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Levy A, Massard C, Michiels S, Deutsch E. Innovative, early-phase clinical trials of drug-radiotherapy combinations. Lancet Oncol 2025; 26:e190-e202. [PMID: 40179915 DOI: 10.1016/s1470-2045(24)00664-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/04/2024] [Accepted: 11/12/2024] [Indexed: 04/05/2025]
Abstract
Over the past few decades, breakthroughs in cancer biology at the molecular level have revolutionised cancer treatment. Enhanced precision in radiotherapy has not only reduced patient side-effects, but also enabled the delivery of high-dose stereotactic extracranial irradiation with unprecedented accuracy. Simultaneously, the number of medical therapies available for clinical care continues to grow. Despite the progress made with combined chemoradiotherapy, only a few drug-radiotherapy combinations have received clinical approval, leaving a vast landscape of untapped opportunities for basic, translational, and clinical research, particularly in early-phase drug-radiotherapy trials. New and promising pharmaceutical therapies, paired with advanced radiotherapy technologies, are now being tested in innovative clinical trial designs. Moreover, the integration of biological and imaging markers-both tumour-specific and peripheral-holds the potential to personalise drug-radiotherapy combinations, thereby enhancing the therapeutic index for specific patient populations. In this Review, we highlight the latest developments and future directions for early-phase clinical trials that combine precision drug-radiotherapy strategies in adult patients, with the aims of improving outcomes and expanding treatment options.
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Affiliation(s)
- Antonin Levy
- Department of Radiation Oncology, Gustave Roussy, Université Paris Saclay, Villejuif, France; Gustave Roussy, Inserm U1030, Radiothérapie Moléculaire et Innovations Thérapeutiques, Université Paris Saclay, Villejuif, France; Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France.
| | - Christophe Massard
- Gustave Roussy, Inserm U1030, Radiothérapie Moléculaire et Innovations Thérapeutiques, Université Paris Saclay, Villejuif, France; Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France; Drug Development Department (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France
| | - Stefan Michiels
- Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France; Office of Biostatistics and Epidemiology Department, Gustave Roussy, Université Paris Saclay, Villejuif, France; Oncostat U1018, Inserm, Labeled Ligue Contre le Cancer, Université Paris Saclay, Villejuif, France
| | - Eric Deutsch
- Department of Radiation Oncology, Gustave Roussy, Université Paris Saclay, Villejuif, France; Gustave Roussy, Inserm U1030, Radiothérapie Moléculaire et Innovations Thérapeutiques, Université Paris Saclay, Villejuif, France; Faculté de Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France
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Lei X, Xu Z, Huang Y, Huang L, Lang J, Qu M, Liu D. Regulation of Mitochondrial Quality Control of Intestinal Stem Cells in Homeostasis and Diseases. Antioxid Redox Signal 2025; 42:494-511. [PMID: 39225500 DOI: 10.1089/ars.2023.0489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Significance: Intestinal stem cells (ISCs) are crucial for the continuous renewal and regeneration of the small intestinal epithelium. ISC fate decisions are strictly controlled by metabolism. Mitochondria act as the central hubs of energetic metabolism and dynamically remodel their morphology to perform required metabolic functions. Mitochondrial dysfunction is closely associated with a variety of gastrointestinal diseases. Recent Advances: In recent years, several studies have reported that mitochondria are potential therapeutic targets for regulating ISC function to alleviate intestinal diseases. However, how mitochondrial quality control mediates ISCs under physiological conditions and protects against intestinal injury remains to be comprehensively reviewed. Critical Issues: In this review, we summarize the available studies about how mitochondrial metabolism, redox state, dynamics, autophagy, and proteostasis impact ISC proliferation, differentiation, and regeneration, respectively. Future Directions: We propose that remodeling the function of mitochondria in ISCs may be a promising potential future direction for the treatment of intestinal diseases. This review may provide new strategies for therapeutically targeting the mitochondria of ISCs in intestinal diseases. Antioxid. Redox Signal. 42, 494-511.
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Affiliation(s)
- Xudan Lei
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Zhenni Xu
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Yujun Huang
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Lingxiao Huang
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Jinyi Lang
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Mingyue Qu
- The PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Dengqun Liu
- Department of Experimental Research, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital and Institute, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
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Haque PS, Kapur N, Barrett TA, Theiss AL. Mitochondrial function and gastrointestinal diseases. Nat Rev Gastroenterol Hepatol 2024; 21:537-555. [PMID: 38740978 PMCID: PMC12036329 DOI: 10.1038/s41575-024-00931-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/10/2024] [Indexed: 05/16/2024]
Abstract
Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer. In this Review, we provide an overview of the current understanding of intestinal epithelial cell mitochondrial metabolism, function and signalling to affect tissue homeostasis, including gut microbiota composition. We also discuss mitochondrial-targeted therapeutics for inflammatory bowel diseases and colorectal cancer and the evolving concept of mitochondrial impairment as a consequence versus initiator of the disease.
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Affiliation(s)
- Parsa S Haque
- Division of Gastroenterology and Hepatology, Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA
| | - Neeraj Kapur
- Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Terrence A Barrett
- Department of Medicine, Division of Digestive Diseases and Nutrition, University of Kentucky College of Medicine, Lexington, KY, USA
- Lexington Veterans Affairs Medical Center Kentucky, Lexington, KY, USA
| | - Arianne L Theiss
- Division of Gastroenterology and Hepatology, Department of Medicine and the Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, CO, USA.
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA.
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Zhou X, Medina-Ramirez IE, Su G, Liu Y, Yan B. All Roads Lead to Rome: Comparing Nanoparticle- and Small Molecule-Driven Cell Autophagy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2310966. [PMID: 38616767 DOI: 10.1002/smll.202310966] [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: 12/05/2023] [Revised: 03/27/2024] [Indexed: 04/16/2024]
Abstract
Autophagy, vital for removing cellular waste, is triggered differently by small molecules and nanoparticles. Small molecules, like rapamycin, non-selectively activate autophagy by inhibiting the mTOR pathway, which is essential for cell regulation. This can clear damaged components but may cause cytotoxicity with prolonged use. Nanoparticles, however, induce autophagy, often causing oxidative stress, through broader cellular interactions and can lead to a targeted form known as "xenophagy." Their impact varies with their properties but can be harnessed therapeutically. In this review, the autophagy induced by nanoparticles is explored and small molecules across four dimensions: the mechanisms behind autophagy induction, the outcomes of such induction, the toxicological effects on cellular autophagy, and the therapeutic potential of employing autophagy triggered by nanoparticles or small molecules. Although small molecules and nanoparticles each induce autophagy through different pathways and lead to diverse effects, both represent invaluable tools in cell biology, nanomedicine, and drug discovery, offering unique insights and therapeutic opportunities.
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Affiliation(s)
- Xiaofei Zhou
- College of Science & Technology, Hebei Agricultural University, Baoding, 071001, China
- Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, Baoding, 071100, China
| | - Iliana E Medina-Ramirez
- Department of Chemistry, Universidad Autónoma de Aguascalientes, Av Universidad 940, Aguascalientes, Aguascalientes, México
| | - Gaoxing Su
- School of Pharmacy, Nantong University, Nantong, 226001, China
| | - Yin Liu
- School of Environment, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 10024, China
| | - Bing Yan
- Institute of Environmental Research at the Greater Bay Area, Key Laboratory for Water Quality and Conservation of the Pearl River Delta, Ministry of Education, Guangzhou University, Guangzhou, 510006, China
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Zhao LJ, Dai XY, Ye YW, Pang XF, Jiang M, Tan WY, Xu YH, Su JF, Shi B. MURAMYL DIPEPTIDE CAUSES MITOCHONDRIAL DYSFUNCTION AND INTESTINAL INFLAMMATORY CYTOKINE RESPONSES IN RATS. Shock 2024; 62:139-145. [PMID: 38546380 DOI: 10.1097/shk.0000000000002369] [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: 05/25/2024]
Abstract
ABSTRACT Introduction: Intestinal flora and the translocation of its products, such as muramyl dipeptide (MDP), are common causes of sepsis. MDP is a common activator of the intracellular pattern recognition receptor NOD2, and MDP translocation can cause inflammatory damage to the small intestine and systemic inflammatory responses in rats. Therefore, this study investigated the effects of MDP on the intestinal mucosa and distant organs during sepsis and the role of the NOD2/AMPK/LC3 pathway in MDP-induced mitochondrial dysfunction in the intestinal epithelium. Methods: Fifty male Sprague Dawley rats were randomly divided into five treatment groups: lipopolysaccharide (LPS) only, 1.5 and 15 mg/kg MDP+LPS, and 1.5 and 15 mg/kg MDP+short-peptide enteral nutrition (SPEN)+LPS. The total caloric intake was the same per group. The rats were euthanized 24 h after establishing the model, and peripheral blood and small intestinal mucosal and lung tissues were collected. Results: Compared to the LPS group, both MDP+LPS groups had aggravated inflammatory damage to the intestinal mucosal and lung tissues, increased IL-6 and MDP production, increased NOD2 expression, decreased AMPK and LC3 expression, increased mitochondrial reactive oxygen species production, and decreased mitochondrial membrane potential. Compared to the MDP+LPS groups, the MDP+SPEN+LPS groups had decreased IL-6 and MDP production, increased AMPK and LC3 protein expression, and protected mitochondrial and organ functions. Conclusions: MDP translocation reduced mitochondrial autophagy by regulating the NOD2/AMPK/LC3 pathway, causing mitochondrial dysfunction. SPEN protected against MDP-induced impairment of intestinal epithelial mitochondrial function during sepsis.
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Affiliation(s)
- Lu-Jia Zhao
- Department of Geriatrics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Yong Dai
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
| | - You-Wen Ye
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
| | - Xiu-Feng Pang
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
| | - Meng Jiang
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
| | - Wan-Yi Tan
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
| | - Ying-Hui Xu
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
| | - Ji-Feng Su
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
| | - Bin Shi
- Department of Emergency Intensive Care Unit, Yangpu Hospital Affiliated to Tongji University, Shanghai, China
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Ding F, Zhou N, Luo Y, Wang T, Li W, Qiao F, Du Z, Zhang M. Probiotic Pediococcus pentosaceus restored gossypol-induced intestinal barrier injury by increasing propionate content in Nile tilapia. J Anim Sci Biotechnol 2024; 15:54. [PMID: 38582865 PMCID: PMC10999087 DOI: 10.1186/s40104-024-01011-w] [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] [Accepted: 02/06/2024] [Indexed: 04/08/2024] Open
Abstract
BACKGROUND Intestinal barrier is a dynamic interface between the body and the ingested food components, however, dietary components or xenobiotics could compromise intestinal integrity, causing health risks to the host. Gossypol, a toxic component in cottonseed meal (CSM), caused intestinal injury in fish or other monogastric animals. It has been demonstrated that probiotics administration benefits the intestinal barrier integrity, but the efficacy of probiotics in maintaining intestinal health when the host is exposed to gossypol remains unclear. Here, a strain (YC) affiliated to Pediococcus pentosaceus was isolated from the gut of Nile tilapia (Oreochromis niloticus) and its potential to repair gossypol-induced intestinal damage was evaluated. RESULTS A total of 270 Nile tilapia (2.20 ± 0.02 g) were allotted in 3 groups with 3 tanks each and fed with 3 diets including CON (control diet), GOS (control diet containing 300 mg/kg gossypol) and GP (control diet containing 300 mg/kg gossypol and 108 colony-forming unit (CFU)/g P. pentosaceus YC), respectively. After 10 weeks, addition of P. pentosaceus YC restored growth retardation and intestinal injury induced by gossypol in Nile tilapia. Transcriptome analysis and siRNA interference experiments demonstrated that NOD-like receptors (NLR) family caspase recruitment domain (CARD) domain containing 3 (Nlrc3) inhibition might promote intestinal stem cell (ISC) proliferation, as well as maintaining gut barrier integrity. 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) revealed that addition of P. pentosaceus YC altered the composition of gut microbiota and increased the content of propionate in fish gut. In vitro studies on propionate's function demonstrated that it suppressed nlrc3 expression and promoted wound healing in Caco-2 cell model. CONCLUSIONS The present study reveals that P. pentosaceus YC has the capacity to ameliorate intestinal barrier injury by modulating gut microbiota composition and elevating propionate level. This finding offers a promising strategy for the feed industry to incorporate cottonseed meal into fish feed formulations.
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Affiliation(s)
- Feifei Ding
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Nannan Zhou
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yuan Luo
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Tong Wang
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Weijie Li
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Fang Qiao
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Zhenyu Du
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Meiling Zhang
- Laboratory of Aquaculture Nutrition and Environmental Health (LANEH), School of Life Sciences, East China Normal University, Shanghai, 200241, China.
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Jin X, You L, Qiao J, Han W, Pan H. Autophagy in colitis-associated colon cancer: exploring its potential role in reducing initiation and preventing IBD-Related CAC development. Autophagy 2024; 20:242-258. [PMID: 37723664 PMCID: PMC10813649 DOI: 10.1080/15548627.2023.2259214] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/20/2023] Open
Abstract
ABBREVIATIONS A. muciniphila: Akkermansia muciniphila; AIEC: adherent invasive Escherichia coli; AOM/DSS: azoxymethane-dextran sodium sulfate; ATG: autophagy related; BECN1: beclin1, autophagy related; CAC: colitis-associated colon cancer; CCDC50: coiled-coil domain containing 50; CLDN2: claudin 2; CoPEC: colibactin-producing Escherichia coli; CRC: colorectal cancer; DAMPs: danger/damage-associated molecular patterns; DC: dendritic cell; DSS: dextran sulfate sodium; DTP: drug-resistant persistent; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IKK: IkappaB kinase; IL: interleukin; IRGM1: immunity-related GTPase family M member 1; ISC: intestinal stem cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDP: muramyl dipeptide; MELK: maternal embryonic leucine zipper kinase; MHC: major histocompatibility complex; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NRBF2: nuclear receptor binding factor 2; PAMPs: pathogen-associated molecular patterns; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PYCARD/ASC: PYD and CARD domain containing; RALGAPA2/RalGAPα2: Ral GTPase activating protein protein, alpha subunit 2 (catalytic); RIPK2/CARD3: receptor (TNFRSF)-interacting serine-threonine kinase 2; RIPK3: receptor-interacting serine-threonine kinase 3; ROS: reactive oxygen species; sCRC: sporadic colorectal cancer; SMARCA4/BRG1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TNF/TNFA: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; WT: wild-type.
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Affiliation(s)
- Xuanhong Jin
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liangkun You
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jincheng Qiao
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Weidong Han
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Wu H, Mu C, Xu L, Yu K, Shen L, Zhu W. Host-microbiota interaction in intestinal stem cell homeostasis. Gut Microbes 2024; 16:2353399. [PMID: 38757687 PMCID: PMC11110705 DOI: 10.1080/19490976.2024.2353399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.
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Affiliation(s)
- Haiqin Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Chunlong Mu
- Food Informatics, AgResearch, Te Ohu Rangahau Kai, Palmerston North, New Zealand
| | - Laipeng Xu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Kaifan Yu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Le Shen
- Department of Surgery, The University of Chicago, Chicago, IL, USA
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
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Okolo O, Honzel E, Britton WR, Yu VX, Flashner S, Martin C, Nakagawa H, Parikh AS. Experimental Modeling of Host-Bacterial Interactions in Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2023; 15:5810. [PMID: 38136355 PMCID: PMC10742111 DOI: 10.3390/cancers15245810] [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: 11/07/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
The microscopic species colonizing the human body, collectively referred to as the microbiome, play a crucial role in the maintenance of tissue homeostasis, immunity, and the development of disease. There is evidence to suggest associations between alterations in the microbiome and the development of head and neck squamous cell carcinomas (HNSCC). The use of two-dimensional (2D) modeling systems has made significant strides in uncovering the role of microbes in carcinogenesis; however, direct mechanistic links remain in their infancy. Patient-derived three-dimensional (3D) HNSCC organoid and organotypic models have recently been described. Compared to 2D models, 3D organoid culture systems effectively capture the genetic and epigenetic features of parent tissue in a patient-specific manner and may offer a more nuanced understanding of the role of host-microbe responses in carcinogenesis. This review provides a topical literature review assessing the current state of the field investigating the role of the microbiome in HNSCC; including in vivo and in vitro modeling methods that may be used to characterize microbiome-epithelial interactions.
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Affiliation(s)
- Ogoegbunam Okolo
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA; (O.O.); (W.R.B.); (V.X.Y.); (S.F.); (C.M.); (H.N.)
- Columbia Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10027, USA;
| | - Emily Honzel
- Columbia Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10027, USA;
| | - William R. Britton
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA; (O.O.); (W.R.B.); (V.X.Y.); (S.F.); (C.M.); (H.N.)
- Columbia Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10027, USA;
| | - Victoria X. Yu
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA; (O.O.); (W.R.B.); (V.X.Y.); (S.F.); (C.M.); (H.N.)
- Department of Otolaryngology-Head and Neck Surgery, Columbia University, New York, NY 10027, USA
| | - Samuel Flashner
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA; (O.O.); (W.R.B.); (V.X.Y.); (S.F.); (C.M.); (H.N.)
| | - Cecilia Martin
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA; (O.O.); (W.R.B.); (V.X.Y.); (S.F.); (C.M.); (H.N.)
- Organoid and Cell Culture Core, Columbia University Digestive and Liver Diseases Research Center, Columbia University, New York, NY 10027, USA
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10027, USA
| | - Hiroshi Nakagawa
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA; (O.O.); (W.R.B.); (V.X.Y.); (S.F.); (C.M.); (H.N.)
- Organoid and Cell Culture Core, Columbia University Digestive and Liver Diseases Research Center, Columbia University, New York, NY 10027, USA
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY 10027, USA
| | - Anuraag S. Parikh
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA; (O.O.); (W.R.B.); (V.X.Y.); (S.F.); (C.M.); (H.N.)
- Department of Otolaryngology-Head and Neck Surgery, Columbia University, New York, NY 10027, USA
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10
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Sun M, Tan Z, Lin K, Li X, Zhu J, Zhan L, Zheng H. Advanced Progression for the Heterogeneity and Homeostasis of Intestinal Stem Cells. Stem Cell Rev Rep 2023; 19:2109-2119. [PMID: 37351833 DOI: 10.1007/s12015-023-10578-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2023] [Indexed: 06/24/2023]
Abstract
Current understanding of the leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) in intestinal stem cells (ISCs) is well established, however, the implications of ISC heterogeneity and homeostasis are poorly understood. Prior studies have provided important evidence for the association between heterogeneity of ISC pools with pathogenesis and therapeutic response of malignant disease. Leveraging the advantages of organoids and single cell RNA sequencing (scRNA-seq), glandular development has been simulated and cell heterogeneity has been clarified. Based on this research, several potential ISCs were identified, such as LGR5 + p27 + quiescent ISCs, LGR5 + Mex3a + slowly proliferating stem cells, and CLU + reverse stem cells. We also illustrated major factors responsible for ISC homeostasis including metabolism-related (LKB1, TGR5, HMGCS2), inflammation-related (IFB-b, IFN2, TNF), and Wnt signaling-related (CREPT, Mex3a, MTG16) factors. ISCs play complex roles in intestinal tumorigenesis, chemoresistance and occasional relapse of colon cancer, which bear discussion. In this review, we focus on novel technical challenges in ISCs fate drawing upon recent research with the goals of clarifying our understanding of complex ISCs, elucidating the integrated intestinal crypt niche, and creating new opportunities for therapeutic development.
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Affiliation(s)
- Minqiong Sun
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China
| | - Zhenya Tan
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China
| | - Keqiong Lin
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China
| | - Xiaofei Li
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China
| | - Jicheng Zhu
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China
| | - Li Zhan
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China
| | - Hong Zheng
- Department of Pathophysiology, Anhui Medical University, Hefei, Anhui, China.
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11
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Yao C, Gou X, Tian C, Zhou L, Hao R, Wan L, Wang Z, Li M, Tong X. Key regulators of intestinal stem cells: diet, microbiota, and microbial metabolites. J Genet Genomics 2023; 50:735-746. [PMID: 36566949 DOI: 10.1016/j.jgg.2022.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/08/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Interactions between diet and the intestinal microbiome play an important role in human health and disease development. It is well known that such interactions, whether direct or indirect, trigger a series of metabolic reactions in the body. Evidence suggests that intestinal stem cells (ISCs), which are phenotypic precursors of various intestinal epithelial cells, play a significant role in the regulation of intestinal barrier function and homeostasis. The advent and evolution of intestinal organoid culture techniques have presented a key opportunity to study the association between the intestinal microenvironment and ISCs. As a result, the effects exerted by dietary factors, intestinal microbiomes, and their metabolites on the metabolic regulation of ISCs and the potential mechanisms underlying such effects are being gradually revealed. This review summarises the effects of different dietary patterns on the behaviour and functioning of ISCs and focuses on the crosstalk between intestinal microbiota, related metabolites, and ISCs, with the aim of fully understanding the relationship between these three factors and providing further insights into the complex mechanisms associated with ISCs in the human body. Gaining an understanding of these mechanisms may lead to the development of novel dietary interventions or drugs conducive to intestinal health.
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Affiliation(s)
- Chensi Yao
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xiaowen Gou
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Chuanxi Tian
- Graduate College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Lijuan Zhou
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Rui Hao
- Graduate College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Li Wan
- Graduate College, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zeyu Wang
- Department of Scientific Research, Changchun University of Chinese Medicine, Changchun, Jilin 130017, China.
| | - Min Li
- Molecular Biology Laboratory, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
| | - Xiaolin Tong
- Institute of Metabolic Diseases, Guang'anmen Hospital of China, Academy of Chinese Medical Sciences, Beijing 100053, China.
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12
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Wang Z, Qu YJ, Cui M. Modulation of stem cell fate in intestinal homeostasis, injury and repair. World J Stem Cells 2023; 15:354-368. [PMID: 37342221 PMCID: PMC10277971 DOI: 10.4252/wjsc.v15.i5.354] [Citation(s) in RCA: 4] [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: 01/14/2023] [Revised: 03/31/2023] [Accepted: 04/24/2023] [Indexed: 05/26/2023] Open
Abstract
The mammalian intestinal epithelium constitutes the largest barrier against the external environment and makes flexible responses to various types of stimuli. Epithelial cells are fast-renewed to counteract constant damage and disrupted barrier function to maintain their integrity. The homeostatic repair and regeneration of the intestinal epithelium are governed by the Lgr5+ intestinal stem cells (ISCs) located at the base of crypts, which fuel rapid renewal and give rise to the different epithelial cell types. Protracted biological and physicochemical stress may challenge epithelial integrity and the function of ISCs. The field of ISCs is thus of interest for complete mucosal healing, given its relevance to diseases of intestinal injury and inflammation such as inflammatory bowel diseases. Here, we review the current understanding of the signals and mechanisms that control homeostasis and regeneration of the intestinal epithelium. We focus on recent insights into the intrinsic and extrinsic elements involved in the process of intestinal homeostasis, injury, and repair, which fine-tune the balance between self-renewal and cell fate specification in ISCs. Deciphering the regulatory machinery that modulates stem cell fate would aid in the development of novel therapeutics that facilitate mucosal healing and restore epithelial barrier function.
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Affiliation(s)
- Zhe Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yan-Ji Qu
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Min Cui
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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13
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Pani G. Fusobacterium & Co. at the Stem of Cancer: Microbe-Cancer Stem Cell Interactions in Colorectal Carcinogenesis. Cancers (Basel) 2023; 15:cancers15092583. [PMID: 37174049 PMCID: PMC10177588 DOI: 10.3390/cancers15092583] [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: 04/12/2023] [Revised: 04/27/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Adult stem cells lie at the crossroads of tissue repair, inflammation, and malignancy. Intestinal microbiota and microbe-host interactions are pivotal to maintaining gut homeostasis and response to injury, and participate in colorectal carcinogenesis. Yet, limited knowledge is available on whether and how bacteria directly crosstalk with intestinal stem cells (ISC), particularly cancerous stem-like cells (CR-CSC), as engines for colorectal cancer initiation, maintenance, and metastatic dissemination. Among several bacterial species alleged to initiate or promote colorectal cancer (CRC), the pathobiont Fusobacterium Nucleatum has recently drawn significant attention for its epidemiologic association and mechanistic linkage with the disease. We will therefore focus on current evidence for an F. nucleatum-CRCSC axis in tumor development, highlighting the commonalities and differences between F. nucleatum-associated colorectal carcinogenesis and gastric cancer driven by Helicobacter Pylori. We will explore the diverse facets of the bacteria-CSC interaction, analyzing the signals and pathways whereby bacteria either confer "stemness" properties to tumor cells or primarily target stem-like elements within the heterogeneous tumor cell populations. We will also discuss the extent to which CR-CSC cells are competent for innate immune responses and participate in establishing a tumor-promoting microenvironment. Finally, by capitalizing on the expanding knowledge of how the microbiota and ISC crosstalk in intestinal homeostasis and response to injury, we will speculate on the possibility that CRC arises as an aberrant repair response promoted by pathogenic bacteria upon direct stimulation of intestinal stem cells.
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Affiliation(s)
- Giovambattista Pani
- Department of Translational Medicine and Surgery, Section of General Pathology, Faculty of Medicine, Università Cattolica del Sacro Cuore, Largo Francesco Vito, 1, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, L. go A. Gemelli 8, 00168 Rome, Italy
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14
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Liu Y, Liu Z, Hu L, He L, Yang L, Qin Z, Xie Y, Peng X, Dai L. Function of stem cells in radiation-induced damage. Int J Radiat Biol 2023; 99:1483-1494. [PMID: 36912588 DOI: 10.1080/09553002.2023.2188935] [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: 09/28/2022] [Accepted: 02/27/2023] [Indexed: 03/14/2023]
Abstract
PURPOSE The aim of this review is to discuss previous studies on the function of stem cells in radiation-induced damage, and the factors affecting these processes, in the hope of improving our understanding of the different stem cells and the communication networks surrounding them. This is essential for the development of effective stem cell-based therapies to regenerate or replace normal tissues damaged by radiation. CONCLUSION In salivary glands, senescence-associated cytokines and inflammation-associated cells have a greater effect on stem cells. In the intestinal glands, Paneth cells strongly affect stem cell-mediated tissue regeneration after radiation treatment. In the pancreas, β-cells as well as protein C receptor positive (Procr) cells are expected to be key cells in the treatment of diabetes. In the bone marrow, a variety of cytokines such as CXC-chemokine ligand 12 (CXCL12) and stem cell factor (SCF), contribute to the functional recovery of hematopoietic stem cells after irradiation.
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Affiliation(s)
- Yingtong Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, and Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zheran Liu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Liqiang Hu
- West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Ling He
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Lianlian Yang
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zijian Qin
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yuping Xie
- Department of Oncology, Chengdu First People's Hospital, Chengdu, Sichuan, China
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Lei Dai
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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15
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Ferreira MR, Andreyev JN, Wedlake L, Dearnaley DP. Comment on "Exploiting dietary fibre and the gut microbiota in pelvic radiotherapy patients". Br J Cancer 2023; 128:711-712. [PMID: 36717675 PMCID: PMC9977733 DOI: 10.1038/s41416-023-02163-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/05/2022] [Accepted: 01/13/2023] [Indexed: 01/31/2023] Open
Affiliation(s)
- Miguel R Ferreira
- Guys and St Thomas NHS Foundation Trust, London, UK.
- King's College London, London, UK.
| | | | | | - David P Dearnaley
- The Royal Marsden NHS Foundation Trust, London, UK
- The Institute of Cancer Research, London, UK
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16
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Abstract
Lactiplantibacillus plantarum promotes growth in undernourished mice.
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Affiliation(s)
- Jitender Yadav
- Department of Immunology, Medical Sciences Building, University of Toronto, Toronto, ON, Canada
| | - Dana J Philpott
- Department of Immunology, Medical Sciences Building, University of Toronto, Toronto, ON, Canada
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17
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Schwarzer M, Gautam UK, Makki K, Lambert A, Brabec T, Joly A, Šrůtková D, Poinsot P, Novotná T, Geoffroy S, Courtin P, Hermanová PP, Matos RC, Landry JJM, Gérard C, Bulteau AL, Hudcovic T, Kozáková H, Filipp D, Chapot-Chartier MP, Šinkora M, Peretti N, Boneca IG, Chamaillard M, Vidal H, De Vadder F, Leulier F. Microbe-mediated intestinal NOD2 stimulation improves linear growth of undernourished infant mice. Science 2023; 379:826-833. [PMID: 36821686 DOI: 10.1126/science.ade9767] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 01/04/2023] [Indexed: 02/25/2023]
Abstract
The intestinal microbiota is known to influence postnatal growth. We previously found that a strain of Lactiplantibacillus plantarum (strain LpWJL) buffers the adverse effects of chronic undernutrition on the growth of juvenile germ-free mice. Here, we report that LpWJL sustains the postnatal growth of malnourished conventional animals and supports both insulin-like growth factor-1 (IGF-1) and insulin production and activity. We have identified cell walls isolated from LpWJL, as well as muramyl dipeptide and mifamurtide, as sufficient cues to stimulate animal growth despite undernutrition. Further, we found that NOD2 is necessary in intestinal epithelial cells for LpWJL-mediated IGF-1 production and for postnatal growth promotion in malnourished conventional animals. These findings indicate that, coupled with renutrition, bacteria cell walls or purified NOD2 ligands have the potential to alleviate stunting.
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Affiliation(s)
- Martin Schwarzer
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Umesh Kumar Gautam
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Kassem Makki
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
| | - Anne Lambert
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Tomáš Brabec
- Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, 14220 Prague, Czech Republic
| | - Amélie Joly
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Dagmar Šrůtková
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Pierre Poinsot
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
- Univ Lyon, Hospices Civil de Lyon, Gastro-enterology and Pediatric Nutrition, Hôpital Femme Mere Enfant, F-69500 Bron, France
| | - Tereza Novotná
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Stéphanie Geoffroy
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Pascal Courtin
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350 Jouy-en-Josas, France
| | - Petra Petr Hermanová
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Renata C Matos
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Jonathan J M Landry
- Genomics Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
| | - Céline Gérard
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
| | - Anne-Laure Bulteau
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - Tomáš Hudcovic
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Hana Kozáková
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Dominik Filipp
- Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, 14220 Prague, Czech Republic
| | | | - Marek Šinkora
- Laboratory of Gnotobiology, Institute of Microbiology of the Czech Academy of Sciences, 54922 Novy Hradek, Czech Republic
| | - Noël Peretti
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
- Univ Lyon, Hospices Civil de Lyon, Gastro-enterology and Pediatric Nutrition, Hôpital Femme Mere Enfant, F-69500 Bron, France
| | - Ivo Gomperts Boneca
- Institut Pasteur, Université Paris Cité, CNRS UMR6047, INSERM U1306, Biology and Genetics of the Bacterial Cell Wall Unit, F-75015 Paris, France
| | | | - Hubert Vidal
- CarMeN Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, 69310 Pierre-Bénite, France
| | - Filipe De Vadder
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
| | - François Leulier
- Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, CNRS UMR5242, UCBL Lyon-1, F-69007 Lyon, France
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18
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Foerster EG, Tsang DKL, Goyal S, Robertson SJ, Robert LM, Maughan H, Streutker CJ, Girardin SE, Philpott DJ. ATG16L1 protects from interferon-γ-induced cell death in the small intestinal crypt. Mucosal Immunol 2023; 16:135-152. [PMID: 36792009 DOI: 10.1016/j.mucimm.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/15/2023]
Abstract
The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.
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Affiliation(s)
| | - Derek K L Tsang
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Shawn Goyal
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | | | - Lukian M Robert
- Department of Immunology, University of Toronto, Toronto, Canada
| | | | - Catherine J Streutker
- Department of Laboratory Medicine, St. Michael's Hospital, Unity Health, Toronto, Canada
| | - Stephen E Girardin
- Department of Immunology, University of Toronto, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
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19
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Kasprzak A. Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia. Int J Mol Sci 2023; 24:ijms24043665. [PMID: 36835075 PMCID: PMC9959216 DOI: 10.3390/ijms24043665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Along with apoptosis and inflammation, autophagy is one of three important mechanisms in CRC. The presence of autophagy/mitophagy in most normal mature intestinal epithelial cells has been confirmed, where it has mainly protective functions against reactive oxygen species (ROS)-induced DNA and protein damage. Autophagy regulates cell proliferation, metabolism, differentiation, secretion of mucins and/or anti-microbial peptides. Abnormal autophagy in intestinal epithelial cells leads to dysbiosis, a decline in local immunity and a decrease in cell secretory function. The insulin-like growth factor (IGF) signaling pathway plays an important role in colorectal carcinogenesis. This is evidenced by the biological activities of IGFs (IGF-1 and IGF-2), IGF-1 receptor type 1 (IGF-1R) and IGF-binding proteins (IGF BPs), which have been reported to regulate cell survival, proliferation, differentiation and apoptosis. Defects in autophagy are found in patients with metabolic syndrome (MetS), inflammatory bowel diseases (IBD) and CRC. In neoplastic cells, the IGF system modulates the autophagy process bidirectionally. In the current era of improving CRC therapies, it seems important to investigate the exact mechanisms not only of apoptosis, but also of autophagy in different populations of tumor microenvironment (TME) cells. The role of the IGF system in autophagy in normal as well as transformed colorectal cells still seems poorly understood. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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20
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Stromal regulation of the intestinal barrier. Mucosal Immunol 2023; 16:221-231. [PMID: 36708806 DOI: 10.1016/j.mucimm.2023.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/27/2022] [Accepted: 01/12/2023] [Indexed: 01/26/2023]
Abstract
The intestinal barrier is a complex structure that allows the absorption of nutrients while ensuring protection against intestinal pathogens and balanced immunity. The development and maintenance of a functional intestinal barrier is a multifactorial process that is only partially understood. Here we review novel findings on the emerging role of mesenchymal cells in this process using insights gained from lineage tracing approaches, Cre-based gene deletion, and single-cell transcriptomics. The current evidence points toward a key organizer role for distinct mesenchymal lineages in intestinal development and homeostasis, regulating both epithelial and immune components of the intestinal barrier. We further discuss recent findings on functional mesenchymal heterogeneity and implications for intestinal regeneration and inflammatory intestinal pathologies.
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21
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Guevara-Garcia A, Soleilhac M, Minc N, Delacour D. Regulation and functions of cell division in the intestinal tissue. Semin Cell Dev Biol 2023:S1084-9521(23)00004-6. [PMID: 36702722 DOI: 10.1016/j.semcdb.2023.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/16/2022] [Accepted: 01/06/2023] [Indexed: 01/26/2023]
Abstract
In multicellular organisms, epithelial cells are key elements of tissue organization. In developing epithelial tissues, cellular proliferation and differentiation are under the tight regulation of morphogenetic programs to ensure correct organ formation and functioning. In these processes, proliferation rates and division orientation regulate the speed, timing and direction of tissue expansion but also its proper patterning. Moreover, tissue homeostasis relies on spatio-temporal modulations of daughter cell behavior and arrangement. These aspects are particularly crucial in the intestine, which is one of the most proliferative tissues in adults, making it a very attractive adult organ system to study the role of cell division on epithelial morphogenesis and organ function. Although epithelial cell division has been the subject of intense research for many years in multiple models, it still remains in its infancy in the context of the intestinal tissue. In this review, we focus on the current knowledge on cell division and regulatory mechanisms at play in the intestinal epithelial tissue, as well as their importance in developmental biology and physiopathology.
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Affiliation(s)
| | - Matis Soleilhac
- Université de Paris, CNRS, Institut Jacques Monod, F-75006 Paris, France
| | - Nicolas Minc
- Université de Paris, CNRS, Institut Jacques Monod, F-75006 Paris, France
| | - Delphine Delacour
- Université de Paris, CNRS, Institut Jacques Monod, F-75006 Paris, France.
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22
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Selvapandiyan A, Puri N, Kumar P, Alam A, Ehtesham NZ, Griffin G, Hasnain SE. Zooming in on common immune evasion mechanisms of pathogens in phagolysosomes: potential broad-spectrum therapeutic targets against infectious diseases. FEMS Microbiol Rev 2023; 47:6780197. [PMID: 36309472 DOI: 10.1093/femsre/fuac041] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 10/06/2022] [Accepted: 10/18/2022] [Indexed: 01/19/2023] Open
Abstract
The intracellular viral, bacterial, or parasitic pathogens evade the host immune challenges to propagate and cause fatal diseases. The microbes overpower host immunity at various levels including during entry into host cells, phagosome formation, phagosome maturation, phagosome-lysosome fusion forming phagolysosomes, acidification of phagolysosomes, and at times after escape into the cytosol. Phagolysosome is the final organelle in the phagocyte with sophisticated mechanisms to degrade the pathogens. The immune evasion strategies by the pathogens include the arrest of host cell apoptosis, decrease in reactive oxygen species, the elevation of Th2 anti-inflammatory response, avoidance of autophagy and antigen cross-presentation pathways, and escape from phagolysosomal killing. Since the phagolysosome organelle in relation to infection/cure is seldom discussed in the literature, we summarize here the common host as well as pathogen targets manipulated or utilized by the pathogens established in phagosomes and phagolysosomes, to hijack the host immune system for their benefit. These common molecules or pathways can be broad-spectrum therapeutic targets for drug development for intervention against infectious diseases caused by different intracellular pathogens.
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Affiliation(s)
| | - Niti Puri
- Cellular and Molecular Immunology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Pankaj Kumar
- Department of Biochemistry, Jamia Hamdard, New Delhi, 110062, India.,Centre for Tuberculosis Research, Department of Medicine, Johns Hopkins University, Baltimore, MD, 21218, United States
| | - Anwar Alam
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India.,Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology-Delhi, New Delhi, 110016, India
| | - Nasreen Zafar Ehtesham
- ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, 110029, India
| | - George Griffin
- Department of Cellular and Molecular Medicine, St. George's University of London, London, SW17 0RE, United Kingdom
| | - Seyed Ehtesham Hasnain
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology-Delhi, New Delhi, 110016, India.,Department of Life Science, School of Basic Sciences and Research, Sharda University, Knowledge Park III, Greater Noida, 201310, India
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23
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Jiang S, Miao Z. High-fat diet induces intestinal mucosal barrier dysfunction in ulcerative colitis: emerging mechanisms and dietary intervention perspective. Am J Transl Res 2023; 15:653-677. [PMID: 36915785 PMCID: PMC10006746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 01/09/2023] [Indexed: 03/16/2023]
Abstract
The incidence of ulcerative colitis (UC) is increasing worldwide, but its pathogenesis remains largely unclear. The intestinal mucosa is a barrier that maintains the stability of the body's internal environment, and dysfunction of this barrier leads to the occurrence and aggravation of UC. A high-fat diet (HFD) contains more animal fat and low fiber, and accumulating evidence has shown that long-term intake of an HFD is associated with UC. The mechanism linking an HFD with intestinal mucosal barrier disruption is multifactorial, and it typically involves microbiota dysbiosis and altered metabolism of fatty acids, bile acids, and tryptophan. Dysbiosis-induced metabolic changes can enhance intestinal permeability through multiple pathways. These changes modulate the programmed death of intestinal epithelial cells, inhibit the secretion of goblet cells and Paneth cells, and impair intercellular interactions. Gut metabolites can also induce intestinal immune imbalance by stimulating multiple proinflammatory signaling pathways and decreasing the effect of anti-inflammatory immune cells. In this review, we critically analyze the molecular mechanisms by which an HFD disrupts the intestinal mucosal barrier (IMB) and contributes to the development of UC. We also discuss the application and future direction of dietary intervention in the treatment of the IMB and prevention of UC.
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Affiliation(s)
- Shijing Jiang
- First Clinical Medical College, Nanjing University of Chinese Medicine Nanjing, Jiangsu, China
| | - Zhiwei Miao
- Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine Zhangjiagang, Suzhou, Jiangsu, China
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24
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The role of NOD2 in intestinal immune response and microbiota modulation: A therapeutic target in inflammatory bowel disease. Int Immunopharmacol 2022; 113:109466. [DOI: 10.1016/j.intimp.2022.109466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/11/2022] [Accepted: 10/24/2022] [Indexed: 11/25/2022]
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25
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You Y, Xiao Y, Lu Y, Du J, Cai H, Cai W, Yan W. Postbiotic muramyl dipeptide alleviates colitis via activating autophagy in intestinal epithelial cells. Front Pharmacol 2022; 13:1052644. [PMID: 36506547 PMCID: PMC9727138 DOI: 10.3389/fphar.2022.1052644] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
The pathogenesis of IBD is complicated and still unclear. Nucleotide-binding oligomerization domain 2 (NOD2) plays a significant role in regulating gut inflammation under the activation of muramyl dipeptide (MDP), which is used as a postbiotic. The study aimed to investigate the effect of MDP on the intestinal barrier in colitis and the mechanism involved. In this study, C57BL/6 mice were challenged with dextran sodium sulfate (DSS) for establishing a colitis model with the pre-treatment of MDP in vivo. Intestinal permeability was reflected by detecting the serum concentration of 4 kDa Fluorescein Isothiocyanate-Dextran. The expression of inflammation, barrier-related proteins, and autophagy was tested by Western Blotting. Proliferation and apoptosis in intestinal epithelial cells were detected by immunohistochemistry. Caco-2 cells were exposed to lipopolysaccharide for imitating inflammation in vitro. The findings showed that administration of MDP ameliorated losses of body weight loss, gross injury, and histology score of the colon in the DSS-induced colitis mice. MDP significantly ameliorated the condition of gut permeability, and promoted intestinal barrier repair by increasing the expression of Zonula occludens-1 and E-cadherin. Meanwhile, MDP promoted proliferation and reduced apoptosis of intestinal epithelial cells. In the experiment group treated with MDP, LC3 was upregulated, and p62 was downregulated, respectively. These results suggested that MDP stimulation attenuates intestinal inflammation both in vivo and in vitro. Potentially, MDP reduced the intestinal barrier damage by regulating autophagy in intestinal epithelial cells. Future trials investigating the effects of MDP-based postbiotics on IBD may be promising.
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Affiliation(s)
- Yaying You
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Yongtao Xiao
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Ying Lu
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jun Du
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Hui Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Wei Cai
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,*Correspondence: Weihui Yan, ; Wei Cai,
| | - Weihui Yan
- Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Shanghai Institute for Pediatric Research, Shanghai, China,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China,*Correspondence: Weihui Yan, ; Wei Cai,
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26
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Reis Ferreira M, Pasto A, Ng T, Patel V, Guerrero Urbano T, Sears C, Wade WG. The microbiota and radiotherapy for head and neck cancer: What should clinical oncologists know? Cancer Treat Rev 2022; 109:102442. [PMID: 35932549 DOI: 10.1016/j.ctrv.2022.102442] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 11/23/2022]
Abstract
Radiotherapy is a linchpin in head and neck squamous cell carcinoma (HN-SCC) treatment. Modulating tumour and/or normal tissue biology offers opportunities to further develop HN-SCC radiotherapy. The microbiota, which can exhibit homeostatic properties and be a modulator of immunity, has recently received considerable interest from the Oncology community. Microbiota research in head and neck oncology has also flourished. However, available data are difficult to interpret for clinical and radiation oncologists. In this review, we focus on how microbiota research can contribute to the improvement of radiotherapy for HN-SCC, focusing on how current and future research can be translated back to the clinic. We include in-depth discussions about the microbiota, its multiple habitats and relevance to human physiology, mechanistic interactions with HN-SCC, available evidence on microbiota and HNC oncogenesis, efficacy and toxicity of treatment. We discuss clinically-relevant areas such as the role of the microbiota as a predictive and prognostic biomarker, as well as the potential of leveraging the microbiota and its interactions with immunity to improve treatment results. Importantly, we draw parallels with other cancers where research is more mature. We map out future directions of research and explain clinical implications in detail.
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Affiliation(s)
- Miguel Reis Ferreira
- King's College London, London, UK; Guys and St Thomas NHS Foundation Trust, London, UK.
| | | | - Tony Ng
- King's College London, London, UK
| | - Vinod Patel
- King's College London, London, UK; Guys and St Thomas NHS Foundation Trust, London, UK
| | | | - Cynthia Sears
- Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, USA
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27
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Luo H, Li M, Wang F, Yang Y, Wang Q, Zhao Y, Du F, Chen Y, Shen J, Zhao Q, Zeng J, Wang S, Chen M, Li X, Li W, Sun Y, Gu L, Wen Q, Xiao Z, Wu X. The role of intestinal stem cell within gut homeostasis: Focusing on its interplay with gut microbiota and the regulating pathways. Int J Biol Sci 2022; 18:5185-5206. [PMID: 35982910 PMCID: PMC9379405 DOI: 10.7150/ijbs.72600] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 07/29/2022] [Indexed: 12/05/2022] Open
Abstract
Intestinal stem cells (ISCs) play an important role in maintaining intestinal homeostasis via promoting a healthy gut barrier. Within the stem cell niche, gut microbiota linking the crosstalk of dietary influence and host response has been identified as a key regulator of ISCs. Emerging insights from recent research reveal that ISC and gut microbiota interplay regulates epithelial self-renewal. This article reviews the recent knowledge on the key role of ISC in their local environment (stem cell niche) associating with gut microbiota and their metabolites as well as the signaling pathways. The current progress of intestinal organoid culture is further summarized. Subsequently, the key challenges and future directions are discussed.
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Affiliation(s)
- Haoming Luo
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yifei Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Qin Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianyun Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Jiuping Zeng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Qinglian Wen
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
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28
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Qiao L, Yan S, Dou X, Song X, Chang J, Pi S, Zhang X, Xu C. Biogenic Selenium Nanoparticles Alleviate Intestinal Epithelial Barrier Damage through Regulating Endoplasmic Reticulum Stress-Mediated Mitophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3982613. [PMID: 36035212 PMCID: PMC9410834 DOI: 10.1155/2022/3982613] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/06/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022]
Abstract
The intestinal barrier plays a fundamental role in body health. Intracellular redox imbalance can trigger endoplasmic reticulum stress (ERS) and mitophagy, leading to intestinal barrier damage. Our previous studies demonstrated that mitophagy is closely associated with the protective effects of biogenic selenium nanoparticles (SeNPs) on intestinal epithelial barrier function. Thus, we hypothesize that ERS and mitophagy are likely involved in the regulatory effects of SeNPs on oxidative stress-induced intestinal epithelial barrier dysfunction. The results showed that oxidative stress or ERS caused the increase of intestinal epithelial permeability. SeNPs effectively alleviated hydrogen peroxide (H2O2-)-induced structural damage of endoplasmic reticulum (ER) and mitochondria of porcine jejunal epithelial cells (IPEC-J2). SeNPs significantly decreased intracellular inositol triphosphate (IP3) and Ca2+ concentration, down-regulated inositol trisphosphate receptor (IP3R) expression level, and up-regulated ER-resident selenoproteins mRNA levels in IPEC-J2 cells exposed to H2O2. In addition, SeNPs pretreatment significantly decreased the intracellular Ca2+, IP3, IP3R, and reactive oxygen species (ROS) levels; protected the structure and function of ER and mitochondria; and effectively alleviated the increase of intestinal epithelial permeability of IPEC-J2 cells exposed to tunicamycin (TM). Moreover, SeNPs significantly inhibited the colocalization of mitochondria and lysosomes. Furthermore, compared with TM model group, SeNPs significantly inhibited the activation of PERK/eIF2α/ATF4 and AMPK/mTOR/PINK1 signaling pathway. The PERK agonist (CCT020312) and the AMPK agonist (AICAR) could reverse the protective effects of SeNPs on IPEC-J2 cells. The PERK inhibitor (GSK2656157) and the AMPK inhibitor (compound C) had a similar effect on IPEC-J2 cells as that of SeNPs. In summary, the protective effects of SeNPs on intestinal barrier dysfunction are closely associated with ERS-related PERK and mitophagy-related AMPK signaling pathway.
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Affiliation(s)
- Lei Qiao
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Shuqi Yan
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xina Dou
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xiaofan Song
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Jiajing Chang
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Shanyao Pi
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xinyi Zhang
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Chunlan Xu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
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29
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Deretic V, Lazarou M. A guide to membrane atg8ylation and autophagy with reflections on immunity. J Cell Biol 2022; 221:e202203083. [PMID: 35699692 PMCID: PMC9202678 DOI: 10.1083/jcb.202203083] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/16/2022] [Accepted: 05/26/2022] [Indexed: 12/11/2022] Open
Abstract
The process of membrane atg8ylation, defined herein as the conjugation of the ATG8 family of ubiquitin-like proteins to membrane lipids, is beginning to be appreciated in its broader manifestations, mechanisms, and functions. Classically, membrane atg8ylation with LC3B, one of six mammalian ATG8 family proteins, has been viewed as the hallmark of canonical autophagy, entailing the formation of characteristic double membranes in the cytoplasm. However, ATG8s are now well described as being conjugated to single membranes and, most recently, proteins. Here we propose that the atg8ylation is coopted by multiple downstream processes, one of which is canonical autophagy. We elaborate on these biological outputs, which impact metabolism, quality control, and immunity, emphasizing the context of inflammation and immunological effects. In conclusion, we propose that atg8ylation is a modification akin to ubiquitylation, and that it is utilized by different systems participating in membrane stress responses and membrane remodeling activities encompassing autophagy and beyond.
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Affiliation(s)
- Vojo Deretic
- Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM
| | - Michael Lazarou
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
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30
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Zhang S, Paul S, Kundu P. NF-κB Regulation by Gut Microbiota Decides Homeostasis or Disease Outcome During Ageing. Front Cell Dev Biol 2022; 10:874940. [PMID: 35846362 PMCID: PMC9285657 DOI: 10.3389/fcell.2022.874940] [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: 02/13/2022] [Accepted: 06/13/2022] [Indexed: 11/15/2022] Open
Abstract
Human beings and their indigenous microbial communities have coexisted for centuries, which led to the development of co-evolutionary mechanisms of communication and cooperation. Such communication machineries are governed by sophisticated multi-step feedback loops, which typically begin with the recognition of microbes by pattern recognition receptors (PRRs), followed by a host transcriptional response leading to the release of effector molecules. Our gastrointestinal tract being the main platform for this interaction, a variety of host intestinal cells tightly regulate these loops to establish tolerance towards the microbial communities of the gut and maintain homeostasis. The transcription factor, nuclear factor kappa B (NF-κB) is an integral component of such a communication apparatus, which plays a critical role in determining the state of homeostasis or inflammation associated with dysbiosis in the host. Here we outline the crucial role of NF-κB in host response to microbial cues in the context of ageing and associated diseases.
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Affiliation(s)
- Shuning Zhang
- Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Soumyajeet Paul
- Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Parag Kundu
- Laboratory for Microbiota-Host Interactions, The Center for Microbes, Development and Health, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
- *Correspondence: Parag Kundu,
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31
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From Intestinal Epithelial Homeostasis to Colorectal Cancer: Autophagy Regulation in Cellular Stress. Antioxidants (Basel) 2022; 11:antiox11071308. [PMID: 35883800 PMCID: PMC9311735 DOI: 10.3390/antiox11071308] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 06/24/2022] [Accepted: 06/27/2022] [Indexed: 02/01/2023] Open
Abstract
The intestinal epithelium is continuously exposed to abundant stress stimuli, which relies on an evolutionarily conserved process, autophagy, to maintain its homeostasis by degrading and recycling unwanted and damaged intracellular substances. Otherwise, disruption of this balance will result in the development of a wide range of disorders, including colorectal cancer (CRC). Dysregulated autophagy is implicated in the regulation of cellular responses to stress during the development, progression, and treatment of CRC. However, experimental investigations addressing the impact of autophagy in different phases of CRC have generated conflicting results, showing that autophagy is context-dependently related to CRC. Thus, both inhibition and activation of autophagy have been proposed as therapeutic strategies against CRC. Here, we will discuss the multifaceted role of autophagy in intestinal homeostasis and CRC, which may provide insights for future research directions.
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32
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Wang J, Liu J, Wang J, Wang S, Li F, Li R, Liu P, Li M, Wang C. Identification of proteomic markers for prediction of the response to 5-Fluorouracil based neoadjuvant chemoradiotherapy in locally advanced rectal cancer patients. Cancer Cell Int 2022; 22:117. [PMID: 35292026 PMCID: PMC8922748 DOI: 10.1186/s12935-022-02530-0] [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: 11/29/2021] [Accepted: 02/21/2022] [Indexed: 11/10/2022] Open
Abstract
Background Neoadjuvant chemoradiotherapy (nCRT) prior to surgery is the standard treatment for patients with locally advanced rectal cancer (LARC), while parts of them show poor therapeutic response accompanied by therapy adverse effects. Predictive biomarkers for nCRT response could facilitate the guidance on treatment decisions but are still insufficient until now, which limits the clinical applications of nCRT in LARC patients. Methods In our study, 37 formalin-fixed paraffin-embedded tumor biopsies were obtained from patients with LARC before receiving 5-fluorouracil based nCRT. Proteomics analyses were conducted to identify the differentially expressed proteins (DEPs) between total responders (TR) and poor responders (PR). The DEPs were validated via ROC plotter web tool and their predictive performance was evaluated by receiver operating characteristic analysis. Functional enrichment analyses were performed to further explore the potential mechanisms underlying nCRT response. Results Among 3,998 total proteins, 91 DEPs between TR and PR were screened out. HSPA4, NIPSNAP1, and SPTB all with areas under the curve (AUC) ~ 0.8 in the internal discovery cohort were independently validated by the external mRNA datasets (AUC ~ 0.7), and their protein levels were linearly correlated with the graded responses to nCRT in the internal cohort. The combination of HSPA4 and SPTB could distinctly discriminate the TR and PR groups (AUC = 0.980, p < 0.0001). Moreover, multiple combinations of the three proteins realized increased specificity and/or sensitivity, while achieving favorable predictive value when moderate responders were introduced into the ROC analysis. Pathways including DNA damage repair, cell cycle, and epithelial mesenchymal transition were involved in nCRT response according to the enrichment analysis results. Conclusions HSPA4, SPTB and NIPSNAP1 in tumor biopsies and/or their optional combinations might be potential predictive markers for nCRT response in patients with LARC. The DEPs and their related functions have implications for the potential mechanisms of treatment response to nCRT in patients with LARC. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02530-0.
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Affiliation(s)
- Jianan Wang
- Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China.,Medical School of Chinese PLA, Beijing, 100853, China
| | - Jiayu Liu
- Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China
| | - Jinyang Wang
- Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China.,School of Laboratory Medicine, Weifang Medical College, Weifang, 261053, Shandong, China
| | - Shijian Wang
- Nankai University School of Medicine, Nankai University, Tianjin, 300071, China
| | - Feifei Li
- Department of Pathology, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China
| | - Ruibing Li
- Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China
| | - Peng Liu
- Department of Pathology, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China
| | - Mianyang Li
- Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China.
| | - Chengbin Wang
- Department of Laboratory Medicine, The First Medical Centre of Chinese PLA General Hospital, Beijing, 100853, China.
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STAT6/VDR Axis Mitigates Lung Inflammatory Injury by Promoting Nrf2 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2485250. [PMID: 35047105 PMCID: PMC8763503 DOI: 10.1155/2022/2485250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/17/2021] [Accepted: 12/14/2021] [Indexed: 11/18/2022]
Abstract
Lung inflammatory injury is a global public health concern. It is characterized by infiltration of diverse inflammatory cells and thickening of pulmonary septum along with oxidative stress to airway epithelial cells. STAT6 is a nuclear transcription factor that plays a crucial role in orchestrating the immune response, but its function in tissue inflammatory injury has not been comprehensively studied. Here, we demonstrated that STAT6 activation can protect against particle-induced lung inflammatory injury by resisting oxidative stress. Specifically, genetic ablation of STAT6 was observed to worsen particle-induced lung injury mainly by disrupting the lungs' antioxidant capacity, as reflected by the downregulation of the Nrf2 signaling pathway, an increase in malondialdehyde levels, and a decrease in glutathione levels. Vitamin D receptor (VDR) has been previously proved to positively regulate Nrf2 signals. In this study, silencing VDR expression in human bronchial epithelial BEAS-2B cells consistently suppressed autophagy-mediated activation of the Nrf2 signaling pathway, thereby aggravating particle-induced cell damage. Mechanically, STAT6 activation promoted the nuclear translocation of VDR, which increased the transcription of autophagy-related genes and induced Nrf2 signals, and silencing VDR abolished these effects. Our research provides important insights into the role of STAT6 in oxidative damage and reveals its potential underlying mechanism. This information not only deepens the appreciation of STAT6 but also opens new avenues for the discovery of therapies for inflammatory respiratory system disorders.
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Shin M, Ferguson M, Willms RJ, Jones LO, Petkau K, Foley E. Immune regulation of intestinal-stem-cell function in Drosophila. Stem Cell Reports 2022; 17:741-755. [PMID: 35303435 PMCID: PMC9023782 DOI: 10.1016/j.stemcr.2022.02.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 11/03/2022] Open
Abstract
Intestinal progenitor cells integrate signals from their niche, and the gut lumen, to divide and differentiate at a rate that maintains an epithelial barrier to microbial invasion of the host interior. Despite the importance of evolutionarily conserved innate immune defenses to maintain stable host-microbe relationships, we know little about contributions of stem-cell immunity to gut homeostasis. We used Drosophila to determine the consequences of intestinal-stem-cell immune activity for epithelial homeostasis. We showed that loss of stem-cell immunity greatly impacted growth and renewal in the adult gut. In particular, we found that inhibition of stem-cell immunity impeded progenitor-cell growth and differentiation, leading to a gradual loss of stem-cell numbers with age and an impaired differentiation of mature enteroendocrine cells. Our results highlight the importance of immune signaling in stem cells for epithelial function in the adult gut.
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Affiliation(s)
- Minjeong Shin
- Department of Medical Microbiology and Immunology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton, AB Canada
| | - Meghan Ferguson
- Department of Medical Microbiology and Immunology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton, AB Canada; Department of Cell Biology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton AB, Canada
| | - Reegan J Willms
- Department of Medical Microbiology and Immunology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton, AB Canada
| | - Lena O Jones
- Department of Medical Microbiology and Immunology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton, AB Canada
| | - Kristina Petkau
- Department of Medical Microbiology and Immunology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton, AB Canada
| | - Edan Foley
- Department of Medical Microbiology and Immunology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton, AB Canada; Department of Cell Biology Faculty of Medicine and Dentistry University of Alberta Edmonton, Edmonton AB, Canada.
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Sheahan BJ, Theriot CM, Cortes JE, Dekaney CM. Prolonged oral antimicrobial administration prevents doxorubicin-induced loss of active intestinal stem cells. Gut Microbes 2022; 14:2018898. [PMID: 35012435 PMCID: PMC8757478 DOI: 10.1080/19490976.2021.2018898] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Acute intestinal mucositis is a common off-target effect of chemotherapy, leading to co-morbidities such as vomiting, diarrhea, sepsis, and death. We previously demonstrated that the presence of enteric bacteria modulates the extent of jejunal epithelial damage induced by doxorubicin (DXR) in mice. Despite conventional thinking of the crypt as a sterile environment, recent evidence suggests that bacterial signaling influences aISC function. In this study, we labeled aISCs using transgenic Lgr5-driven fluorescence or with immunostaining for OLFM4. We examined the effect of DXR in both germ free (GF) mice and mice depleted of microbiota using an established antimicrobial treatment protocol (AMBx). We found differences in DXR-induced loss of aISCs between GF mice and mice treated with AMBx. aISCs were decreased after DXR in GF mice, whereas AMBx mice retained aISC expression after DXR. Neither group of mice exhibited an inflammatory response to DXR, suggesting the difference in aISC retention was not due to differences in local tissue inflammation. Therefore, we suspected that there was a protective microbial signal present in the AMBx mice that was not present in the GF mice. 16S rRNA sequencing of jejunal luminal contents demonstrated that AMBx altered the fecal and jejunal microbiota. In the jejunal contents, AMBx mice had increased abundance of Ureaplasma and Burkholderia. These results suggest pro-survival signaling from microbiota in AMBx-treated mice to the aISCs, and that this signaling maintains aISCs in the face of chemotherapeutic injury. Manipulation of the enteric microbiota presents a therapeutic target for reducing the severity of chemotherapy-associated mucositis.
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Affiliation(s)
- Breanna J Sheahan
- Molecular Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NCUSA,Department of Pharmacology and Cancer Biology, Duke University, Durham, NcUSA
| | - Casey M Theriot
- Population Health and Pathobiology, College of Veterinary Medicine, NC State University, Raleigh, NCUSA
| | - Jocsa E. Cortes
- Molecular Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NCUSA
| | - Christopher M Dekaney
- Molecular Biomedical Sciences, College of Veterinary Medicine, NC State University, Raleigh, NCUSA,CONTACT Christopher M Dekaney Molecular Biomedical Sciences, College of Veterinary Medicine,NC State University1060 William Moore Drive, Campus Box 8401, Raleigh, North Carolina27607
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Li H, Pang B, Nie B, Qu S, Zhang K, Xu J, Yang M, Liu J, Li S. Dioscin promotes autophagy by regulating the AMPK-mTOR pathway in ulcerative colitis. Immunopharmacol Immunotoxicol 2022; 44:238-246. [PMID: 35174751 DOI: 10.1080/08923973.2022.2037632] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dioscin is reported to alleviate the dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in mice. Autophagy plays an anti-inflammatory role in UC. We herein aimed to explore the biological functions of dioscin in autophagy in UC. METHODS To explore the effects of dioscin on UC progression, a DSS-induced mouse model of UC was established. Body weight, disease activity index and macroscopic damage index scores were recorded for seven days. Hematoxylin & Eosin (HE) staining was used to stain colon sections and an BX53 microscope was prepared to observe pathological changes. The activities of glutathione, superoxidative dismutase, and malondialdehyde were determined by commercially available kits. Western blotting was performed to measure the protein levels of p-AMPK/AMPK, p-mTOR/mTOR and autophagy-related genes. RESULTS The DSS-induced colitis and oxidative stress in mice were ameliorated after dioscin treatment. Dioscin promoted the phosphorylation of AMPK to inhibit mTOR activation and facilitated autophagy in DSS-induced mice model of UC. CONCLUSION Dioscin promotes autophagy by promoting the phosphorylation of AMPK to inhibit mTOR activation in ulcerative colitis.
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Affiliation(s)
- Han Li
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Bo Pang
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Bin Nie
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Shifang Qu
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Kuanxin Zhang
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Jinxiu Xu
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Ming Yang
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Jie Liu
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Shasha Li
- Department of Geriatrics, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
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Markandey M, Bajaj A, Ilott NE, Kedia S, Travis S, Powrie F, Ahuja V. Gut microbiota: sculptors of the intestinal stem cell niche in health and inflammatory bowel disease. Gut Microbes 2022; 13:1990827. [PMID: 34747326 PMCID: PMC8583176 DOI: 10.1080/19490976.2021.1990827] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Intestinal epithelium represents a dynamic and diverse cellular system that continuously interacts with gut commensals and external cues. Intestinal stem cells, which lie at the heart of epithelial renewal and turnover, proliferate to maintain a steady stem cell population and differentiate to form functional epithelial cell types. This rather sophisticated assembly-line is maintained by an elaborate micro-environment, sculpted by a myriad of host and gut microbiota-derived signals, forming an intestinal stem cell niche. This complex, yet crucial signaling niche undergoes dynamic changes during homeostasis and chronic intestinal inflammation. Inflammatory bowel disease refers to a chronic inflammatory response toward pathogenic or commensal microbiota, in a genetically susceptible host. Compositional and functional alterations in gut microbiota are pathognomonic of IBD.The present review highlights the modulatory role of gut microbiota on the intestinal stem cell niche during homeostasis and inflammatory bowel disease. We discuss the mechanisms of direct action of gut commensals (through microbiota-derived or microbiota-influenced metabolites) on ISCs, followed by their effects via other epithelial and immune cell types.
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Affiliation(s)
- Manasvini Markandey
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Aditya Bajaj
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Simon Travis
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India,CONTACT Vineet Ahuja Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India, 110029
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Foerster EG, Mukherjee T, Cabral-Fernandes L, Rocha JD, Girardin SE, Philpott DJ. How autophagy controls the intestinal epithelial barrier. Autophagy 2022; 18:86-103. [PMID: 33906557 PMCID: PMC8865220 DOI: 10.1080/15548627.2021.1909406] [Citation(s) in RCA: 203] [Impact Index Per Article: 67.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 03/15/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
Macroautophagy/autophagy is a cellular catabolic process that results in lysosome-mediated recycling of organelles and protein aggregates, as well as the destruction of intracellular pathogens. Its role in the maintenance of the intestinal epithelium is of particular interest, as several autophagy-related genes have been associated with intestinal disease. Autophagy and its regulatory mechanisms are involved in both homeostasis and repair of the intestine, supporting intestinal barrier function in response to cellular stress through tight junction regulation and protection from cell death. Furthermore, a clear role has emerged for autophagy not only in secretory cells but also in intestinal stem cells, where it affects their metabolism, as well as their proliferative and regenerative capacity. Here, we review the physiological role of autophagy in the context of intestinal epithelial maintenance and how genetic mutations affecting autophagy contribute to the development of intestinal disease.Abbreviations: AKT1S1: AKT1 substrate 1; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; APC: APC regulator of WNT signaling pathway; ATF6: activating transcription factor 6; ATG: autophagy related; atg16l1[ΔIEC] mice: mice with a specific deletion of Atg16l1 in intestinal epithelial cells; ATP: adenosine triphosphate; BECN1: beclin 1; bsk/Jnk: basket; CADPR: cyclic ADP ribose; CALCOCO2: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CD: Crohn disease; CDH1/E-cadherin: cadherin 1; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator; CGAS: cyclic GMP-AMP synthase; CLDN2: claudin 2; CoPEC: colibactin-producing E. coli; CRC: colorectal cancer; CYP1A1: cytochrome P450 family 1 subfamily A member 1; DC: dendritic cell; DDIT3: DNA damage inducible transcript 3; DEPTOR: DEP domain containing MTOR interacting protein; DSS: dextran sulfate sodium; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2AK4/GCN2: eukaryotic translation initiation factor 2 alpha kinase 4; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; GABARAP: GABA type A receptor-associated protein; HMGB1: high mobility group box 1; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; IBD: inflammatory bowel disease; IEC: intestinal epithelial cell; IFN: interferon; IFNG/IFNγ:interferon gamma; IL: interleukin; IRGM: immunity related GTPase M; ISC: intestinal stem cell; LGR5: leucine rich repeat containing G protein-coupled receptor 5; LRRK2: leucine rich repeat kinase 2; MAP1LC3A/LC3: microtubule associated protein 1 light chain 3 alpha; MAPK/JNK: mitogen-activated protein kinase; MAPK14/p38 MAPK: mitogen-activated protein kinase 14; MAPKAP1: MAPK associated protein 1; MAVS: mitochondrial antiviral signaling protein; miRNA: microRNA; MLKL: mixed lineage kinase domain like pseudokinase; MLST8: MTOR associated protein, LST8 homolog; MNV: murine norovirus; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NLRP: NLR family pyrin domain containing; NOD: nucleotide binding oligomerization domain containing; NRBF2: nuclear receptor binding factor 2; OPTN: optineurin; OXPHOS: oxidative phosphorylation; P: phosphorylation; Patj: PATJ crumbs cell polarity complex component; PE: phosphatidyl-ethanolamine; PI3K: phosphoinositide 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PPARG: peroxisome proliferator activated receptor gamma; PRR5: proline rich 5; PRR5L: proline rich 5 like; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RER: rough endoplasmic reticulum; RHEB: Ras homolog, MTORC1 binding; RICTOR: RPTOR independent companion of MTOR complex 2; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; RPTOR: regulatory associated protein of MTOR complex 1; RPS6KB1: ribosomal protein S6 kinase B1; SH3GLB1: SH3 domain containing GRB2 like, endophilin B1; SNP: single-nucleotide polymorphism; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; STING1: stimulator of interferon response cGAMP interactor 1; TA: transit-amplifying; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TGM2: transglutaminase 2; TJ: tight junction; TJP1/ZO1: tight junction protein 1; TNBS: 2,4,6-trinitrobenzene sulfonic acid; TNF/TNFα: tumor necrosis factor; Tor: target of rapamycin; TRAF: TNF receptor associated factor; TRIM11: tripartite motif containing 11; TRP53: transformation related protein 53; TSC: TSC complex subunit; Ub: ubiquitin; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; USO1/p115: USO1 vesicle transport factor; UVRAG: UV radiation resistance associated; WIPI: WD repeat domain, phosphoinositide interacting; WNT: WNT family member; XBP1: X-box binding protein 1; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.
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Affiliation(s)
| | - Tapas Mukherjee
- Department of Immunology, University of Toronto, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | | | | | - Stephen E. Girardin
- Department of Immunology, University of Toronto, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Dana J. Philpott
- Department of Immunology, University of Toronto, Toronto, Canada
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Ahmed I, Yusuf K, Roy BC, