBL) family ubiquitin ligases are negative regulators of RTKs, but their stem cell regulatory roles remain unclear. Here, we show that Lgr5+ intestinal stem cell (ISC)-specific inducible Cbl-knockout (KO) on a Cblb null mouse background (iDKO) induced rapid loss of the Lgr5 Hi ISCs with transient expansion of the Lgr5 Lo transit-amplifying population. LacZ-based lineage tracing revealed increased ISC commitment toward enterocyte and goblet cell fate at the expense of Paneth cells. Functionally, Cbl/Cblb iDKO impaired the recovery from radiation-induced intestinal epithelial injury. In vitro, Cbl/Cblb iDKO led to inability to maintain intestinal organoids. Single-cell RNA sequencing in organoids identified Akt-mTOR (mammalian target of rapamycin) pathway hyperactivation upon iDKO, and pharmacological Akt-mTOR axis inhibition rescued the iDKO defects. Our results demonstrate a requirement for Cbl/Cblb in the maintenance of ISCs by fine-tuning the Akt-mTOR axis to balance stem cell maintenance vs. commitment to differentiation.
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Affiliation(s)
- Neha Zutshi
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Bhopal C. Mohapatra
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Pinaki Mondal
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Wei An
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Benjamin T. Goetz
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shuo Wang
- Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sicong Li
- Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Matthew D. Storck
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - David F. Mercer
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Adrian R. Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sarah P. Thayer
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jennifer D. Black
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Chi Lin
- Department of Radiation Oncology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Vimla Band
- Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Hamid Band
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Genetics, Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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31
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Capdevila C, Miller J, Cheng L, Kornberg A, George JJ, Lee H, Botella T, Moon CS, Murray JW, Lam S, Calderon RI, Malagola E, Whelan G, Lin CS, Han A, Wang TC, Sims PA, Yan KS. Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells. Cell 2024; 187:3039-3055.e14. [PMID: 38848677 PMCID: PMC11770878 DOI: 10.1016/j.cell.2024.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 01/16/2024] [Accepted: 05/01/2024] [Indexed: 06/09/2024]
Abstract
In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreERT2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.
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Affiliation(s)
- Claudia Capdevila
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Jonathan Miller
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA; Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Liang Cheng
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Adam Kornberg
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Joel J George
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Hyeonjeong Lee
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Theo Botella
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Christine S Moon
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - John W Murray
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA
| | - Stephanie Lam
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Ruben I Calderon
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Ermanno Malagola
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Gary Whelan
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Chyuan-Sheng Lin
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - Arnold Han
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA; Department of Microbiology & Immunology, Columbia University Irving Medical Center, New York, NY, USA
| | - Timothy C Wang
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Peter A Sims
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA; Departments of Biochemistry & Molecular Biophysics and of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Kelley S Yan
- Department of Medicine, Division of Digestive & Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA; Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Digestive & Liver Diseases Research Center, Columbia University Irving Medical Center, New York, NY, USA.
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32
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Malagola E, Vasciaveo A, Ochiai Y, Kim W, Zheng B, Zanella L, Wang ALE, Middelhoff M, Nienhüser H, Deng L, Wu F, Waterbury QT, Belin B, LaBella J, Zamechek LB, Wong MH, Li L, Guha C, Cheng CW, Yan KS, Califano A, Wang TC. Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury. Cell 2024; 187:3056-3071.e17. [PMID: 38848678 PMCID: PMC11164536 DOI: 10.1016/j.cell.2024.05.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 01/15/2024] [Accepted: 05/01/2024] [Indexed: 06/09/2024]
Abstract
The currently accepted intestinal epithelial cell organization model proposes that Lgr5+ crypt-base columnar (CBC) cells represent the sole intestinal stem cell (ISC) compartment. However, previous studies have indicated that Lgr5+ cells are dispensable for intestinal regeneration, leading to two major hypotheses: one favoring the presence of a quiescent reserve ISC and the other calling for differentiated cell plasticity. To investigate these possibilities, we studied crypt epithelial cells in an unbiased fashion via high-resolution single-cell profiling. These studies, combined with in vivo lineage tracing, show that Lgr5 is not a specific ISC marker and that stemness potential exists beyond the crypt base and resides in the isthmus region, where undifferentiated cells participate in intestinal homeostasis and regeneration following irradiation (IR) injury. Our results provide an alternative model of intestinal epithelial cell organization, suggesting that stemness potential is not restricted to CBC cells, and neither de-differentiation nor reserve ISC are drivers of intestinal regeneration.
