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1
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Gurdal M, Baysal K, Durak I, Selver OB. Limbal explant cultures on amniotic membrane: The effects of passaging the explants on cell phenotype. Exp Eye Res 2025; 255:110392. [PMID: 40250725 DOI: 10.1016/j.exer.2025.110392] [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: 02/12/2025] [Revised: 04/04/2025] [Accepted: 04/15/2025] [Indexed: 04/20/2025]
Abstract
In vitro expansion of limbal epithelial stem cells (LESCs) while maintaining their characteristics has the potential to address the urgent need in ophthalmology clinics for the treatment of limbal stem cell deficiency (LSCD). Herein, we investigated the impact of explant passaging on the phenotype of LESCs cultured on human amniotic membrane (hAM). Following initial coverage of the hAM surface by cells (passage 0), the rabbit limbal explants underwent two additional passages. Expanded cells were then counted using a hemocytometer and examined by immunocytochemistry and RT-qPCR to assess markers associated with LESCs (ABCG2, P63, CK14, CXCR4, BMI-1, and vimentin) and differentiated LESCs (CK3 and connexin 43). The cell yield of passage 1 was the highest among all passages. Immunocytochemistry analysis revealed that the number of CK14-positive cells was similar across all passages; vimentin-positive cells were the lowest in passage 0, while vimentin-positive cells were the highest in passage 1; and CK3-positive cells were the highest in passage 0. RT-qPCR analysis revealed that CK3 and connexin 43 expression was significantly higher in passage 0 cells than in passage 2 cells; and CXCR4 and BMI-1 expressions were significantly higher in passage 1 cells than in passage 0 cells. Our data highlight that the passaging of limbal explant on hAM results in varying cell characteristics. The decrease in CK3 and increase in ABCG2 expression in cells obtained by passaging the limbal explant suggest that passaging could potentially enhance the stem cell population within the in vitro limbal explant culture on hAM.
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Affiliation(s)
- Mehmet Gurdal
- Dokuz Eylül University, Faculty of Medicine, Department of Medical Biochemistry, Izmir, Türkiye; Ege University, Faculty of Medicine, Ocular Surface Research Laboratory, Izmir, Türkiye; Limbustem R&D Medical Products Ltd., Ege University Technopark, Izmir, Türkiye.
| | - Kemal Baysal
- Dokuz Eylül University, Faculty of Medicine, Department of Medical Biochemistry, Izmir, Türkiye; Koc University, School of Medicine, Department of Biochemistry, Istanbul, Türkiye.
| | - Ismet Durak
- Dokuz Eylül University, Faculty of Medicine, Department of Ophthalmology, Izmir, Türkiye.
| | - Ozlem Barut Selver
- Ege University, Faculty of Medicine, Ocular Surface Research Laboratory, Izmir, Türkiye; Limbustem R&D Medical Products Ltd., Ege University Technopark, Izmir, Türkiye; Ege University, Faculty of Medicine, Department of Ophthalmology, Izmir, Türkiye; Department of Stem Cell, Institute of Health Sciences, Ege University, Izmir, Türkiye; Institute of Health Sciences, Department of Stem Cell, Ege University, Izmir, Türkiye; Cord Blood Cell-Tissue Application and Research Center, Ege University, Izmir, Türkiye.
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2
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Tobias IC, Moorthy SD, Shchuka VM, Langroudi L, Cherednychenko M, Gillespie ZE, Duncan AG, Tian R, Gajewska NA, Di Roberto RB, Mitchell JA. A Sox2 enhancer cluster regulates region-specific neural fates from mouse embryonic stem cells. G3 (BETHESDA, MD.) 2025; 15:jkaf012. [PMID: 39849901 PMCID: PMC12005160 DOI: 10.1093/g3journal/jkaf012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/14/2025] [Accepted: 01/19/2025] [Indexed: 01/25/2025]
Abstract
Sex-determining region Y box 2 (Sox2) is a critical transcription factor for embryogenesis and neural stem and progenitor cell (NSPC) maintenance. While distal enhancers control Sox2 in embryonic stem cells (ESCs), enhancers closer to the gene are implicated in Sox2 transcriptional regulation in neural development. We hypothesize that a downstream enhancer cluster, termed Sox2 regulatory regions 2-18 (SRR2-18), regulates Sox2 transcription in neural stem cells and we investigate this in NSPCs derived from mouse ESCs. Using functional genomics and CRISPR-Cas9-mediated deletion analyses, we investigate the role of SRR2-18 in Sox2 regulation during neural differentiation. Transcriptome analyses demonstrate that the loss of even 1 copy of SRR2-18 disrupts the region-specific identity of NSPCs, reducing the expression of genes associated with more anterior regions of the embryonic nervous system. Homozygous deletion of this Sox2 neural enhancer cluster causes reduced SOX2 protein, less frequent interaction with transcriptional machinery, and leads to perturbed chromatin accessibility genome-wide further affecting the expression of neurodevelopmental and anterior-posterior regionalization genes. Furthermore, homozygous NSPC deletants exhibit self-renewal defects and impaired differentiation into cell types found in the brain. Altogether, our data define a cis-regulatory enhancer cluster controlling Sox2 transcription in NSPCs and highlight the sensitivity of neural differentiation processes to decreased Sox2 transcription, which causes differentiation into posterior neural fates, specifically the caudal neural tube. This study highlights the importance of precise Sox2 regulation by SRR2-18 in neural differentiation.
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Affiliation(s)
- Ian C Tobias
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Sakthi D Moorthy
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Virlana M Shchuka
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Lida Langroudi
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Mariia Cherednychenko
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Zoe E Gillespie
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Andrew G Duncan
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Ruxiao Tian
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Natalia A Gajewska
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Raphaël B Di Roberto
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
| | - Jennifer A Mitchell
- Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada
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3
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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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Hoffmann J, Schütze TM, Kolodziejczyk A, Küster K, Kränkel A, Reinhardt S, Derihaci RP, Birdir C, Wimberger P, Koseki H, Albert M. Canonical and non-canonical PRC1 differentially contribute to regulation of neural stem cell fate. Life Sci Alliance 2025; 8:e202403006. [PMID: 39933923 PMCID: PMC11814486 DOI: 10.26508/lsa.202403006] [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: 08/21/2024] [Revised: 01/30/2025] [Accepted: 01/31/2025] [Indexed: 02/13/2025] Open
Abstract
Neocortex development is characterized by sequential phases of neural progenitor cell (NPC) expansion, neurogenesis, and gliogenesis. Polycomb-mediated epigenetic mechanisms are known to play important roles in regulating the lineage potential of NPCs during development. The composition of Polycomb repressive complex 1 (PRC1) is highly diverse in mammals and was hypothesized to contribute to context-specific regulation of cell fate. Here, we have performed a side-by-side comparison of the role of canonical PRC1.2/1.4 and non-canonical PRC1.3/1.5, all of which are expressed in the developing neocortex, in NSC proliferation and differentiation. We found that the deletion of Pcgf2/4 in NSCs led to a strong reduction in proliferation and to altered lineage fate, both during the neurogenic and gliogenic phase, whereas Pcgf3/5 played a minor role. Mechanistically, genes encoding stem cell and neurogenic factors were bound by PRC1 and differentially expressed upon Pcgf2/4 deletion. Thus, rather than different PRC1 subcomplexes contributing to different phases of neural development, we found that canonical PRC1 played a more significant role in NSC regulation during proliferative, neurogenic, and gliogenic phases compared with non-canonical PRC1.
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Affiliation(s)
- Janine Hoffmann
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Theresa M Schütze
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Annika Kolodziejczyk
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Karolin Küster
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
| | - Annekathrin Kränkel
- DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, Technology Platform of the TUD Dresden University of Technology, Dresden, Germany
| | - Susanne Reinhardt
- DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, Technology Platform of the TUD Dresden University of Technology, Dresden, Germany
| | - Razvan P Derihaci
- Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases, Dresden, Germany
| | - Cahit Birdir
- Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
- Center for Feto/Neonatal Health, Technische Universität Dresden, Dresden, Germany
| | - Pauline Wimberger
- Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases, Dresden, Germany
| | - Haruhiko Koseki
- Laboratory of Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Mareike Albert
- Center for Regenerative Therapies Dresden, TUD Dresden University of Technology, Dresden, Germany
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5
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Shaalan F, Ballout N, Chamoun WT. Insights Into the Role of Bmi-1 Deregulation in Promoting Stemness and Therapy Resistance in Glioblastoma: A Narrative Review. Cancer Med 2025; 14:e70566. [PMID: 39791545 PMCID: PMC11719125 DOI: 10.1002/cam4.70566] [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: 09/17/2024] [Revised: 11/25/2024] [Accepted: 12/20/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND Glioblastoma (GBM) is the most common primary brain tumor in adults and has a median survival of less than 15 months. Advancements in the field of epigenetics have expanded our understanding of cancer biology and helped explain the molecular heterogeneity of these tumors. B-cell-specific Moloney murine leukemia virus insertion site-1 (Bmi-1) is a member of the highly conserved polycomb group (PcG) protein family that acts as a transcriptional repressor of multiple genes, including those that determine cell proliferation and differentiation. We hereby aim to explore the specific involvement of Bmi-1 in glioma pathogenesis. METHODS A comprehensive narrative review was employed using "PubMed". Articles were screened for relevance specific keywords and medical subject headings (MeSH) terms related to the topic combined with Boolean operators (AND, OR). Keywords and MeSH terms included the following: "glioma", "polycomb repressive complex 1", and "Bmi1". RESULTS In GBMs, several reports have shown that Bmi-1 is overexpressed and might serve as a prognostic biomarker. We find that Bmi-1 participates in regulating the gene expression and chromatin structure of several tumor suppressor genes or cell cycle inhibitors. Bmi-1 has a critical role in modulating the tumor microenvironment to support the plasticity of GBM stem cells.We explore Bmi-1's involvement in maintaining glioma stem cell (GSC) proliferation and senescence evasion upon regulating the chromatin structure of several tumor suppressor genes, cell cycle inhibitors, or stem cell genes in tumor cells. Additionally, we analyze Bmi-1's involvement in modulating the DNA repair machinery or activating anti-apoptotic pathways to confer therapy resistance. Importantly, our research discusses the importance of targeting Bmi-1 that could be a promising therapeutic target for GBM treatment. Bmi-1 activates and interacts with NF-κB to promote angiogenesis and invasion, regulates the INK4a-ARF locus, and interacts with various microRNAs to influence tumor progression and proliferation. In addition, Bmi-1 confers radioresistance and chemotherapy by promoting cell senescence evasion and DNA repair. CONCLUSION Bmi-1 regulates self-renewal, proliferation, and differentiation of GBM cells, promoting stemness and therapy resistance. Targeting Bmi-1 could be a promising novel therapeutic strategy for GBM treatment.
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Affiliation(s)
- Fatima Shaalan
- Faculty of Medical Sciences, Neuroscience Research CenterLebanese UniversityHadathLebanon
| | - Nissrine Ballout
- Faculty of Medical Sciences, Neuroscience Research CenterLebanese UniversityHadathLebanon
| | - Wafaa Takash Chamoun
- Faculty of Medical Sciences, Neuroscience Research CenterLebanese UniversityHadathLebanon
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6
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Lu Z, Morales MG, Liu S, Ramkumar HL. The Endogenous Expression of BMI1 in Adult Human Eyes. Cells 2024; 13:1672. [PMID: 39404434 PMCID: PMC11475477 DOI: 10.3390/cells13191672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/19/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024] Open
Abstract
BMI1, also known as B lymphoma Mo-MLV insertion region 1, is a protein in the Polycomb group that is implicated in various cellular processes, including stem cell self-renewal and the regulation of cellular senescence. BMI1 plays a role in the regulation of retinal progenitor cells and the renewal of adult neuronal cells. However, the presence, location, and quantification of BMI1 in the adult human eye have never previously been reported. In this study, we collected 45 frozen globes from eye banks, and ocular tissues were dissected. Protein was quantified by utilizing a custom electrochemiluminescence (ECL) assay developed to quantify the BMI1 protein. BMI1 was found in all ocular tissues at the following levels: the retina (1483.6 ± 191.7 pg/mL) and the RPE (296.4 ± 78.1 pg/mL). BMI1 expression was noted ubiquitously in the GCL (ganglion cell layer), the INL (inner nuclear layer), the ONL (outer nuclear layer), and the RPE (retinal pigment epithelium) via immunofluorescence, with higher levels in the inner than in the outer retinal layers and the RPE. These data confirm that BMI1 is expressed in the human retina. Further studies will illuminate the role that BMI1 plays in ocular cells. BMI1 levels are lower in aged retinas, possibly reflecting changes in retinal somatic and stem cell maintenance and disease susceptibility.
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Mohajer F, Khoradmehr A, Riazalhosseini B, Zendehboudi T, Nabipour I, Baghban N. In vitro detection of marine invertebrate stem cells: utilizing molecular and cellular biology techniques and exploring markers. Front Cell Dev Biol 2024; 12:1440091. [PMID: 39239558 PMCID: PMC11374967 DOI: 10.3389/fcell.2024.1440091] [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: 05/28/2024] [Accepted: 08/07/2024] [Indexed: 09/07/2024] Open
Abstract
Marine invertebrate stem cells (MISCs) represent a distinct category of pluripotent and totipotent cells with remarkable abilities for self-renewal and differentiation into multiple germ layers, akin to their vertebrate counterparts. These unique cells persist throughout an organism's adult life and have been observed in various adult marine invertebrate phyla. MISCs play crucial roles in numerous biological processes, including developmental biology phenomena specific to marine invertebrates, such as senescence, delayed senescence, whole-body regeneration, and asexual reproduction. Furthermore, they serve as valuable models for studying stem cell biology. Despite their significance, information about MISCs remains scarce and scattered in the scientific literature. In this review, we have carefully collected and summarized valuable information about MISC detection by perusing the articles that study and detect MISCs in various marine invertebrate organisms. The review begins by defining MISCs and highlighting their unique features compared to vertebrates. It then discusses the common markers for MISC detection and in vitro techniques employed in invertebrate and vertebrates investigation. This comprehensive review provides researchers and scientists with a cohesive and succinct overview of MISC characteristics, detection methods, and associated biological phenomena in marine invertebrate organisms. We aim to offer a valuable resource to researchers and scientists interested in marine invertebrate stem cells, fostering a better understanding of their broader implications in biology. With ongoing advancements in scientific techniques and the continued exploration of marine invertebrate species, we anticipate that further discoveries will expand our knowledge of MISCs and their broader implications in biology.
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Affiliation(s)
- Fatemeh Mohajer
- Student Research and Technology Committee, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Arezoo Khoradmehr
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Behnaz Riazalhosseini
- The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Tuba Zendehboudi
- Student Research and Technology Committee, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Neda Baghban
- Food Control Laboratory, Food and Drug Deputy, Bushehr University of Medical Sciences, Bushehr, Iran
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8
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Thor S. Indirect neurogenesis in space and time. Nat Rev Neurosci 2024; 25:519-534. [PMID: 38951687 DOI: 10.1038/s41583-024-00833-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/29/2024] [Indexed: 07/03/2024]
Abstract
During central nervous system (CNS) development, neural progenitor cells (NPCs) generate neurons and glia in two different ways. In direct neurogenesis, daughter cells differentiate directly into neurons or glia, whereas in indirect neurogenesis, neurons or glia are generated after one or more daughter cell divisions. Intriguingly, indirect neurogenesis is not stochastically deployed and plays instructive roles during CNS development: increased generation of cells from specific lineages; increased generation of early or late-born cell types within a lineage; and increased cell diversification. Increased indirect neurogenesis might contribute to the anterior CNS expansion evident throughout the Bilateria and help to modify brain-region size without requiring increased NPC numbers or extended neurogenesis. Increased indirect neurogenesis could be an evolutionary driver of the gyrencephalic (that is, folded) cortex that emerged during mammalian evolution and might even have increased during hominid evolution. Thus, selection of indirect versus direct neurogenesis provides a powerful developmental and evolutionary instrument that drives not only the evolution of CNS complexity but also brain expansion and modulation of brain-region size, and thereby the evolution of increasingly advanced cognitive abilities. This Review describes indirect neurogenesis in several model species and humans, and highlights some of the molecular genetic mechanisms that control this important process.
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Affiliation(s)
- Stefan Thor
- School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia.
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Finkel Z, Esteban F, Rodriguez B, Clifford T, Joseph A, Alostaz H, Dalmia M, Gutierrez J, Tamasi MJ, Zhang SM, Simone J, Petekci H, Nath S, Escott M, Garg SK, Gormley AJ, Kumar S, Gulati S, Cai L. AAV6 mediated Gsx1 expression in neural stem progenitor cells promotes neurogenesis and restores locomotor function after contusion spinal cord injury. Neurotherapeutics 2024; 21:e00362. [PMID: 38664194 PMCID: PMC11452562 DOI: 10.1016/j.neurot.2024.e00362] [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: 12/04/2023] [Revised: 03/29/2024] [Accepted: 04/11/2024] [Indexed: 05/05/2024] Open
Abstract
Genomic screened homeobox 1 (Gsx1 or Gsh1) is a neurogenic transcription factor required for the generation of excitatory and inhibitory interneurons during spinal cord development. In the adult, lentivirus (LV) mediated Gsx1 expression promotes neural regeneration and functional locomotor recovery in a mouse model of lateral hemisection spinal cord injury (SCI). The LV delivery method is clinically unsafe due to insertional mutations to the host DNA. In addition, the most common clinical case of SCI is contusion/compression. In this study, we identify that adeno-associated virus serotype 6 (AAV6) preferentially infects neural stem/progenitor cells (NSPCs) in the injured spinal cord. Using a rat model of contusion SCI, we demonstrate that AAV6 mediated Gsx1 expression promotes neurogenesis, increases the number of neuroblasts/immature neurons, restores excitatory/inhibitory neuron balance and serotonergic neuronal activity through the lesion core, and promotes locomotor functional recovery. Our findings support that AAV6 preferentially targets NSPCs for gene delivery and confirmed Gsx1 efficacy in clinically relevant rat model of contusion SCI.
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Affiliation(s)
- Zachary Finkel
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Fatima Esteban
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Brianna Rodriguez
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Tanner Clifford
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Adelina Joseph
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Hani Alostaz
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Mridul Dalmia
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Juan Gutierrez
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA; University of California, Santa Barbara, CA 93106, USA
| | - Matthew J Tamasi
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Samuel Ming Zhang
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Jonah Simone
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Hafize Petekci
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Susmita Nath
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Miriam Escott
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Shivam Kumar Garg
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Adam J Gormley
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Suneel Kumar
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA
| | - Sonia Gulati
- NeuroNovus Therapeutics Inc., 135 E 57th St., New York, NY 10022, USA
| | - Li Cai
- Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd, Piscataway, NJ 08854, USA; NeuroNovus Therapeutics Inc., 135 E 57th St., New York, NY 10022, USA.
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10
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Kunoh S, Nakashima H, Nakashima K. Epigenetic Regulation of Neural Stem Cells in Developmental and Adult Stages. EPIGENOMES 2024; 8:22. [PMID: 38920623 PMCID: PMC11203245 DOI: 10.3390/epigenomes8020022] [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: 02/14/2024] [Revised: 05/18/2024] [Accepted: 05/31/2024] [Indexed: 06/27/2024] Open
Abstract
The development of the nervous system is regulated by numerous intracellular molecules and cellular signals that interact temporally and spatially with the extracellular microenvironment. The three major cell types in the brain, i.e., neurons and two types of glial cells (astrocytes and oligodendrocytes), are generated from common multipotent neural stem cells (NSCs) throughout life. However, NSCs do not have this multipotentiality from the beginning. During cortical development, NSCs sequentially obtain abilities to differentiate into neurons and glial cells in response to combinations of spatiotemporally modulated cell-intrinsic epigenetic alterations and extrinsic factors. After the completion of brain development, a limited population of NSCs remains in the adult brain and continues to produce neurons (adult neurogenesis), thus contributing to learning and memory. Many biological aspects of brain development and adult neurogenesis are regulated by epigenetic changes via behavioral control of NSCs. Epigenetic dysregulation has also been implicated in the pathogenesis of various brain diseases. Here, we present recent advances in the epigenetic regulation of NSC behavior and its dysregulation in brain disorders.
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Affiliation(s)
| | - Hideyuki Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
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11
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Woods C, Flockton AR, Belkind-Gerson J. Phosphatase and Tensin Homolog Inhibition in Proteolipid Protein 1-Expressing Cells Stimulates Neurogenesis and Gliogenesis in the Postnatal Enteric Nervous System. Biomolecules 2024; 14:346. [PMID: 38540765 PMCID: PMC10967813 DOI: 10.3390/biom14030346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 04/04/2024] Open
Abstract
Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which Pten was conditionally ablated, (1) in glia (Plp1-expressing cells) and (2) in neurons (Calb2-expressing cells). Tamoxifen-treated adult (7-12 weeks of age; n = 4-15) mice were given DSS to induce colitis, EdU to monitor cell proliferation, and were evaluated at two timepoints: (1) early (3-4 days post-DSS) and (2) late (3-4 weeks post-DSS). We investigated gut motility and evaluated the enteric nervous system. Pten inhibition in Plp1-expressing cells elicited gliogenesis at baseline and post-DSS (early and late) in the colon, and neurogenesis post-DSS late in the proximal colon. They also exhibited an increased frequency of colonic migrating motor complexes (CMMC) and slower whole gut transit times. Pten inhibition in Calb2-expressing cells did not induce enteric neuro- or gliogenesis, and no alterations were detected in CMMC or whole gut transit times when compared to the control at baseline or post-DSS (early and late). Our results merit further research into Pten modulation where increased glia and/or slower intestinal transit times are desired (e.g., short-bowel syndrome and rapid-transit disorders).
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Affiliation(s)
- Crystal Woods
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado, Aurora, CO 80045, USA; (C.W.); (A.R.F.)
| | - Amanda R. Flockton
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado, Aurora, CO 80045, USA; (C.W.); (A.R.F.)
| | - Jaime Belkind-Gerson
- Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Colorado, Aurora, CO 80045, USA; (C.W.); (A.R.F.)
- Neurogastroenterology and Motility Program, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO 80045, USA
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12
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Queiroz LY, Kageyama R, Cimarosti HI. SUMOylation effects on neural stem cells self-renewal, differentiation, and survival. Neurosci Res 2024; 199:1-11. [PMID: 37742800 DOI: 10.1016/j.neures.2023.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/14/2023] [Accepted: 09/20/2023] [Indexed: 09/26/2023]
Abstract
SUMO (small ubiquitin-like modifier) conjugation or SUMOylation, a post-translational modification, is a crucial regulator of protein function and cellular processes. In the context of neural stem cells (NSCs), SUMOylation has emerged as a key player, affecting their proliferation, differentiation, and survival. By modifying transcription factors, such as SOX1, SOX2, SOX3, SOX6, Bmi1, and Nanog, SUMOylation can either enhance or impair their transcriptional activity, thus impacting on NSCs self-renewal. Moreover, SUMOylation regulates neurogenesis and neuronal differentiation by modulating key proteins, such as Foxp1, Mecp2, MEF2A, and SOX10. SUMOylation is also crucial for the survival and proliferation of NSCs in both developing and adult brains. By regulating the activity of transcription factors, coactivators, and corepressors, SUMOylation acts as a molecular switch, inducing cofactor recruitment and function during development. Importantly, dysregulation of NSCs SUMOylation has been implicated in various disorders, including embryonic defects, ischemic cerebrovascular disease, glioma, and the harmful effects of benzophenone-3 exposure. Here we review the main findings on SUMOylation-mediated regulation of NSCs self-renewal, differentiation and survival. Better understanding NSCs SUMOylation mechanisms and its functional consequences might provide new strategies to promote neuronal differentiation that could contribute for the development of novel therapies targeting neurodegenerative diseases.
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Affiliation(s)
- Letícia Yoshitome Queiroz
- Postgraduate Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florianopolis, Brazil
| | - Ryoichiro Kageyama
- Graduate School of Medicine, Kyoto University, Kyoto, Japan; RIKEN Center for Brain Science, Wako, Japan
| | - Helena I Cimarosti
- Postgraduate Program in Pharmacology, Federal University of Santa Catarina (UFSC), Florianopolis, Brazil; Postgraduate Program in Neuroscience, UFSC, Florianopolis, Brazil.
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13
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Zhang S, Yang R, Ouyang Y, Shen Y, Hu L, Xu C. Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0333. [PMID: 38164743 PMCID: PMC10845928 DOI: 10.20892/j.issn.2095-3941.2023.0333] [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: 09/04/2023] [Accepted: 11/20/2023] [Indexed: 01/03/2024] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.
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Affiliation(s)
- Shuo Zhang
- Department of Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610042, China
| | - Rui Yang
- Department of Ultrasound in Medicine, Chengdu Wenjiang District People’s Hospital, Chengdu 611130, China
| | - Yujie Ouyang
- Acupuncture and Massage College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yang Shen
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- School of Pharmacy, Macau University of Science and Technology, Macau SAR 999078, China
| | - Lanlin Hu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
| | - Chuan Xu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China
- Yu-Yue Pathology Scientific Research Center, Chongqing 400039, China
- Jinfeng Laboratory, Chongqing 401329, China
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14
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Hodeib H, El Amrousy D, Youssef A, Khedr R, Al-Asy H, Shabana A, Elnemr S, Abdelhai D. Acute lymphoblastic leukemia in children and SALL4 and BMI-1 gene expression. Pediatr Res 2023; 94:1510-1515. [PMID: 34782707 DOI: 10.1038/s41390-021-01854-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/21/2021] [Accepted: 11/02/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Sal-like protein 4 transcription factor (SALL4) and B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) gene were reported to cause treatment failure and relapse in several malignancies. We aimed to evaluate the prognostic value of SALL4 and BMI-1 in children with acute lymphoblastic leukemia (ALL). METHODS This prospective cohort study was carried out on 60 children with ALL as the patient group and 60 age- and sex-matched children as the control group. We evaluated the expression pattern of both SALL4 and BMI-1 genes in the peripheral blood using real-time reverse transcriptase-polymerase chain reaction in children with ALL at initial diagnosis before chemotherapy. We followed up with the patient group for 2 years for relapse or death. RESULTS Both SALL4 and BMI-1 were overexpressed in ALL children compared to the control group. Moreover, the expression of SALL4 and BMI-1 in patients with relapse was significantly higher than those with complete remission. The best cut-off of SALL4 and BMI-1 to predict relapse were >2.21 and 0.55 yielding sensitivity of 92.3% and 84.6%, respectively. Patients with overexpression of SALL4 and BMI-1 had significantly shorter overall and disease-free survival. CONCLUSIONS SALL4 and BMI-1 could be useful prognostic markers in children with ALL to predict relapse.
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Affiliation(s)
- Hossam Hodeib
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Doaa El Amrousy
- Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
| | - Amira Youssef
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rasha Khedr
- Clinical Oncology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Hassan Al-Asy
- Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ahmed Shabana
- Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Shimaa Elnemr
- Pediatric Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Dina Abdelhai
- Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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15
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Agh F, Mousavi SH, Aryaeian N, Amiri F, Jalilvand MR, Hasani M, Vahid F, Sepahvand F, Vosugh M. Senescence of bone marrow mesenchymal stem cells in Wistar male rats receiving normal chow/high-calorie diets with/without vitamin D. Biogerontology 2023; 24:801-812. [PMID: 37606875 DOI: 10.1007/s10522-023-10048-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 06/23/2023] [Indexed: 08/23/2023]
Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) have a momentous function in the composition of the bone marrow microenvironment because of their many valuable properties and abilities, such as immunomodulation and hematopoiesis. The features and actions of MSCs are influenced by senescence, which may be affected by various factors such as nutritional/micronutrients status, e.g., vitamin D. This study aimed to examine the effects of a high-calorie diet (HCD) with/without vitamin D on BM-MSCs senescence. In the first phase, 48 middle-aged rats were fed a normal chow diet (NCD, n = 24) and an HCD (n = 24) for 26 weeks. Afterward, the rats in each group were randomly divided into three equal subgroups. Immediately, eight-rat from each diet group were sacrificed to assess the HCD effects on the first phase measurements. In the second phase, the remaining 4 groups of rats were fed either NCD or HCD with (6 IU/g) or without vitamin D (standard intake: 1 IU/g); in other words, in this phase, the animals were fed (a) NCD, (b) NCD plus vitamin D, (c) HCD, and (d) HCD plus vitamin D for 4 months. BM-MSCs were isolated and evaluated for P16INK4a, P38 MAPK, and Bmi-1 gene expression, reactive oxygen species (ROS) levels, SA-β-gal activity, and cell cycle profile at the end of both phases. After 26 weeks (first phase), the ROS level, SA-β-gal-positive cells, and cells in the G1 phase were significantly higher in HCD-fed rats than in NCD-fed ones (P < 0.05). HCD prescription did not significantly affect cells in the S and G2 phases (p > 0.05). Compared with the NCD-fed animals, P16INK4a and P38 MAPK gene expression were up-regulated in the HCD-fed animals; also, Bmi-1 gene expression was down-regulated (P < 0.05). BM-MSCs from vitamin D-treated rats (second phase) exhibited reduced mRNA levels of P16INK4a and P38 MAPK genes and increased Bmi-1 mRNA levels (all P < 0.05). Vitamin D prescription also declined the percentage of SA-β-gal-positive cells, ROS levels, and the cells in the G1 phase and increased the cells in the S phase in both NCD and HCD-fed animals (P < 0.05). The reduction of the cells in the G2 phase in rats fed with an NCD plus vitamin D was statistically non-significant (P = 0.128) and significant in HCD plus vitamin D rats (P = 0.002). HCD accelerates BM-MSCs senescence, and vitamin D reduces BM-MSCs senescence biomarkers.
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Affiliation(s)
- Fahimeh Agh
- Saveh University of Medical Sciences, Saveh, Iran
- Student Research Committee, Saveh University of Medical Sciences, Saveh, Iran
| | - Seyed Hadi Mousavi
- Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
| | - Naheed Aryaeian
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.
| | - Fatemehsadat Amiri
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Jalilvand
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Motahareh Hasani
- Department of Nutrition, School of Public Health, Golestan University of Medical Sciences, Gorgan, Iran
| | - Farhad Vahid
- Nutrition and Health Research Group, Department of Precision Health, Luxembourg Institute of Health, Strassen, Luxembourg
| | - Fatemeh Sepahvand
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Imitola J, Hollingsworth EW, Watanabe F, Olah M, Elyaman W, Starossom S, Kivisäkk P, Khoury SJ. Stat1 is an inducible transcriptional repressor of neural stem cells self-renewal program during neuroinflammation. Front Cell Neurosci 2023; 17:1156802. [PMID: 37663126 PMCID: PMC10469489 DOI: 10.3389/fncel.2023.1156802] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 07/20/2023] [Indexed: 09/05/2023] Open
Abstract
A central issue in regenerative medicine is understanding the mechanisms that regulate the self-renewal of endogenous stem cells in response to injury and disease. Interferons increase hematopoietic stem cells during infection by activating STAT1, but the mechanisms by which STAT1 regulates intrinsic programs in neural stem cells (NSCs) during neuroinflammation is less known. Here we explored the role of STAT1 on NSC self-renewal. We show that overexpressing Stat1 in NSCs derived from the subventricular zone (SVZ) decreases NSC self-renewal capacity while Stat1 deletion increases NSC self-renewal, neurogenesis, and oligodendrogenesis in isolated NSCs. Importantly, we find upregulation of STAT1 in NSCs in a mouse model of multiple sclerosis (MS) and an increase in pathological T cells expressing IFN-γ rather than interleukin 17 (IL-17) in the cerebrospinal fluid of affected mice. We find IFN-γ is superior to IL-17 in reducing proliferation and precipitating an abnormal NSC phenotype featuring increased STAT1 phosphorylation and Stat1 and p16ink4a gene expression. Notably, Stat1-/- NSCs were resistant to the effect of IFN-γ. Lastly, we identified a Stat1-dependent gene expression profile associated with an increase in the Sox9 transcription factor, a regulator of self-renewal. Stat1 binds and transcriptionally represses Sox9 in a transcriptional luciferase assay. We conclude that Stat1 serves as an inducible checkpoint for NSC self-renewal that is upregulated during chronic brain inflammation leading to decreased self-renewal. As such, Stat1 may be a potential target to modulate for next generation therapies to prevent progression and loss of repair function in NSCs/neural progenitors in MS.
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Affiliation(s)
- Jaime Imitola
- Laboratory for Neural Stem Cells and Functional Neurogenetics, Division of Multiple Sclerosis and Neuroimmunology, University of Connecticut Health Center, Farmington, CT, United States
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Ethan W. Hollingsworth
- Medical Scientist Training Program, University of California, Irvine, Irvine, CA, United States
| | - Fumihiro Watanabe
- Laboratory for Neural Stem Cells and Functional Neurogenetics, Division of Multiple Sclerosis and Neuroimmunology, University of Connecticut Health Center, Farmington, CT, United States
| | - Marta Olah
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Department of Neurology, Columbia University Medical Center, New York City, NY, United States
| | - Wassim Elyaman
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Department of Neurology, Columbia University Medical Center, New York City, NY, United States
| | - Sarah Starossom
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Pia Kivisäkk
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Alzheimer’s Clinical and Translational Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Samia J. Khoury
- Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Abu Haidar Neuroscience Institute, American University of Beirut Medical Center, Beirut, Lebanon
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17
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Kim JJ, Steinson ER, Lau MS, de Rooij DG, Page DC, Kingston RE. Cell type-specific role of CBX2 and its disordered region in spermatogenesis. Genes Dev 2023; 37:640-660. [PMID: 37553262 PMCID: PMC10499018 DOI: 10.1101/gad.350393.122] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 07/28/2023] [Indexed: 08/10/2023]
Abstract
Polycomb group (PcG) proteins maintain the repressed state of lineage-inappropriate genes and are therefore essential for embryonic development and adult tissue homeostasis. One critical function of PcG complexes is modulating chromatin structure. Canonical Polycomb repressive complex 1 (cPRC1), particularly its component CBX2, can compact chromatin and phase-separate in vitro. These activities are hypothesized to be critical for forming a repressed physical environment in cells. While much has been learned by studying these PcG activities in cell culture models, it is largely unexplored how cPRC1 regulates adult stem cells and their subsequent differentiation in living animals. Here, we show in vivo evidence of a critical nonenzymatic repressive function of cPRC1 component CBX2 in the male germline. CBX2 is up-regulated as spermatogonial stem cells differentiate and is required to repress genes that were active in stem cells. CBX2 forms condensates (similar to previously described Polycomb bodies) that colocalize with target genes bound by CBX2 in differentiating spermatogonia. Single-cell analyses of mosaic Cbx2 mutant testes show that CBX2 is specifically required to produce differentiating A1 spermatogonia. Furthermore, the region of CBX2 responsible for compaction and phase separation is needed for the long-term maintenance of male germ cells in the animal. These results emphasize that the regulation of chromatin structure by CBX2 at a specific stage of spermatogenesis is critical, which distinguishes this from a mechanism that is reliant on histone modification.
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Affiliation(s)
- Jongmin J Kim
- Department of Molecular Biology, MGH Research Institute, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
- Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Emma R Steinson
- Department of Molecular Biology, MGH Research Institute, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
| | - Mei Sheng Lau
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A*STAR), Proteos, Singapore 138673, Republic of Singapore
| | - Dirk G de Rooij
- Reproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, Utrecht 3584 CH, the Netherlands
| | - David C Page
- Whitehead Institute, Cambridge, Massachusetts 02142, USA
- Howard Hughes Medical Institute, Whitehead Institute, Cambridge, Massachusetts 02142, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Robert E Kingston
- Department of Molecular Biology, MGH Research Institute, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
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18
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Ji X, Chen H, Liu B, Zhuang H, Bu S. Chk2 deletion rescues Bmi1 deficiency-induced mandibular osteoporosis by blocking DNA damage response pathway. Am J Transl Res 2023; 15:2220-2232. [PMID: 37056849 PMCID: PMC10086904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 03/15/2023] [Indexed: 04/15/2023]
Abstract
OBJECTIVES Bmi1 deficiency has been proved to be able to cause mandibular osteoporosis through suppressing oxidative stress. However, the role of DNA damage response pathway in this pathogenesis had not been well understood. In this study, we investigate whether mandibular osteoporosis induced by Bmi1 deficiency could be rescued by blocked DNA damage response pathway. METHODS The protein expression levels of antioxidant enzymes and DNA damage and damage response pathway molecules in mandibular tissue were examined using Western blots. Double knockout mice that lacked both Bmi1 and Chk2 were generated and their mandibular phenotypes were compared at 6 weeks old to wild-type, Chk2-/-, and Bmi1-/- mice using radiograph, micro-CT, histopathology, cellular and molecular techniques. RESULTS Bmi1 deficiency induces oxidative stress and DNA damage and activates DNA damage response pathways in mouse mandibles. Chk2 deletion rescued mandibular osteoporosis through promoting formation of osteoblastic bone as well as decreasing osteoclastic bone resorption. Mechanistically, Chk2 deletion suppressed oxidative stress, DNA damage, as well as cell senescence. In addition, it boosted proliferation of bone marrow mesenchymal stem cells (BM-MSCs) that derived from mandible through blocking the DNA damage response pathway. CONCLUSION Abolish the expression of Chk2 could rescue Bmi1 deficiency-related mandibular osteoporosis through promoting BM-MSC proliferation and osteoblastic bone formation, reducing osteoclastic bone resorption, decreasing oxidative stress, inhibiting damage of DNA and associated response pathways, suppressing cell senescence as well as senescence-associated secretory phenotype (SASP). These findings offer a theoretical basis for using Chk2 or p53 inhibitors to prevent and treat age-related mandibular osteoporosis.
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Affiliation(s)
- Xiaolei Ji
- Department of Stomatology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
- Department of Stomatology, The Affiliated BenQ Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Haiyun Chen
- Department of Plastic Surgery, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Boyang Liu
- The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Hai Zhuang
- Department of Stomatology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
| | - Shoushan Bu
- Department of Stomatology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing, Jiangsu, China
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19
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Miwata T, Suga H, Kawaguchi Y, Sakakibara M, Kano M, Taga S, Soen M, Ozaki H, Asano T, Sasaki H, Miyata T, Yasuda Y, Kobayashi T, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Iwama S, Arima H. Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells. Stem Cell Reports 2023; 18:869-883. [PMID: 36963388 PMCID: PMC10147555 DOI: 10.1016/j.stemcr.2023.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 03/26/2023] Open
Abstract
When damaged, restoring the function of the hypothalamus is currently impossible. It is unclear whether neural stem cells exist in the hypothalamus. Studies have reported that adult rodent tanycytes around the third ventricle function as hypothalamic neural stem cell-like cells. However, it is currently impossible to collect periventricular cells from humans. We attempted to generate hypothalamic neural stem cell-like cells from human embryonic stem cells (ESCs). We focused on retina and anterior neural fold homeobox (RAX) because its expression is gradually restricted to tanycytes during the late embryonic stage. We differentiated RAX::VENUS knockin human ESCs (hESCs) into hypothalamic organoids and sorted RAX+ cells from mature organoids. The isolated RAX+ cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX+ hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells.
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Affiliation(s)
- Tsutomu Miwata
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hidetaka Suga
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Yohei Kawaguchi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mayu Sakakibara
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mayuko Kano
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Shiori Taga
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan; Regenerative & Cellular Medicine Kobe Center, Sumitomo Pharma Co., Ltd., Kobe, Japan
| | - Mika Soen
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hajime Ozaki
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoyoshi Asano
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroo Sasaki
- Department of Neurosurgery, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Takashi Miyata
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshinori Yasuda
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoko Kobayashi
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mariko Sugiyama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Onoue
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Takagi
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Daisuke Hagiwara
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shintaro Iwama
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroshi Arima
- Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine, Nagoya, Japan
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20
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Plakkot B, Di Agostino A, Subramanian M. Implications of Hypothalamic Neural Stem Cells on Aging and Obesity-Associated Cardiovascular Diseases. Cells 2023; 12:cells12050769. [PMID: 36899905 PMCID: PMC10000584 DOI: 10.3390/cells12050769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/14/2023] [Accepted: 02/25/2023] [Indexed: 03/06/2023] Open
Abstract
The hypothalamus, one of the major regulatory centers in the brain, controls various homeostatic processes, and hypothalamic neural stem cells (htNSCs) have been observed to interfere with hypothalamic mechanisms regulating aging. NSCs play a pivotal role in the repair and regeneration of brain cells during neurodegenerative diseases and rejuvenate the brain tissue microenvironment. The hypothalamus was recently observed to be involved in neuroinflammation mediated by cellular senescence. Cellular senescence, or systemic aging, is characterized by a progressive irreversible state of cell cycle arrest that causes physiological dysregulation in the body and it is evident in many neuroinflammatory conditions, including obesity. Upregulation of neuroinflammation and oxidative stress due to senescence has the potential to alter the functioning of NSCs. Various studies have substantiated the chances of obesity inducing accelerated aging. Therefore, it is essential to explore the potential effects of htNSC dysregulation in obesity and underlying pathways to develop strategies to address obesity-induced comorbidities associated with brain aging. This review will summarize hypothalamic neurogenesis associated with obesity and prospective NSC-based regenerative therapy for the treatment of obesity-induced cardiovascular conditions.
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21
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Miao D, Goltzman D. Mechanisms of action of vitamin D in delaying aging and preventing disease by inhibiting oxidative stress. VITAMINS AND HORMONES 2022; 121:293-318. [PMID: 36707138 DOI: 10.1016/bs.vh.2022.09.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Although several recent studies have shown that vitamin D supplementation beneficially decreases oxidative stress parameters, there is no consensus on this subject in humans. Thus the role of vitamin D supplementation has recently become a controversial topic because large intervention studies in humans have not shown significant benefits. These studies have indicated that supplementation with precursor forms of active vitamin D has no effect on all-cause mortality, cannot reduce the fracture risk of the elderly, cannot reduce the incidence of cancer or cardiovascular disease in the elderly, and cannot significantly reduce the incidence risk of diabetes in the elderly. However, a link between several age-related diseases and enhanced oxidative stress has been found in mice with insufficient or deficient 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of vitamin D, which indicates that reduced active vitamin D accelerates aging and age-related diseases by increasing oxidative stress. Furthermore, supplementation of exogenous 1,25(OH)2D3, or antioxidants, could dramatically postpone aging, prevent osteoporosis and spontaneous tumor development induced by 1,25(OH)2D insufficiency or deficiency, by inhibiting oxidative stress. Mechanistically, the antioxidative effects of 1,25(OH)2D3 are carried out via the vitamin D receptor (VDR) by activation of the Nrf2 oxidative stress response pathway though transcriptional or posttranscriptional activation of Nrf2 or transcriptional upregulation of Sirt1 and Bmi1 expression. Whether discrepancies between studies in humans and in mice reflect the different forms of vitamin D examined remains to be determined.
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Affiliation(s)
| | - David Goltzman
- McGill University Health Centre and McGill University, Montreal, QC, Canada.
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22
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Fessé P, Nyman J, Hermansson I, Book ML, Ahlgren J, Turesson I. Human cutaneous interfollicular melanocytes differentiate temporarily under genotoxic stress. iScience 2022; 25:105238. [PMID: 36274944 PMCID: PMC9579029 DOI: 10.1016/j.isci.2022.105238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 08/30/2022] [Accepted: 09/26/2022] [Indexed: 12/05/2022] Open
Abstract
DNA-damage response of cutaneous interfollicular melanocytes to fractionated radiotherapy was investigated by immunostaining of tissue sections from punch biopsies collected before, during, and after the treatment of patients for breast cancer. Our clinical assay with sterilized hair follicles, excluded the migration of immature melanocytes from the bulge, and highlighted interfollicular melanocytes as an autonomous self-renewing population. About thirty percent are immature. Surrounding keratinocytes induced and maintained melanocyte differentiation as long as treatment was ongoing. Concomitant with differentiation, melanocytes were protected from apoptosis by transient upregulation of Bcl-2 and CXCR2. CXCR2 upregulation also indicated the instigation of premature senescence, preventing proliferation. The stem cell factor BMI1 was constitutively expressed exclusively in interfollicular melanocytes and further upregulated upon irradiation. BMI1 prevents apoptosis, terminal differentiation, and premature senescence, allowing dedifferentiation post-treatment, by suppressing the p53/p21-and p16-mediated response and upregulating CXCR2 to genotoxic damage. The pre-treatment immature subset of interfollicular melanocytes was restored after the exposure ended.
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Affiliation(s)
- Per Fessé
- Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden
- Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden
| | - Jan Nyman
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ingegerd Hermansson
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Maj-Lis Book
- Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden
| | - Johan Ahlgren
- Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro Sweden
| | - Ingela Turesson
- Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala University, Uppsala, Sweden
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23
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Mori T. Involvement of the p53-p16/RB pathway control mechanism in early-stage carcinogenesis in head and neck squamous cell carcinoma. Pathol Int 2022; 72:577-588. [PMID: 36218243 DOI: 10.1111/pin.13279] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/16/2022] [Indexed: 11/28/2022]
Abstract
Head and neck squamous cell carcinoma develops through a heterogeneous process involving human papillomavirus infection, smoking, and alcohol consumption. A comprehensive genomic analysis of head and neck squamous cell carcinomas to date has identified a few single driver gene mutations, the most frequent of which involve TP53 and CDKN2A/p16. To investigate the involvement of the tumorigenesis mechanism in early-stage carcinogenesis, HPV-derived genomes E6 and E7, which are carcinogens, and stem/progenitor-associated, polycomb (PcG) genes Bmi1 and TERT were induced into human stromal cells and immortalized as the head and neck squamous cell carcinoma model. We found that Bmi1 suppressed both the p16INK4a and p16/Rb-p53 pathway cross-talks. The E7 group showed that endogenous p53 is highly expressed and eludes chromosome number aberration, even on long-term observation. Bmi1 was predominantly expressed in early head and neck squamous cell carcinoma, and PcG was essential in early cancer development. Additionally, TP53 whole exon analysis revealed categories useful for estimating malignant potential, such as poor prognosis and high recurrence at the transection site. Therefore, understanding the p53-p16/RB pathway in head and neck squamous cell carcinoma is an essential factor to elucidate the early carcinogenesis of head and neck squamous cell carcinoma.
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Affiliation(s)
- Taisuke Mori
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
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24
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Altamirano-Samaniego F, Enciso-Benavides J, Rojas N, Iglesias-Pedraz JM, Enciso N, Fossatti M, Enciso J. First report of canine morbillivirus infection of adipose tissue-derived stem cells from dogs with distemper. Vet World 2022; 15:1835-1842. [PMID: 36185532 PMCID: PMC9394121 DOI: 10.14202/vetworld.2022.1835-1842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/15/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aim: Ribonucleic acid viruses remain latent in different cell types, including mesenchymal stem cells; however, the distemper virus remains undetected in these cells. This study aimed to determine whether adipose stem cells (ASCs) from dogs with distemper disease are infected with the canine morbillivirus (CM). Materials and Methods: Twelve dogs with the neurological phase of the disease and who were positive for CM by reverse transcription polymerase chain reaction (RT-PCR), were studied. ASCs from adipose tissue of the lesser omentum of these infected dogs were isolated and characterized. Direct fluorescence was used to detect the viral antigen in cell cultures. Flow cytometry and RT-PCR identified detectable quantities of the virus in two cultures, while electron microscopy confirmed the CM particles within ASCs. Results: This study revealed that ASCs of the omentum of dogs with distemper disease can be infected with CM, indicating their possible involvement in this virus latency and persistence. This suggests that its detection should be considered within the quality control process of stem cells intended for regenerative medicine. Conclusion: To the best of our knowledge, this is the first study that demonstrates that omentum ASCs from dogs with distemper disease can be infected with CM and may be involved in viral latency or persistence. Our study also suggests that the detection of CM should be considered within the quality control process of stem cells intended for regenerative medicine.
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Affiliation(s)
| | | | - Nancy Rojas
- Laboratorio de Microscopía Electrónica, Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú
| | | | - Nathaly Enciso
- Grupo de Medicina Regenerativa, Universidad Científica del Sur, Lima, Perú
| | - Matia Fossatti
- Laboratorio de Bioquímica y Genética Molecular, Universidad Científica del Sur, Lima, Perú
| | - Javier Enciso
- Grupo de Medicina Regenerativa, Universidad Científica del Sur, Lima, Perú
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25
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Al-Nadaf S, Peacott-Ricardos KS, Dickinson PJ, Rebhun RB, York D. Expression and therapeutic targeting of BMI1 in canine gliomas. Vet Comp Oncol 2022; 20:871-880. [PMID: 35833892 DOI: 10.1111/vco.12852] [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: 03/01/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 12/01/2022]
Abstract
The BMI1 proto-oncogene, polycomb ring finger protein (BMI1) is a key component of the epigenetic polycomb repressor complex 1, and has been associated with aggressive behavior and chemotherapeutic resistance in various malignances including human gliomas. Similar to humans, spontaneous canine gliomas carry a poor prognosis with limited therapeutic options. BMI1 expression and the effects of BMI1 inhibition have not been evaluated in canine gliomas. Here, we demonstrate that BMI1 is highly expressed in canine gliomas. Although increased BMI1 protein expression correlated with higher glioma grade in western blot assays, this correlation was not observed in a larger sample set using immunohistochemical analysis. The BMI1 inhibitor, PTC-209, suppressed BMI1 expression in established canine glioma cell lines and resulted in antiproliferative activity when used alone and in combination with chemotherapeutic agents. PTC-209 targeting of BMI1 activated the RB pathway through downregulation of total and phosphorylated RB, independent of INK4A/ARF signaling, likely through BMI1-inhibition mediated upregulation of p21. These data support the rationale for targeting of BMI1 signaling and the use of canine glioma as a translational therapeutic model for human disease. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Sami Al-Nadaf
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Kyle S Peacott-Ricardos
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Peter J Dickinson
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Robert B Rebhun
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - Daniel York
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
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26
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Hisamori S, Mukohyama J, Koul S, Hayashi T, Rothenberg ME, Maeda M, Isobe T, Valencia Salazar LE, Qian X, Johnston DM, Qian D, Lao K, Asai N, Kakeji Y, Gennarino VA, Sahoo D, Dalerba P, Shimono Y. Upregulation of BMI1-suppressor miRNAs (miR-200c, miR-203) during terminal differentiation of colon epithelial cells. J Gastroenterol 2022; 57:407-422. [PMID: 35244768 PMCID: PMC10091510 DOI: 10.1007/s00535-022-01865-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 02/10/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) are key regulators of stem cell functions, including self-renewal and differentiation. In this study, we aimed to identify miRNAs that are upregulated during terminal differentiation in the human colon epithelium, and elucidate their role in the mechanistic control of stem cell properties. METHODS "Bottom-of-the-crypt" (EPCAM+/CD44+/CD66alow) and "top-of-the-crypt" (EPCAM+/CD44neg/CD66ahigh) epithelial cells from 8 primary colon specimens (6 human, 2 murine) were purified by flow cytometry and analyzed for differential expression of 335 miRNAs. The miRNAs displaying the highest upregulation in "top-of-the-crypt" (terminally differentiated) epithelial cells were tested for positive correlation and association with survival outcomes in a colon cancer RNA-seq database (n = 439 patients). The two miRNAs with the strongest "top-of-the-crypt" expression profile were evaluated for capacity to downregulate self-renewal effectors and inhibit in vitro proliferation of colon cancer cells, in vitro organoid formation by normal colon epithelial cells and in vivo tumorigenicity by patient-derived xenografts (PDX). RESULTS Six miRNAs (miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-345) were upregulated in "top-of-the-crypt" cells and positively correlated in expression among colon carcinomas. Overexpression of the three miRNAs with the highest inter-correlation coefficients (miR-200a, miR-200b, miR-200c) associated with improved survival. The top two over-expressed miRNAs (miR-200c, miR-203) cooperated synergistically in suppressing expression of BMI1, a key regulator of self-renewal in stem cell populations, and in inhibiting proliferation, organoid-formation and tumorigenicity of colon epithelial cells. CONCLUSION In the colon epithelium, terminal differentiation associates with the coordinated upregulation of miR-200c and miR-203, which cooperate to suppress BMI1 and disable the expansion capacity of epithelial cells.
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Affiliation(s)
- Shigeo Hisamori
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA.,Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Junko Mukohyama
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA.,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA.,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA.,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA.,Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, 6500017, Japan.,Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, International University of Health and Welfare (IUHW), Tokyo, 1088329, Japan
| | - Sanjay Koul
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA.,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA.,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA.,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA.,Department of Biological Sciences and Geology, Queensboro Community College (QCC), City University of New York (CUNY), New York, NY, 11364, USA
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Michael Evan Rothenberg
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Masao Maeda
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan.,Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Taichi Isobe
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Luis Enrique Valencia Salazar
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA.,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA.,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA.,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA
| | - Xin Qian
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Darius Michael Johnston
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA.,Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, 94305, USA
| | - Dalong Qian
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA
| | - Kaiqin Lao
- Genetic Sciences Division (GSD), Thermo Fisher Scientific, South San Francisco, CA, 94080, USA
| | - Naoya Asai
- Department of Pathology, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan
| | - Yoshihiro Kakeji
- Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo, 6500017, Japan
| | - Vincenzo Alessandro Gennarino
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, 10032, USA.,Department of Neurology, Columbia University, New York, NY, 10032, USA.,Department of Pediatrics, Columbia University, New York, NY, 10032, USA.,Initiative for Columbia Ataxia and Tremor (ICAT), Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Debashis Sahoo
- Department of Computer Science and Engineering and Department of Pediatrics, University of California San Diego (UCSD), San Diego, CA, 92123, USA
| | - Piero Dalerba
- Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA. .,Department of Medicine (Division of Digestive and Liver Diseases), Columbia University, New York, NY, 10032, USA. .,Herbert Irving Comprehensive Cancer Center (HICCC), Columbia University, New York, NY, 10032, USA. .,Digestive and Liver Disease Research Center (DLDRC), Columbia University, New York, NY, 10032, USA. .,Columbia Stem Cell Initiative (CSCI), Columbia University, New York, NY, 10032, USA.
| | - Yohei Shimono
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, 94305, USA. .,Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Aichi, 4701192, Japan.
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27
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Corales LG, Inada H, Hiraoka K, Araki S, Yamanaka S, Kikkawa T, Osumi N. The subcommissural organ maintains features of neuroepithelial cells in the adult mouse. J Anat 2022; 241:820-830. [PMID: 35638289 PMCID: PMC9358730 DOI: 10.1111/joa.13709] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 04/28/2022] [Accepted: 05/18/2022] [Indexed: 11/27/2022] Open
Abstract
The subcommissural organ (SCO) is a part of the circumventricular organs located in the dorsocaudal region of the third ventricle at the entrance of the aqueduct of Sylvius. The SCO comprises epithelial cells and produces high molecular weight glycoproteins, which are secreted into the third ventricle and become part of Reissner's fibre in the cerebrospinal fluid. Abnormal development of the SCO has been linked with congenital hydrocephalus, a condition characterized by excessive accumulation of cerebrospinal fluid in the brain. In the present study, we characterized the SCO cells in the adult mouse brain to gain insights into the possible role of this brain region. Immunohistochemical analyses revealed that expression of Pax6, a transcription factor essential for SCO differentiation during embryogenesis, is maintained in the SCO at postnatal stages from P0 to P84. SCO cells in the adult brain expressed known neural stem/progenitor cell (NSPC) markers, Sox2 and vimentin. The adult SCO cells also expressed proliferating marker PCNA, although expression of another proliferation marker Ki67, indicating a G2/M phase, was not detected. The SCO cells did not incorporate BrdU, a marker for DNA synthesis in the S phase. Therefore, the SCO cells have a potential for proliferation but are quiescent for cell division in the adult. The SCO cells also expressed GFAP, a marker for astrocytes or NSPCs, but not NeuN (for neurons). A few cells positive for Iba1 (microglia), Olig2 (for oligodendrocytes) and PDGFRα (oligodendrocyte progenitors) existed within or on the periphery of the SCO. These findings revealed that the SCO cells have a unique feature as secretory yet immature neuroepithelial cells in the adult mouse brain.
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Affiliation(s)
- Laarni Grace Corales
- Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hitoshi Inada
- Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan.,Laboratory of Health and Sports Sciences, Division of Biomedical Engineering for Health and Welfare, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan
| | - Kotaro Hiraoka
- Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan
| | - Shun Araki
- Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinya Yamanaka
- Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takako Kikkawa
- Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Noriko Osumi
- Department of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan
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28
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Subventricular zone adult mouse neural stem cells require insulin receptor for self-renewal. Stem Cell Reports 2022; 17:1411-1427. [PMID: 35523180 PMCID: PMC9213826 DOI: 10.1016/j.stemcr.2022.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 11/25/2022] Open
Abstract
The insulin receptor (INSR) is an evolutionarily conserved signaling protein that regulates development and cellular metabolism. INSR signaling promotes neurogenesis in Drosophila; however, a specific role for the INSR in maintaining adult neural stem cells (NSCs) in mammals has not been investigated. We show that conditionally deleting the Insr gene in adult mouse NSCs reduces subventricular zone NSCs by ∼70% accompanied by a corresponding increase in progenitors. Insr deletion also produced hyposmia caused by aberrant olfactory bulb neurogenesis. Interestingly, hippocampal neurogenesis and hippocampal-dependent behaviors were unperturbed. Highly aggressive proneural and mesenchymal glioblastomas had high INSR/insulin-like growth factor (IGF) pathway gene expression, and isolated glioma stem cells had an aberrantly high ratio of INSR:IGF type 1 receptor. Moreover, INSR knockdown inhibited GBM tumorsphere growth. Altogether, these data demonstrate that the INSR is essential for a subset of normal NSCs, as well as for brain tumor stem cell self-renewal.
Insulin receptor (INSR) is essential for adult SVZ neural stem cell self-renewal INSR deletion causes hyposmia with increased olfactory bulb neurogenesis Hippocampal stem cells (and associated behaviors) do not require INSR Glioblastomas overexpress INSR pathway components required for tumorsphere growth
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29
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Huang JL, Chen SY, Lin CS. Targeting Cancer Stem Cells through Epigenetic Modulation of Interferon Response. J Pers Med 2022; 12:jpm12040556. [PMID: 35455671 PMCID: PMC9027081 DOI: 10.3390/jpm12040556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/26/2022] [Accepted: 03/30/2022] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cancer cells and are thought to play a critical role in the initiation and maintenance of tumor mass. CSCs exhibit similar hallmarks to normal stem cells, such as self-renewal, differentiation, and homeostasis. In addition, CSCs are equipped with several features so as to evade anticancer mechanisms. Therefore, it is hard to eliminate CSCs by conventional anticancer therapeutics that are effective at clearing bulk cancer cells. Interferons are innate cytokines and are the key players in immune surveillance to respond to invaded pathogens. Interferons are also crucial for adaptive immunity for the killing of specific aliens including cancer cells. However, CSCs usually evolve to escape from interferon-mediated immune surveillance and to shape the niche as a “cold” tumor microenvironment (TME). These CSC characteristics are related to their unique epigenetic regulations that are different from those of normal and bulk cancer cells. In this review, we introduce the roles of epigenetic modifiers, focusing on LSD1, BMI1, G9a, and SETDB1, in contributing to CSC characteristics and discussing the interplay between CSCs and interferon response. We also discuss the emerging strategy for eradicating CSCs by targeting these epigenetic modifiers, which can elevate cytosolic nuclei acids, trigger interferon response, and reshape a “hot” TME for improving cancer immunotherapy. The key epigenetic and immune genes involved in this crosstalk can be used as biomarkers for precision oncology.
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Affiliation(s)
- Jau-Ling Huang
- Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan 711, Taiwan;
| | - Si-Yun Chen
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Chang-Shen Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
- Correspondence:
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Yin Y, Wang Q, Xie C, Chen H, Jin J, Miao D. Amniotic membrane mesenchymal stem cells-based therapy improves Bmi-1-deficient mandible osteoporosis through stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. J Tissue Eng Regen Med 2022; 16:538-549. [PMID: 35319819 DOI: 10.1002/term.3300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 03/13/2022] [Accepted: 03/14/2022] [Indexed: 11/10/2022]
Abstract
Mandible osteoporosis with age is characterized by greater fragility and accompanied with abnormal oral function. Mesenchymal stem cell transplantation can ameliorate osteoporosis. Bmi-1 is a transcriptional repressor which is an important regulator of cell cycle, stem cells self-renewal, and cell senescence. Here, we use a new kind of membrane mesenchymal stem cells (MSCs), amniotic membrane mesenchymal stem cells (AMSCs), to explore therapeutic effects on Bmi-1-deficient caused mandible osteoporosis. Phenotypes of mandibles from 5-week-old Bmi-1-deficient mice with AMSCs-based therapy were compared with age-matched Bmi-1-deficient mandibles without AMSCs-based therapy and wild-type mice. Bmi-1-deficient mice without AMSCs-based therapy displayed mandible osteoporosis accompanied with the rising senescence-associated molecules and imbalance redox homeostasis. Results showed that the alveolar bone volume, cortical thickness, type I collagen and osteocalcin immunopositive areas, mRNA expression levels of alkaline phosphatase, superoxide dismutase, gluathione reductase, and protein expression level of Runx2 were all reduced significantly in Bmi-1-/- mandibles. Protein levels of PPARγ, p16, p21, p53, and redox gene levels of Bnip3l, Cdo1, Duox1, and Duox2 were up-regulated in mandibles from vehicle-transplanted Bmi-1-/- mice. Also, osteoclasts were activated in Bmi-1-/- alveolar bone. Transplanted AMSCs migrated into mandibles and improved all the parameters in Bmi-1-/- mandibles with AMSCs-based therapy. These findings indicate that AMSCs-based therapy could rescue mandible osteoporosis induced by Bmi-1 deficiency through stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. Our findings implied that AMSCs-based therapy had preventative and therapeutic potential for mandible osteoporosis.
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Affiliation(s)
- Ying Yin
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Qiujiao Wang
- Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China.,Department of Stomatology, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin, China
| | - Chunfeng Xie
- Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Haiyun Chen
- Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Jianliang Jin
- Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Dengshun Miao
- Department of Anatomy, Histology and Embryology, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China.,Department of Plastic Surgery, The Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
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31
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Reinitz F, Chen EY, Nicolis di Robilant B, Chuluun B, Antony J, Jones RC, Gubbi N, Lee K, Ho WHD, Kolluru SS, Qian D, Adorno M, Piltti K, Anderson A, Monje M, Heller HC, Quake SR, Clarke MF. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. eLife 2022; 11:66037. [PMID: 35311644 PMCID: PMC9122497 DOI: 10.7554/elife.66037] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.
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Affiliation(s)
- Felicia Reinitz
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Elizabeth Y Chen
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Benedetta Nicolis di Robilant
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | | | - Jane Antony
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Robert C Jones
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Neha Gubbi
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Karen Lee
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - William Hai Dang Ho
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Sai Saroja Kolluru
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Dalong Qian
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Maddalena Adorno
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Katja Piltti
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Aileen Anderson
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Michelle Monje
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - H Craig Heller
- Department of Biology, Stanford University, Stanford, United States
| | - Stephen R Quake
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Michael F Clarke
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
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Abstract
Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.
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Repression of the Antioxidant Pyrroloquinoline Quinone in Skin Aging Induced by Bmi-1 Deficiency. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1732438. [PMID: 35187158 PMCID: PMC8849985 DOI: 10.1155/2022/1732438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/11/2021] [Accepted: 01/04/2022] [Indexed: 11/18/2022]
Abstract
It is uncertain whether Bmi-1 deficiency could lead to skin aging by redox imbalance and DNA damage. In this study, we first confirmed that Bmi-1 had a relatively high expression level in the skin and Bmi-1 expression levels gradually decreased with age. Then, we studied the role of Bmi-1 in the skin using a Bmi-1−/− mouse model. Bmi-1−/− mice were supplemented with or without pyrroloquinoline quinone (PQQ) for 5 weeks, and their skin phenotypes were compared with Bmi1−/− and wild-type littermates. Our results showed that Bmi-1−/− mice displayed decreased vertical thickness of skin, sparse hair follicles, and thinner and more irregular collagen bundles. Mechanistically, increased oxidative stress with reducing antioxidant capacity and induced DNA damage occurred in Bmi-1−/− mice. Subsequently, this would lead to reduced cell proliferation, increased cell senescence and matrix metalloproteinases (MMPs), and the degradation of fibroblast function and further reduce collagen synthesis. All pathological alterations in the skin of Bmi-1−/− mice were alleviated by PQQ supplementation. These results demonstrated that Bmi-1 might play a key role in protection from skin aging by maintaining redox balance and inhibiting DNA damage response and will be a novel and potential target for preventing skin aging.
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Azzoni V, Wicinski J, Macario M, Castagné M, Finetti P, Ambrosova K, Rouault CD, Sergé A, Farina A, Agavnian E, Coslet S, Josselin E, Guille A, Adelaide J, Zacharioudakis E, Castellano R, Bertucci F, Birnbaum D, Rodriguez R, Charafe-Jauffret E, Ginestier C. BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells. Cell Death Dis 2022; 13:96. [PMID: 35110528 PMCID: PMC8811067 DOI: 10.1038/s41419-022-04538-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/21/2021] [Accepted: 01/17/2022] [Indexed: 12/22/2022]
Abstract
Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells’ (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.
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Affiliation(s)
- Violette Azzoni
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Julien Wicinski
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Manon Macario
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Martin Castagné
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Pascal Finetti
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Katerina Ambrosova
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Célia D Rouault
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Arnaud Sergé
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, leuko/stromal interactions in normal and pathological hematopoiesis Lab, Marseille, France
| | - Anne Farina
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Experimental Pathology Platform, Marseille, France
| | - Emilie Agavnian
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Experimental Pathology Platform, Marseille, France
| | - Sergiu Coslet
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Experimental Pathology Platform, Marseille, France
| | - Emmanuelle Josselin
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, TrGET Plateform, Marseille, France
| | - Arnaud Guille
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - José Adelaide
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Emmanouil Zacharioudakis
- Institut Curie, CNRS, INSERM, PSL Research University, Chemical Cell Biology Group, Paris, France
| | - Rémy Castellano
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, TrGET Plateform, Marseille, France
| | - Francois Bertucci
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Daniel Birnbaum
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Predictive Oncology, "Equipe labellisée Ligue Contre le Cancer", Marseille, France
| | - Raphael Rodriguez
- Institut Curie, CNRS, INSERM, PSL Research University, Chemical Cell Biology Group, Paris, France
| | - Emmanuelle Charafe-Jauffret
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France.
| | - Christophe Ginestier
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, "Equipe labellisée Ligue Contre le Cancer", Marseille, France.
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Hidalgo I, Wahlestedt M, Yuan O, Zhang Q, Bryder D, Pronk CJ. Bmi1 induction protects hematopoietic stem cells against pronounced long-term hematopoietic stress. Exp Hematol 2022; 109:35-44. [DOI: 10.1016/j.exphem.2022.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 11/04/2022]
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Sawai A, Pfennig S, Bulajić M, Miller A, Khodadadi-Jamayran A, Mazzoni EO, Dasen JS. PRC1 sustains the integrity of neural fate in the absence of PRC2 function. eLife 2022; 11:e72769. [PMID: 34994686 PMCID: PMC8765755 DOI: 10.7554/elife.72769] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 01/06/2022] [Indexed: 12/13/2022] Open
Abstract
Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We found that PRC1 is essential for the specification of segmentally restricted spinal motor neuron (MN) subtypes, while PRC2 activity is dispensable to maintain MN positional identities during terminal differentiation. Mutation of the core PRC1 component Ring1 in mice leads to increased chromatin accessibility and ectopic expression of a broad variety of fates determinants, including Hox transcription factors, while neuronal class-specific features are maintained. Loss of MN subtype identities in Ring1 mutants is due to the suppression of Hox-dependent specification programs by derepressed Hox13 paralogs (Hoxa13, Hoxb13, Hoxc13, Hoxd13). These results indicate that PRC1 can function in the absence of de novo PRC2-dependent histone methylation to maintain chromatin topology and postmitotic neuronal fate.
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Affiliation(s)
- Ayana Sawai
- Neuroscience Institute, Department of Neuroscience and Physiology, NYU School of MedicineNew YorkUnited States
| | - Sarah Pfennig
- Neuroscience Institute, Department of Neuroscience and Physiology, NYU School of MedicineNew YorkUnited States
| | - Milica Bulajić
- Department of Biology, New York UniversityNew YorkUnited States
| | - Alexander Miller
- Neuroscience Institute, Department of Neuroscience and Physiology, NYU School of MedicineNew YorkUnited States
| | - Alireza Khodadadi-Jamayran
- Applied Bioinformatics Laboratories, Office of Science and Research, NYU School of MedcineNew YorkUnited States
| | | | - Jeremy S Dasen
- Neuroscience Institute, Department of Neuroscience and Physiology, NYU School of MedicineNew YorkUnited States
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Li Q, Chen J, Liang F, Zhang J, Qu W, Huang X, Cheng X, Zhao X, Yang Z, Xu S, Li X. RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern. Stem Cell Reports 2021; 16:2988-3004. [PMID: 34798064 PMCID: PMC8693662 DOI: 10.1016/j.stemcr.2021.10.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 11/26/2022] Open
Abstract
RYBP (Ring1 and YY1 binding protein), an essential component of the Polycomb repressive complex 1 (PRC1), plays pivotal roles in development and diseases. However, the roles of Rybp in neuronal development remains completely unknown. In the present study, we have shown that the depletion of Rybp inhibits proliferation and promotes neuronal differentiation of embryonic neural progenitor cells (eNPCs). In addition, Rybp deficiency impairs the morphological development of neurons. Mechanistically, Rybp deficiency does not affect the global level of ubiquitination of H2A, but it inhibits Notch signaling pathway in eNPCs. The direct interaction between RYBP and CIR1 facilitates the binding of RBPJ to Notch intracellular domain (NICD) and consequently activated Notch signaling. Rybp loss promotes CIR1 competing with RBPJ to bind with NICD, and inhibits Notch signaling. Furthermore, ectopic Hes5, Notch signaling downstream target, rescues Rybp-deficiency-induced deficits. Collectively, our findings show that RYBP regulates embryonic neurogenesis and neuronal development through modulating Notch signaling in a PRC1-independent manner.
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Affiliation(s)
- Qian Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Junchen Chen
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Feng Liang
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310002, China
| | - Jinyu Zhang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Wenzheng Qu
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xiaoli Huang
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xuejun Cheng
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Xingsen Zhao
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China
| | - Zhanjun Yang
- Department of Human Anatomy, Baotou Medical College, Baotou, 014040, China
| | - Shunliang Xu
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
| | - Xuekun Li
- The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China; The Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310029, China; National Clinical Research Center for Child Health, Hangzhou 310052, China; Zhejiang University Cancer Center, Zhejiang University, Hangzhou 310029, China.
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Cao Q, Wang T, Xiao M, Bai L. Increased endogenous reactive oxygen species normalizes proliferation defects of Bmi1 heterozygous knockout neural stem cells. Neuroreport 2021; 32:1388-1394. [PMID: 34718251 DOI: 10.1097/wnr.0000000000001740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES The Bmi1gene, one of transcriptional suppressor genes in multi-comb family, maintains proliferation of neural stem cells (NSCs) and redox homeostasis. However, heterozygous deletion of the Bmi1 gene (Bmi1+/-) does not reduce the proliferative ability of NSCs. The aim of the present study was to reveal the underlying mechanism of this phenotype. METHODS NSCs derived from the cortex of newborn Bmi1+/- and wild-type (WT) mice were treated with different concentrations of hydrogen peroxide (H2O2) and antioxidant N-acetyl-L-cysteine (NAC) for 24 h followed by analyses of NSC proliferation and oxidative stress-related indexes. RESULTS The levels of reactive oxygen species (ROS) of Bmi1+/--NSCs were slightly higher than that of WT-NSCs at baseline. H2O2 increased ROS and NAC reduced ROS in a concentration-dependent pattern, but the change was significantly greater in Bmi1+/--NSCs than WT-NSCs. The proliferation and self-renewal ability of Bmi1+/--NSCs and WT-NSCs were comparable in a basic state. After 1 μM H2O2 treatment, Brdu incorporation ratio, cell viability, total antioxidant capacity (T-AOC) and total superoxide dismutase activity were increased slightly in WT-NSCs, but decreased in Bmi1+/--NSCs. H2O2 at 10 μM decreased proliferation and self-renewal ability of both genotype NSCs, with greater effect in Bmi1+/-. After treatment with 1 mM NAC, the number and diameter of neurospheres, Brdu incorporation rate, cell viability, T-AOC and total superoxide dismutase activity of Bmi1+/--NSCs were lower than those of WT-NSCs. CONCLUSION These results suggest that Bmi1+/--NSCs exhibit normal proliferation and self-renewal due to a slight increase in ROS, but are more vulnerable to changes in redox status.
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Affiliation(s)
- Qiuchen Cao
- Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China
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39
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Herzog AE, Warner KA, Zhang Z, Bellile E, Bhagat MA, Castilho RM, Wolf GT, Polverini PJ, Pearson AT, Nör JE. The IL-6R and Bmi-1 axis controls self-renewal and chemoresistance of head and neck cancer stem cells. Cell Death Dis 2021; 12:988. [PMID: 34689150 PMCID: PMC8542035 DOI: 10.1038/s41419-021-04268-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 09/28/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022]
Abstract
Despite major progress in elucidating the pathobiology of head and neck squamous cell carcinoma (HNSCC), the high frequency of disease relapse correlates with unacceptably deficient patient survival. We previously showed that cancer stem-like cells (CSCs) drive tumorigenesis and progression of HNSCC. Although CSCs constitute only 2–5% of total tumor cells, CSCs contribute to tumor progression by virtue of their high tumorigenic potential and their resistance to chemo-, radio-, and immunotherapy. Not only are CSCs resistant to therapy, but cytotoxic agents actually enhance cancer stemness by activating transcription of pluripotency factors and by inducing expression of Bmi-1, a master regulator of stem cell self-renewal. We hypothesized therapeutic inhibition of interleukin-6 receptor (IL-6R) suppresses Bmi-1 to overcome intrinsic chemoresistance of CSCs. We observed that high Bmi-1 expression correlates with decreased (p = 0.04) recurrence-free survival time in HNSCC patients (n = 216). Blockade of IL-6R by lentiviral knockdown or pharmacologic inhibition with a humanized monoclonal antibody (Tocilizumab) is sufficient to inhibit Bmi-1 expression, secondary sphere formation, and to decrease the CSC fraction even in Cisplatin-resistant HNSCC cells. IL-6R inhibition with Tocilizumab abrogates Cisplatin-mediated increase in CSC fraction and induction of Bmi-1 in patient-derived xenograft (PDX) models of HNSCC. Notably, Tocilizumab inhibits Bmi-1 and suppresses growth of xenograft tumors generated with Cisplatin-resistant HNSCC cells. Altogether, these studies demonstrate that therapeutic blockade of IL-6R suppresses Bmi-1 function and inhibits cancer stemness. These results suggest therapeutic inhibition of IL-6R might be a viable strategy to overcome the CSC-mediated chemoresistance typically observed in HNSCC patients.
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Affiliation(s)
- Alexandra E Herzog
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Kristy A Warner
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Zhaocheng Zhang
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Emily Bellile
- Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Meera A Bhagat
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Rogerio M Castilho
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
| | - Gregory T Wolf
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Peter J Polverini
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.,Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.,Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
| | - Alexander T Pearson
- Department of Hematology/Oncology, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA. .,University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
| | - Jacques E Nör
- Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA. .,Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. .,Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA. .,University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
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Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease. Cells 2021; 10:cells10082045. [PMID: 34440814 PMCID: PMC8392301 DOI: 10.3390/cells10082045] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cerebrospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, proliferation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine.
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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Lv Z, Xiao L, Tang Y, Chen Y, Chen D. Rb deficiency induces p21cip1 expression and delays retinal degeneration in rd1 mice. Exp Eye Res 2021; 210:108701. [PMID: 34252413 DOI: 10.1016/j.exer.2021.108701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/04/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023]
Abstract
Retinitis pigmentosa (RP) is a major cause of inherited blindness, and there is presently no cure for RP. Rd1 mouse is the most commonly used RP animal model. Re-expression of cell cycle proteins in post-mitotic neurons is considered an important mechanism of neurodegenerative diseases, including RP. The retinoblastoma tumor suppressor (Rb) is a major regulator of cell cycle progression, yet its role in rd1 mouse retina and related signaling pathways have never been analyzed. By crossing α-Cre, Rbf/f mice with rd1 mice, p21cip1-/- mice, Cdk1f/f mice and Cdk2f/f mice, we established multiple rd1 mouse models with deletions of Rb gene, Cdkn1a (p21cip1) gene, Cdk1 and Cdk2 gene in the retina. Cdk inhibitor CR8 was injected into the vitreous of rd1 mouse to investigate its effects on photoreceptor survival. Rb gene knockout (KO) induces cell death in excitatory retinal neurons (rods, rod bipolar and ganglions) and ectopic proliferation of retinal cells; but it paradoxically delays the rod death of rd1 mice, which is primarily mediated by the Cdk inhibitor Cdkn1a (p21cip1). Interestingly, p21cip1 protects the ectopic dividing rd1 rod cells by inhibiting Cdk1 and Cdk2. However, inhibiting Cdk1 and Cdk2 in rd1 mice with non-dividing rods only has limited and transient protective effects. Our data suggest that there is no ectopic division of rd1 rod cells, and RbKO induces ectopic division but delays the death of rd1 rod cells. This reveals the important protective role of Rb-p21cip1-Cdk axis in rd1 rod cells. P21cip1 is a potential target for future therapy of RP.
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Affiliation(s)
- Zhongping Lv
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lirong Xiao
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yunjing Tang
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongjiang Chen
- The School of Optometry and Vision Science, University of Waterloo, 200 University Ave. W., Waterloo, ON, N2L 3G1, Canada
| | - Danian Chen
- The Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; The Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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43
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Gairola K, Gururani S, Bahuguna A, Garia V, Pujari R, Dubey SK. Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics. J Food Biochem 2021; 45:e13772. [PMID: 34028051 DOI: 10.1111/jfbc.13772] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/06/2021] [Accepted: 05/03/2021] [Indexed: 12/14/2022]
Abstract
Cancer, being the leading cause of death in the globe, has been one of the major thrust areas of research worldwide. In a new paradigm about neoplastic transformations, the initiation and recurrence of disease is attributed to few mutated cells in bulk of tumor called cancer stem cells (CSCs). CSCs have capacity of self-renewal and differentiation, which are known for resistance to radio and chemotherapy leading to recurrence of the disease even after treatment. Most of traditional drugs implicated in cancer therapy targeting primary tumors have substantial toxicity to the physiological system and have not been efficient in targeting these CSCs leading to poor prognosis. Targeting these CSCs in bulk of tumor might be novel strategy for cancer chemoprevention and therapeutics. Diet-derived interventions and diverse natural products are known to target these CSCs and related signaling pathways, namely, Wnt, Notch, and Hedgehog pathways, which are implicated for CSC self-renewal. PRACTICAL APPLICATIONS: Cancer remains a global challenge even in this century. Poor prognosis, survival rate, and recurrence of the disease have been the major concerns in traditional cancer therapy regimes. Targeting cancer stem cells might be novel strategy for elimination and cure of the chronic disease as they are known to modulate all stages of carcinogenesis and responsible for recurrence and resistance to chemotherapy and radiotherapy. The evidence support that natural products might inhibit, delay, or reverse the process of tumorigenesis and modulate the different signaling pathways implicated for cancer stem cells self-renewal and differentiation. Natural products have minimal toxicity compared to traditional cancer therapy drugs since they have long been utilized in our food habits without any major side effects reported. Thus, targeting cancer stem cells with natural product might be a novel strategy for drug development in cancer chemoprevention and therapeutics.
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Affiliation(s)
- Kanchan Gairola
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shriya Gururani
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Ananya Bahuguna
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Vaishali Garia
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Rohit Pujari
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
| | - Shiv K Dubey
- Department of Biochemistry, G. B. Pant University of Agriculture and Technology, Pantnagar, India
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Kostin A, Alam MA, McGinty D, Alam MN. Adult hypothalamic neurogenesis and sleep-wake dysfunction in aging. Sleep 2021; 44:5986548. [PMID: 33202015 DOI: 10.1093/sleep/zsaa173] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 07/22/2020] [Indexed: 12/21/2022] Open
Abstract
In the mammalian brain, adult neurogenesis has been extensively studied in the hippocampal sub-granular zone and the sub-ventricular zone of the anterolateral ventricles. However, growing evidence suggests that new cells are not only "born" constitutively in the adult hypothalamus, but many of these cells also differentiate into neurons and glia and serve specific functions. The preoptic-hypothalamic area plays a central role in the regulation of many critical functions, including sleep-wakefulness and circadian rhythms. While a role for adult hippocampal neurogenesis in regulating hippocampus-dependent functions, including cognition, has been extensively studied, adult hypothalamic neurogenic process and its contributions to various hypothalamic functions, including sleep-wake regulation are just beginning to unravel. This review is aimed at providing the current understanding of the hypothalamic adult neurogenic processes and the extent to which it affects hypothalamic functions, including sleep-wake regulation. We propose that hypothalamic neurogenic processes are vital for maintaining the proper functioning of the hypothalamic sleep-wake and circadian systems in the face of regulatory challenges. Sleep-wake disturbance is a frequent and challenging problem of aging and age-related neurodegenerative diseases. Aging is also associated with a decline in the neurogenic process. We discuss a hypothesis that a decrease in the hypothalamic neurogenic process underlies the aging of its sleep-wake and circadian systems and associated sleep-wake disturbance. We further discuss whether neuro-regenerative approaches, including pharmacological and non-pharmacological stimulation of endogenous neural stem and progenitor cells in hypothalamic neurogenic niches, can be used for mitigating sleep-wake and other hypothalamic dysfunctions in aging.
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Affiliation(s)
- Andrey Kostin
- Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA
| | - Md Aftab Alam
- Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA.,Department of Psychiatry, University of California, Los Angeles, CA
| | - Dennis McGinty
- Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA.,Department of Psychology, University of California, Los Angeles, CA
| | - Md Noor Alam
- Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA.,Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA
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45
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Yu J, Wu Y, Li H, Zhou H, Shen C, Gao T, Lin M, Dai X, Ou J, Liu M, Huang X, Zheng B, Sun F. BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway. Front Cell Dev Biol 2021; 9:665089. [PMID: 33928089 PMCID: PMC8076678 DOI: 10.3389/fcell.2021.665089] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 03/22/2021] [Indexed: 11/18/2022] Open
Abstract
Testosterone biosynthesis progressively decreases in aging males primarily as a result of functional changes to Leydig cells. Despite this, the mechanisms underlying steroidogenesis remain largely unclear. Using gene knock-out approaches, we and others have recently identified Bmi1 as an anti-aging gene. Herein, we investigate the role of BMI1 in steroidogenesis using mouse MLTC-1 and primary Leydig cells. We show that BMI1 can positively regulate testosterone production. Mechanistically, in addition to its known role in antioxidant activity, we also report that p38 mitogen-activated protein kinase (MAPK) signaling is activated, and testosterone levels reduced, in BMI1-deficient cells; however, the silencing of the p38 MAPK pathway restores testosterone production. Furthermore, we reveal that BMI1 directly binds to the promoter region of Map3k3, an upstream activator of p38, thereby modulating its chromatin status and repressing its expression. Consequently, this results in the inhibition of the p38 MAPK pathway and the promotion of steroidogenesis. Our study uncovered a novel epigenetic mechanism in steroidogenesis involving BMI1-mediated gene silencing and provides potential therapeutic targets for the treatment of hypogonadism.
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Affiliation(s)
- Jun Yu
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, China
| | - Yibo Wu
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Hong Li
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, China
| | - Hui Zhou
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Cong Shen
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, China
| | - Tingting Gao
- Center of Clinical Reproductive Medicine, The Affiliated Changzhou Maternity and Child Health Care Hospital of Nanjing Medical University, Changzhou, China
| | - Meng Lin
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Xiuliang Dai
- Center of Clinical Reproductive Medicine, The Affiliated Changzhou Maternity and Child Health Care Hospital of Nanjing Medical University, Changzhou, China
| | - Jian Ou
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, China
| | - Meiling Liu
- National Health Commission Key Laboratory of Male Reproductive Health, National Research Institute for Family Planning, Beijing, China
| | - Xiaoyan Huang
- State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
| | - Bo Zheng
- State Key Laboratory of Reproductive Medicine, Center for Reproduction and Genetics, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, China.,National Health Commission Key Laboratory of Male Reproductive Health, National Research Institute for Family Planning, Beijing, China
| | - Fei Sun
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, China
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Yin Y, Zhou N, Zhang H, Dai X, Lv X, Chen N, Miao D, Hu Q. Bmi1 regulate tooth and mandible development by inhibiting p16 signal pathway. J Cell Mol Med 2021; 25:4195-4203. [PMID: 33745198 PMCID: PMC8093977 DOI: 10.1111/jcmm.16468] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 02/02/2021] [Accepted: 03/05/2021] [Indexed: 12/31/2022] Open
Abstract
To determine whether the deletion of p16 can correct tooth and mandible growth retardation caused by Bmi1 deficiency, we compared the tooth and mandible phenotypes of homozygous p16‐deficient (p16−/−) mice, homozygous Bmi1‐deficient (Bmi1−/−) mice, double homozygous Bmi1 and p16‐deficient (Bmi1−/−p16−/−) mice to those of their wild‐type littermates at 4 weeks of age by radiograph, histochemistry and immunohistochemistry. Results showed that compared to Bmi1−/− mice, the dental mineral density, dental volume and dentin sialoprotein immunopositive areas were increased, whereas the ratio of the predentin area to total dentin area and that of biglycan immunopositive area to dentin area were decreased in Bmi1−/−p16−/− mice. These results indicate that the deletion of p16 can improve tooth development in Bmi1 knockout mice. Compared to Bmi1−/− mice, the mandible mineral density, cortical thickness, alveolar bone volume, osteoblast number and activity, alkaline phosphatase positive area were all increased significantly in Bmi1−/−p16−/− mice. These results indicate that the deletion of p16 can improve mandible growth in Bmi1 knockout mice. Furthermore, the protein expression levels of cyclin D, CDK4 and p53 were increased significantly in p16−/− mice compared with those from wild‐type mice; the protein expression levels of cyclin D and CDK4 were decreased significantly, whereas those of p27 and p53 were increased significantly in Bmi1−/− mice; these parameters were partly rescued in Bmi1−/−p16−/− mice compared with those from Bmi1−/− mice. Therefore, our results indicate that Bmi1 plays roles in regulating tooth and mandible development by inhibiting p16 signal pathway which initiated entry into cell cycle.
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Affiliation(s)
- Ying Yin
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Nan Zhou
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Non-communicable Disease Prevention, Nanjing Municipal Center for Disease Control and Prevention, Nanjing, China
| | - Hui Zhang
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xiuliang Dai
- Reproductive Center, Nanjing Medical University Affiliated Changzhou Maternal and Child Health Care Hospital, Changzhou, China
| | - Xianhui Lv
- Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China
| | - Ning Chen
- Institute of Stomatology, Nanjing Medical University, Nanjing, China
| | - Dengshun Miao
- Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, China.,The Research Center for Aging, Affiliated Friendship Plastic Surgery Hospital of Nanjing Medical University, Nanjing, China
| | - Qingang Hu
- Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
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Zheng X, Wang Q, Xie Z, Li J. The elevated level of IL-1α in the bone marrow of aged mice leads to MSC senescence partly by down-regulating Bmi-1. Exp Gerontol 2021; 148:111313. [PMID: 33740618 DOI: 10.1016/j.exger.2021.111313] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 11/30/2022]
Abstract
Osteoporosis is becoming increasingly prevalent with individual aging. Recent studies found that bone marrow mesenchymal stem cells (MSCs) undergo senescence along with the progression of age-related osteoporosis, leading to a decreased rate of new bone formation and fracture repair. The underlying mechanism of MSC senescence in the aged bone marrow has not been clarified yet. Here we found that MSCs from aged mice (12-month-old, O-MSCs) exhibited apparent senescent phenotypes compared with those from young controls (2-month-old, Y-MSCs), including lower proliferation rate, impaired self-renewal capacity, increased p16Ink4a expression and shifted differentiation balance to favor adipocytes over osteoblasts. Bmi-1, one of the main factors that regulate stem cell self-renewal, is dramatically decreased in O-MSCs. Knocking-down of Bmi-1 in Y-MSCs lead to cellular senescence, while over-expression of it rejuvenated O-MSCs. We further showed that the level of IL-1α is much higher in the bone marrow fluid of aged mice, which significantly inhibited Bmi-1 expression in MSCs. Our present study indicated that IL-1α, a key component of the senescence-associated secretory phenotype (SASP), is elevated in the aged bone marrow microenvironment, leading to decreased Bmi-1 expression in MSCs and consequently, MSC senescence.
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Affiliation(s)
- Xueling Zheng
- Department of Cell Biology, Zunyi Medical University, Zunyi 563000, Guizhou, China
| | - Qianxing Wang
- Department of Cell Biology, Zunyi Medical University, Zunyi 563000, Guizhou, China
| | - Zhuo Xie
- Department of Cell Biology, Zunyi Medical University, Zunyi 563000, Guizhou, China
| | - Jiao Li
- Department of Cell Biology, Zunyi Medical University, Zunyi 563000, Guizhou, China.
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48
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Sugiura A, Shimizu T, Kameyama T, Maruo T, Kedashiro S, Miyata M, Mizutani K, Takai Y. Identification of Sox2 and NeuN Double-Positive Cells in the Mouse Hypothalamic Arcuate Nucleus and Their Reduction in Number With Aging. Front Aging Neurosci 2021; 12:609911. [PMID: 33776740 PMCID: PMC7991304 DOI: 10.3389/fnagi.2020.609911] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 12/22/2020] [Indexed: 01/17/2023] Open
Abstract
The hypothalamus plays a central role in homeostasis and aging. The hypothalamic arcuate nucleus (ARC) controls homeostasis of food intake and energy expenditure and retains adult neural stem cells (NSCs)/progenitor cells. Aging induces the loss of NSCs and the enhancement of inflammation, including the activation of glial cells in the ARC, but aging-associated alterations of the hypothalamic cells remain obscure. Here, we identified Sox2 and NeuN double-positive cells in a subpopulation of cells in the mouse ARC. These cells were reduced in number with aging, although NeuN-positive neuronal cells were unaltered in the total number. Diet-induced obesity mice fed with high-fat diet presented a similar hypothalamic alteration to aged mice. This study provides a new insight into aging-induced changes in the hypothalamus.
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Affiliation(s)
- Ayumu Sugiura
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tatsuhiro Shimizu
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takeshi Kameyama
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomohiko Maruo
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shin Kedashiro
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Muneaki Miyata
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kiyohito Mizutani
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshimi Takai
- Division of Pathogenetic Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
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Gillispie GJ, Sah E, Krishnamurthy S, Ahmidouch MY, Zhang B, Orr ME. Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells-Implications for Cancer and Neurodegeneration. Life (Basel) 2021; 11:153. [PMID: 33671362 PMCID: PMC7922097 DOI: 10.3390/life11020153] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/09/2021] [Accepted: 02/09/2021] [Indexed: 01/10/2023] Open
Abstract
Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.
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Affiliation(s)
- Gregory J. Gillispie
- Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (G.J.G.); (E.S.); (S.K.); (M.Y.A.)
- Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Eric Sah
- Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (G.J.G.); (E.S.); (S.K.); (M.Y.A.)
| | - Sudarshan Krishnamurthy
- Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (G.J.G.); (E.S.); (S.K.); (M.Y.A.)
- Bowman Gray Center for Medical Education, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA
| | - Mohamed Y. Ahmidouch
- Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (G.J.G.); (E.S.); (S.K.); (M.Y.A.)
- Wake Forest University, Winston-Salem, NC 27109, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Department of Pharmacological Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Miranda E. Orr
- Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (G.J.G.); (E.S.); (S.K.); (M.Y.A.)
- Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Salisbury VA Medical Center, Salisbury, NC 28144, USA
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Shah K, King GD, Jiang H. A chromatin modulator sustains self-renewal and enables differentiation of postnatal neural stem and progenitor cells. J Mol Cell Biol 2021; 12:4-16. [PMID: 31065682 PMCID: PMC7052987 DOI: 10.1093/jmcb/mjz036] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 03/31/2019] [Accepted: 04/07/2019] [Indexed: 12/17/2022] Open
Abstract
It remains unknown whether H3K4 methylation, an epigenetic modification associated with gene activation, regulates fate determination of the postnatal neural stem and progenitor cells (NSPCs). By inactivating the Dpy30 subunit of the major H3K4 methyltransferase complexes in specific regions of mouse brain, we demonstrate a crucial role of efficient H3K4 methylation in maintaining both the self-renewal and differentiation capacity of postnatal NSPCs. Dpy30 deficiency disrupts development of hippocampus and especially the dentate gyrus and subventricular zone, the major regions for postnatal NSC activities. Dpy30 is indispensable for sustaining the self-renewal and proliferation of NSPCs in a cell-intrinsic manner and also enables the differentiation of mouse and human neural progenitor cells to neuronal and glial lineages. Dpy30 directly regulates H3K4 methylation and the induction of several genes critical in neurogenesis. These findings link a prominent epigenetic mechanism of gene expression to the fundamental properties of NSPCs and may have implications in neurodevelopmental disorders.
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Affiliation(s)
- Kushani Shah
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gwendalyn D King
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hao Jiang
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA
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