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Affiliation(s)
- Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | | | - Yosuke Ochiai
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Woosook Kim
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Biyun Zheng
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA; Department of Gastroenterology, Fujian Medical University Union Hospital, Fujian 350000, China
| | - Luca Zanella
- Department of Systems Biology, Columbia University, New York, NY 10032, USA
| | - Alexander L E Wang
- Department of Systems Biology, Columbia University, New York, NY 10032, USA
| | - Moritz Middelhoff
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Henrik Nienhüser
- Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Lu Deng
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66107, USA
| | - Feijing Wu
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Quin T Waterbury
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Bryana Belin
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Jonathan LaBella
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Leah B Zamechek
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Melissa H Wong
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, L215, Portland, OR, USA
| | - Linheng Li
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66107, USA
| | - Chandan Guha
- Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
| | - Chia-Wei Cheng
- Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA
| | - Kelley S Yan
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA; Columbia Stem Cell Initiative, Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA; Columbia University Digestive and Liver Disease Research Center, New York, NY 10032, USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Andrea Califano
- Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biochemistry & Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA; Chan Zuckerberg Biohub NY, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA; Columbia University Digestive and Liver Disease Research Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
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33
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Abstract
All cancers arise from normal cells whose progeny acquire the cancer-initiating mutations and epigenetic modifications leading to frank tumorigenesis. The identity of those "cells-of-origin" has historically been a source of controversy across tumor types, as it has not been possible to witness the dynamic events giving rise to human tumors. Genetically engineered mouse models (GEMMs) of cancer provide an invaluable substitute, enabling researchers to interrogate the competence of various naive cellular compartments to initiate tumors in vivo. Researchers using these models have relied on lineage-specific promoters, knowledge of preneoplastic disease states in humans, and technical advances allowing more precise manipulations of the mouse germline. These approaches have given rise to the emerging view that multiple lineages within a given organ may generate tumors with similar histopathology. Here, we review some of the key studies leading to this conclusion in solid tumors and highlight the biological and clinical ramifications.
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Affiliation(s)
- Jason R Pitarresi
- Division of Hematology and Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, USA
| | - Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
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34
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Shi R, Wang B. Nutrient metabolism in regulating intestinal stem cell homeostasis. Cell Prolif 2024; 57:e13602. [PMID: 38386338 PMCID: PMC11150145 DOI: 10.1111/cpr.13602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 02/23/2024] Open
Abstract
Intestinal stem cells (ISCs) are known for their remarkable proliferative capacity, making them one of the most active cell populations in the body. However, a high turnover rate of intestinal epithelium raises the likelihood of dysregulated homeostasis, which is known to cause various diseases, including cancer. Maintaining precise control over the homeostasis of ISCs is crucial to preserve the intestinal epithelium's integrity during homeostasis or stressed conditions. Recent research has indicated that nutrients and metabolic pathways can extensively modulate the fate of ISCs. This review will explore recent findings concerning the influence of various nutrients, including lipids, carbohydrates, and vitamin D, on the delicate balance between ISC proliferation and differentiation.
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Affiliation(s)
- Ruicheng Shi
- Department of Comparative Biosciences, College of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
| | - Bo Wang
- Department of Comparative Biosciences, College of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
- Division of Nutritional Sciences, College of Agricultural, Consumer and Environmental SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
- Cancer Center at IllinoisUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
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35
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McConnell BB, Liang Z, Xu C, Han Y, Yun CC. LPA 5-Dependent signaling regulates regeneration of the intestinal epithelium following irradiation. Am J Physiol Gastrointest Liver Physiol 2024; 326:G631-G642. [PMID: 38593468 PMCID: PMC11376986 DOI: 10.1152/ajpgi.00269.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/20/2024] [Accepted: 03/30/2024] [Indexed: 04/11/2024]
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Cont or Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared with Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA5) in intestinal epithelial cells and intestinal organoids to show that the LPA5 receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA5 induces YAP signaling and regulates Paneth cells.
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Affiliation(s)
- Beth B McConnell
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Zhongxing Liang
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Chad Xu
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Yiran Han
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
| | - C Chris Yun
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States
- Gastroenterology Research, Atlanta Veterans Administration Medical Center, Decatur, Georgia, United States
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States
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36
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Vilardi A, Przyborski S, Mobbs C, Rufini A, Tufarelli C. Current understanding of the interplay between extracellular matrix remodelling and gut permeability in health and disease. Cell Death Discov 2024; 10:258. [PMID: 38802341 PMCID: PMC11130177 DOI: 10.1038/s41420-024-02015-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/25/2024] [Accepted: 05/07/2024] [Indexed: 05/29/2024] Open
Abstract
The intestinal wall represents an interactive network regulated by the intestinal epithelium, extracellular matrix (ECM) and mesenchymal compartment. Under healthy physiological conditions, the epithelium undergoes constant renewal and forms an integral and selective barrier. Following damage, the healthy epithelium is restored via a series of signalling pathways that result in remodelling of the scaffolding tissue through finely-regulated proteolysis of the ECM by proteases such as matrix metalloproteinases (MMPs). However, chronic inflammation of the gastrointestinal tract, as occurs in Inflammatory Bowel Disease (IBD), is associated with prolonged disruption of the epithelial barrier and persistent damage to the intestinal mucosa. Increased barrier permeability exhibits distinctive signatures of inflammatory, immunological and ECM components, accompanied by increased ECM proteolytic activity. This narrative review aims to bring together the current knowledge of the interplay between gut barrier, immune and ECM features in health and disease, discussing the role of barrier permeability as a discriminant between homoeostasis and IBD.
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Affiliation(s)
- Aurora Vilardi
- Cancer Research Centre, University of Leicester, Leicester, LE2 7LX, United Kingdom
| | - Stefan Przyborski
- Department of Biosciences, Durham University, Durham, DH1 3LE, United Kingdom
| | - Claire Mobbs
- Department of Biosciences, Durham University, Durham, DH1 3LE, United Kingdom
| | - Alessandro Rufini
- Cancer Research Centre, University of Leicester, Leicester, LE2 7LX, United Kingdom.
- Department of Biosciences, University of Milan, Milan, 20133, Italy.
| | - Cristina Tufarelli
- Cancer Research Centre, University of Leicester, Leicester, LE2 7LX, United Kingdom.
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Hu X, Yuan X, Zhang G, Song H, Ji P, Guo Y, Liu Z, Tian Y, Shen R, Wang D. The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis. Life Sci 2024; 344:122452. [PMID: 38462226 DOI: 10.1016/j.lfs.2024.122452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 03/12/2024]
Abstract
The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.
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Affiliation(s)
- Xiaohui Hu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Xinyi Yuan
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Guokun Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Haoyun Song
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Pengfei Ji
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Yanan Guo
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Zihua Liu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu Province 73000, China
| | - Yixiao Tian
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Rong Shen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Degui Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Lanzhou, Gansu Province 730000, China.
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38
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Higa T, Nakayama KI. Cell cycle heterogeneity and plasticity of colorectal cancer stem cells. Cancer Sci 2024; 115:1370-1377. [PMID: 38413370 PMCID: PMC11093209 DOI: 10.1111/cas.16117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/23/2024] [Accepted: 02/05/2024] [Indexed: 02/29/2024] Open
Abstract
Cancer stem cells (CSCs) are a long-lived and self-renewing cancer cell population that drives tumor propagation and maintains cancer heterogeneity. They are also implicated in the therapeutic resistance of various types of cancer. Recent studies of CSCs in colorectal cancer (CRC) have uncovered fundamental paradigms that have increased understanding of CSC systems in solid tumors. Colorectal CSCs share multiple biological properties with normal intestinal stem cells (ISCs), including expression of the stem cell marker Lgr5. New evidence suggests that colorectal CSCs manifest substantial heterogeneity, as exemplified by the existence of both actively cycling Lgr5+ CSCs as well as quiescent Lgr5+ CSCs that are resistant to conventional anticancer therapies. The classical view of a rigid cell hierarchy and irreversible cell differentiation trajectory in normal and neoplastic tissues is now challenged by the finding that differentiated cells have the capacity to revert to stem cells through dynamic physiological reprogramming events. Such plasticity of CSC systems likely underlies both carcinogenesis and therapeutic resistance in CRC. Further characterization of the mechanisms underpinning the heterogeneity and plasticity of CSCs should inform future development of eradicative therapeutic strategies for CRC.
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Affiliation(s)
- Tsunaki Higa
- Department of Molecular and Cellular Biology, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
| | - Keiichi I. Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
- Anticancer Strategies Laboratory, TMDU Advanced Research InstituteTokyo Medical and Dental UniversityTokyoJapan
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Ford NC, Benedeck RE, Mattoon MT, Peterson JK, Mesler AL, Veniaminova NA, Gardon DJ, Tsai SY, Uchida Y, Wong SY. Hair follicles modulate skin barrier function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.23.590728. [PMID: 38712094 PMCID: PMC11071379 DOI: 10.1101/2024.04.23.590728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
Our skin provides a protective barrier that shields us from our environment. Barrier function is typically associated with interfollicular epidermis; however, whether hair follicles influence this process remains unclear. Here, we utilize a potent genetic tool to probe barrier function by conditionally ablating a quintessential epidermal barrier gene, Abca12, which is mutated in the most severe skin barrier disease, harlequin ichthyosis. With this tool, we deduced 4 ways by which hair follicles modulate skin barrier function. First, the upper hair follicle (uHF) forms a functioning barrier. Second, barrier disruption in the uHF elicits non-cell autonomous responses in the epidermis. Third, deleting Abca12 in the uHF impairs desquamation and blocks sebum release. Finally, barrier perturbation causes uHF cells to move into the epidermis. Neutralizing Il17a, whose expression is enriched in the uHF, partially alleviated some disease phenotypes. Altogether, our findings implicate hair follicles as multi-faceted regulators of skin barrier function.
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Affiliation(s)
- Noah C. Ford
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rachel E. Benedeck
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
| | - Matthew T. Mattoon
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jamie K. Peterson
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Arlee L. Mesler
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Natalia A. Veniaminova
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Danielle J. Gardon
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Shih-Ying Tsai
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yoshikazu Uchida
- Department of Food Science and Nutrition, and Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, Republic of Korea
| | - Sunny Y. Wong
- Department of Dermatology, Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
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40
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Wang K, Liu Y, Li H, Liang X, Hao M, Yuan D, Ding L. Claudin-7 is essential for the maintenance of colonic stem cell homoeostasis via the modulation of Wnt/Notch signalling. Cell Death Dis 2024; 15:284. [PMID: 38654000 PMCID: PMC11039680 DOI: 10.1038/s41419-024-06658-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/25/2024]
Abstract
Intestinal stem cells (ISCs) play a crucial role in the continuous self-renewal and recovery of the intestinal epithelium. In previous studies, we have revealed that the specific absence of Claudin-7 (Cldn-7) in intestinal epithelial cells (IECs) can lead to the development of spontaneous colitis. However, the mechanisms by which Cldn-7 maintains homeostasis in the colonic epithelium remain unclear. Therefore, in the present study, we used IEC- and ISC-specific Cldn-7 knockout mice to investigate the regulatory effects of Cldn-7 on colonic Lgr5+ stem cells in the mediation of colonic epithelial injury and repair under physiological and inflammatory conditions. Notably, our findings reveal that Cldn-7 deletion disrupts the self-renewal and differentiation of colonic stem cells alongside the formation of colonic organoids in vitro. Additionally, these Cldn-7 knockout models exhibited heightened susceptibility to experimental colitis, limited epithelial repair and regeneration, and increased differentiation toward the secretory lineage. Mechanistically, we also established that Cldn-7 facilitates the proliferation, differentiation, and organoid formation of Lgr5+ stem cells through the maintenance of Wnt and Notch signalling pathways in the colonic epithelium. Overall, our study provides new insights into the maintenance of ISC function and colonic epithelial homoeostasis.
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Affiliation(s)
- Kun Wang
- Gastrointestinal Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yin Liu
- Gastrointestinal Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Huimin Li
- Gastrointestinal Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Xiaoqing Liang
- Gastrointestinal Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Mengdi Hao
- Gastrointestinal Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Dajin Yuan
- Gastrointestinal Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lei Ding
- Gastrointestinal Oncology Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
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41
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Morral C, Ayyaz A, Kuo HC, Fink M, Verginadis II, Daniel AR, Burner DN, Driver LM, Satow S, Hasapis S, Ghinnagow R, Luo L, Ma Y, Attardi LD, Koumenis C, Minn AJ, Wrana JL, Lee CL, Kirsch DG. p53 promotes revival stem cells in the regenerating intestine after severe radiation injury. Nat Commun 2024; 15:3018. [PMID: 38589357 PMCID: PMC11001929 DOI: 10.1038/s41467-024-47124-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 03/20/2024] [Indexed: 04/10/2024] Open
Abstract
Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53. However, p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Through single-cell RNA-sequencing of the irradiated mouse small intestine, we find that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract. Accordingly, in mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce fetal-like revSCs. Using intestinal organoids, we show that transient p53 expression is required for the induction of revival stem cells and is controlled by an Mdm2-mediated negative feedback loop. Together, our findings reveal that p53 suppresses severe radiation-induced GI injury by promoting fetal-like reprogramming of irradiated intestinal epithelial cells.
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Affiliation(s)
- Clara Morral
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Arshad Ayyaz
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Biological Sciences, University of Calgary, Calgary, AB, Canada
| | - Hsuan-Cheng Kuo
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Mardi Fink
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Ioannis I Verginadis
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrea R Daniel
- Department of Radiation Oncology, Duke University, Durham, NC, USA
| | - Danielle N Burner
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
| | - Lucy M Driver
- Department of Radiation Oncology, Duke University, Durham, NC, USA
- Department of Pathology, Duke University, Durham, NC, USA
| | - Sloane Satow
- Department of Radiation Oncology, Duke University, Durham, NC, USA
| | | | - Reem Ghinnagow
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lixia Luo
- Department of Radiation Oncology, Duke University, Durham, NC, USA
| | - Yan Ma
- Department of Radiation Oncology, Duke University, Durham, NC, USA
| | - Laura D Attardi
- Departments of Radiation Oncology and Genetics, Stanford University, Palo Alto, CA, USA
| | - Constantinos Koumenis
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andy J Minn
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, University of Pennsylvania, Philadelphia, PA, USA
| | - Jeffrey L Wrana
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
| | - Chang-Lung Lee
- Department of Radiation Oncology, Duke University, Durham, NC, USA.
- Department of Pathology, Duke University, Durham, NC, USA.
| | - David G Kirsch
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
- Department of Radiation Oncology, Duke University, Durham, NC, USA.
- Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
- Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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42
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Estrach S, Vivier CM, Féral CC. ECM and epithelial stem cells: the scaffold of destiny. Front Cell Dev Biol 2024; 12:1359585. [PMID: 38572486 PMCID: PMC10987781 DOI: 10.3389/fcell.2024.1359585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/08/2024] [Indexed: 04/05/2024] Open
Abstract
Adult stem cells play a critical role in maintaining tissue homeostasis and promoting longevity. The intricate organization and presence of common markers among adult epithelial stem cells in the intestine, lung, and skin serve as hallmarks of these cells. The specific location pattern of these cells within their respective organs highlights the significance of the niche in which they reside. The extracellular matrix (ECM) not only provides physical support but also acts as a reservoir for various biochemical and biophysical signals. We will consider differences in proliferation, repair, and regenerative capacities of the three epithelia and review how environmental cues emerging from the niche regulate cell fate. These cues are transduced via mechanosignaling, regulating gene expression, and bring us to the concept of the fate scaffold. Understanding both the analogies and discrepancies in the mechanisms that govern stem cell fate in various organs can offer valuable insights for rejuvenation therapy and tissue engineering.
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Affiliation(s)
- Soline Estrach
- INSERM, CNRS, IRCAN, Université Côte d’Azur, Nice, France
| | | | - Chloé C. Féral
- INSERM, CNRS, IRCAN, Université Côte d’Azur, Nice, France
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43
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Beumer J, Clevers H. Hallmarks of stemness in mammalian tissues. Cell Stem Cell 2024; 31:7-24. [PMID: 38181752 PMCID: PMC10769195 DOI: 10.1016/j.stem.2023.12.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/03/2023] [Accepted: 12/08/2023] [Indexed: 01/07/2024]
Abstract
All adult tissues experience wear and tear. Most tissues can compensate for cell loss through the activity of resident stem cells. Although the cellular maintenance strategies vary greatly between different adult (read: postnatal) tissues, the function of stem cells is best defined by their capacity to replace lost tissue through division. We discuss a set of six complementary hallmarks that are key enabling features of this basic function. These include longevity and self-renewal, multipotency, transplantability, plasticity, dependence on niche signals, and maintenance of genome integrity. We discuss these hallmarks in the context of some of the best-understood adult stem cell niches.
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Affiliation(s)
- Joep Beumer
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Basel, Switzerland.
| | - Hans Clevers
- Institute of Human Biology (IHB), Roche Pharma Research and Early Development, Basel, Switzerland.
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44
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Wu H, Mu C, Xu L, Yu K, Shen L, Zhu W. Host-microbiota interaction in intestinal stem cell homeostasis. Gut Microbes 2024; 16:2353399. [PMID: 38757687 PMCID: PMC11110705 DOI: 10.1080/19490976.2024.2353399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.
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Affiliation(s)
- Haiqin Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Chunlong Mu
- Food Informatics, AgResearch, Te Ohu Rangahau Kai, Palmerston North, New Zealand
| | - Laipeng Xu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Kaifan Yu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Le Shen
- Department of Surgery, The University of Chicago, Chicago, IL, USA
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
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45
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Boman BM, Viswanathan V, Facey COB, Fields JZ, Stave JW. The v8-10 variant isoform of CD44 is selectively expressed in the normal human colonic stem cell niche and frequently is overexpressed in colon carcinomas during tumor development. Cancer Biol Ther 2023; 24:2195363. [PMID: 37005380 PMCID: PMC10072056 DOI: 10.1080/15384047.2023.2195363] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/02/2023] [Accepted: 03/20/2023] [Indexed: 04/04/2023] Open
Abstract
CD44 protein and its variant isoforms are expressed in cancer stem cells (CSCs), and various CD44 isoforms can have different functional roles in cells. Our goal was to investigate how different CD44 isoforms contribute to the emergence of stem cell (SC) overpopulation that drives colorectal cancer (CRC) development. Specific CD44 variant isoforms are selectively expressed in normal colonic SCs and become overexpressed in CRCs during tumor development. We created a unique panel of anti-CD44 rabbit genomic antibodies to 16 specific epitopes that span the entire length of the CD44 molecule. Our panel was used to comprehensively investigate the expression of different CD44 isoforms in matched pairs (n = 10) of malignant colonic tissue and adjacent normal mucosa, using two (IHC & IF) immunostaining approaches. We found that: i) CD44v8-10 is selectively expressed in the normal human colonic SC niche; ii) CD44v8-10 is co-expressed with the SC markers ALDH1 and LGR5 in normal and malignant colon tissues; iii) colon carcinoma tissues frequently (80%) stain for CD44v8-10 while staining for CD44v6 was less frequent (40%). Given that CD44v8-10 expression is restricted to cells in the normal human colonic SC niche and CD44v8-10 expression progressively increases during CRC development, CD44v8-10 expression likely contributes to the SC overpopulation that drives the development and growth of colon cancers. Since the CD44 variant v8-10 epitope is located on CD44's extracellular region, it offers great promise for targeted anti-CSC treatment approaches.
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Affiliation(s)
- Bruce M. Boman
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
- Department of Biologic Sciences, University of Delaware, Newark, DE, USA
- Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Vignesh Viswanathan
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
- Department of Biologic Sciences, University of Delaware, Newark, DE, USA
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Caroline O. B. Facey
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
| | - Jeremy Z. Fields
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
- Department of Cancer Research and Innovation, CA*TX Inc, Princeton, NJ, USA
| | - James W. Stave
- Department of Cancer Research and Innovation, Strategic Diagnostics Inc, Newark, DE, USA
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Parham LR, Williams PA, Katada K, Nettleford SK, Chatterji P, Acheampong KK, Danan CH, Ma X, Simon LA, Naughton KE, Mizuno R, Karakasheva T, McMillan EA, Whelan KA, Brady DC, Shaffer SM, Hamilton KE. IGF2BP1/IMP1 Deletion Enhances a Facultative Stem Cell State via Regulation of MAP1LC3B. Cell Mol Gastroenterol Hepatol 2023; 17:439-451. [PMID: 38081361 PMCID: PMC10835461 DOI: 10.1016/j.jcmgh.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/30/2023] [Accepted: 12/04/2023] [Indexed: 01/02/2024]
Abstract
BACKGROUND & AIMS The intestinal epithelium interfaces with a diverse milieu of luminal contents while maintaining robust digestive and barrier functions. Facultative intestinal stem cells are cells that survive tissue injury and divide to re-establish the epithelium. Prior studies have shown autophagic state as functional marker of facultative intestinal stem cells, but regulatory mechanisms are not known. The current study evaluated a post-transcriptional regulation of autophagy as an important factor for facultative stem cell state and tissue regeneration. METHODS We evaluated stem cell composition, autophagic vesicle content, organoid formation, and in vivo regeneration in mice with intestinal epithelial deletion of the RNA binding protein IGF2 messenger RNA binding protein 1 (IMP1). The contribution of autophagy to resulting in vitro and in vivo phenotypes was evaluated via genetic inactivation of Atg7. Molecular analyses of IMP1 modulation of autophagy at the protein and transcript localization levels were performed using IMP1 mutant studies and single-molecule fluorescent in situ hybridization. RESULTS Epithelial Imp1 deletion reduced leucine rich repeat containing G protein coupled receptor 5 cell frequency but enhanced both organoid formation efficiency and in vivo regeneration after irradiation. We confirmed prior studies showing increased autophagy with IMP1 deletion. Deletion of Atg7 reversed the enhanced regeneration observed with Imp1 deletion. IMP1 deletion or mutation of IMP1 phosphorylation sites enhanced expression of essential autophagy protein microtubule-associated protein 1 light chain 3β. Furthermore, immunofluorescence imaging coupled with single-molecule fluorescent in situ hybridization showed IMP1 colocalization with MAP1LC3B transcripts at homeostasis. Stress induction led to decreased colocalization. CONCLUSIONS Depletion of IMP1 enhances autophagy, which promotes intestinal regeneration via expansion of facultative intestinal stem cells.
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Affiliation(s)
- Louis R Parham
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Patrick A Williams
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Kay Katada
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Shaneice K Nettleford
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Priya Chatterji
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Kofi K Acheampong
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Charles H Danan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Xianghui Ma
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Lauren A Simon
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Kaitlyn E Naughton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Rei Mizuno
- Department of Surgery, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan
| | - Tatiana Karakasheva
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Emily A McMillan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Kelly A Whelan
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania; Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Donita C Brady
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sydney M Shaffer
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kathryn E Hamilton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
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Hopton RE, Jahahn NJ, Zemper AE. Lrig1 drives cryptogenesis and restrains proliferation during colon development. Am J Physiol Gastrointest Liver Physiol 2023; 325:G570-G581. [PMID: 37873577 PMCID: PMC11192189 DOI: 10.1152/ajpgi.00094.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 10/04/2023] [Accepted: 10/13/2023] [Indexed: 10/25/2023]
Abstract
Growth and specification of the mouse intestine occurs in utero and concludes after birth. Although numerous studies have examined this developmental process in the small intestine, far less is known about the cellular and molecular cues required for colon development. In this study, we examine the morphological events leading to crypt formation, epithelial cell differentiation, proliferation, and the emergence and expression of a stem and progenitor cell marker Lrig1. Through multicolor lineage tracing, we show Lrig1-expressing cells are present at birth and behave as stem cells to establish clonal crypts within 3 wk of life. In addition, we use an inducible knockout mouse to eliminate Lrig1 and show Lrig1 restrains proliferation within a critical developmental time window, without impacting colonic epithelial cell differentiation. Our study illustrates morphological changes during crypt development and the importance of Lrig1 in the developing colon.NEW & NOTEWORTHY Our studies define the importance of studying Lrig1 in colon development. We address a critical gap in the intestinal development literature and provide new information about the molecular cues that guide colon development. Using a novel, inducible knockout of Lrig1, we show Lrig1 is required for appropriate colon epithelial growth and illustrate the importance of Lrig1-expressing cells in the establishment of colonic crypts.
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Affiliation(s)
- Rachel E Hopton
- Institute of Molecular Biology, University of Oregon, Eugene, Oregon, United States
- Department of Biology, University of Oregon, Eugene, Oregon, United States
| | - Nicholas J Jahahn
- Institute of Molecular Biology, University of Oregon, Eugene, Oregon, United States
- Department of Biology, University of Oregon, Eugene, Oregon, United States
| | - Anne E Zemper
- Department of Biology, University of Oregon, Eugene, Oregon, United States
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48
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Huang L, Xu Z, Lei X, Huang Y, Tu S, Xu L, Xia J, Liu D. Paneth cell-derived iNOS is required to maintain homeostasis in the intestinal stem cell niche. J Transl Med 2023; 21:852. [PMID: 38007452 PMCID: PMC10675917 DOI: 10.1186/s12967-023-04744-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023] Open
Abstract
BACKGROUND Mammalian intestinal epithelium constantly undergoes rapid self-renewal and regeneration sustained by intestinal stem cells (ISCs) within crypts. Inducible nitric oxide synthase (iNOS) is an important regulator in tissue homeostasis and inflammation. However, the functions of iNOS on ISCs have not been clarified. Here, we aimed to investigate the expression pattern of inducible nitric oxide synthase (iNOS) within crypts and explore its function in the homeostatic maintenance of the ISC niche. METHODS Expression of iNOS was determined by tissue staining and qPCR. iNOS-/- and Lgr5 transgenic mice were used to explore the influence of iNOS ablation on ISC proliferation and differentiation. Enteroids were cultured to study the effect of iNOS on ISCs in vitro. Ileum samples from wild-type and iNOS-/- mice were collected for RNA-Seq to explore the molecular mechanisms by which iNOS regulates ISCs. RESULTS iNOS was physiologically expressed in Paneth cells. Knockout of iNOS led to apparent morphological changes in the intestine, including a decrease in the small intestine length and in the heights of both villi and crypts. Knockout of iNOS decreased the number of Ki67+ or BrdU+ proliferative cells in crypts. Loss of iNOS increased the number of Olfm4+ ISCs but inhibited the differentiation and migration of Lgr5+ ISCs in vivo. iNOS depletion also inhibited enteroid formation and the budding efficiency of crypts in vitro. Moreover, iNOS deficiency altered gluconeogenesis and the adaptive immune response in the ileum transcriptome. CONCLUSION Paneth cell-derived iNOS is required to maintain a healthy ISC niche, and Knockout of iNOS hinders ISC function in mice. Therefore, iNOS represents a potential target for the development of new drugs and other therapeutic interventions for intestinal disorders.
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Affiliation(s)
- Lingxiao Huang
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Zhenni Xu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Xudan Lei
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Yujun Huang
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Siyu Tu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Lu Xu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Jieying Xia
- Animal Experiment Center of Sichuan Academy of Traditional Chinese Medicine Sciences, Chengdu, 610041, China
| | - Dengqun Liu
- Radiation Oncology Key Laboratory of Sichuan Province, Department of Experimental Research, Sichuan Cancer Hospital & Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
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49
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Liu CY, Girish N, Gomez ML, Kalski M, Bernard JK, Simons BD, Polk DB. Wound-healing plasticity enables clonal expansion of founder progenitor cells in colitis. Dev Cell 2023; 58:2309-2325.e7. [PMID: 37652012 PMCID: PMC10872951 DOI: 10.1016/j.devcel.2023.08.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/30/2023] [Accepted: 08/05/2023] [Indexed: 09/02/2023]
Abstract
Chronic colonic injury and inflammation pose high risks for field cancerization, wherein injury-associated mutations promote stem cell fitness and gradual clonal expansion. However, the long-term stability of some colitis-associated mutational fields could suggest alternate origins. Here, studies of acute murine colitis reveal a punctuated mechanism of massive, neutral clonal expansion during normal wound healing. Through three-dimensional (3D) imaging, quantitative fate mapping, and single-cell transcriptomics, we show that epithelial wound repair begins with the loss of structural constraints on regeneration, forming fused labyrinthine channels containing epithelial cells reprogrammed to a non-proliferative plastic state. A small but highly proliferative set of epithelial founder progenitor cells (FPCs) subsequently emerges and undergoes extensive cell division, enabling fluid-like lineage mixing and spreading across the colonic surface. Crypt budding restores the glandular organization, imprinting the pattern of clonal expansion. The emergence and functions of FPCs within a critical window of plasticity represent regenerative targets with implications for preneoplasia.
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Affiliation(s)
- Cambrian Y Liu
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
| | - Nandini Girish
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA
| | - Marie L Gomez
- Program in Biomedical and Biological Sciences, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Martin Kalski
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Jessica K Bernard
- Program in Craniofacial Biology, Herman Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA 90033, USA
| | - Benjamin D Simons
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge CB3 0WA, UK; Wellcome Trust, Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK
| | - D Brent Polk
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Rady Children's Hospital, San Diego, CA 92123, USA.
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50
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Carlin CR, Ngalula S. Loss of EGF receptor polarity enables homeostatic imbalance in epithelial-cell models. Mol Biol Cell 2023; 34:ar116. [PMID: 37647145 PMCID: PMC10846618 DOI: 10.1091/mbc.e23-04-0133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/26/2023] [Accepted: 08/22/2023] [Indexed: 09/01/2023] Open
Abstract
The polarized distribution of membrane proteins into apical and basolateral domains provides the basis for specialized functions of epithelial tissues. The EGF receptor (EGFR) plays important roles in embryonic development, adult-epithelial tissue homeostasis, and growth and survival of many carcinomas. Typically targeted to basolateral domains, there is also considerable evidence of EGFR sorting plasticity but very limited knowledge regarding domain-specific EGFR substrates. Here we have investigated effects of selective EGFR mistargeting because of inactive-basolateral sorting signals on epithelial-cell homeostatic responses to growth-induced stress in MDCK cell models. Aberrant EGFR localization was associated with multilayer formation, anchorage-independent growth, and upregulated expression of the intermediate filament-protein vimentin characteristically seen in cells undergoing epithelial-to-mesenchymal transition. EGFRs were selectively retained following their internalization from apical membranes, and a signaling pathway involving the signaling adaptor Gab1 protein and extracellular signal-regulated kinase ERK5 had an essential role integrating multiple responses to growth-induced stress. Our studies highlight the potential importance of cellular machinery specifying EGFR polarity in epithelial pathologies associated with homeostatic imbalance.
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Affiliation(s)
- Cathleen R. Carlin
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106-4970
- Case Western Reserve University Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4970
| | - Syntyche Ngalula
- Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106-4970
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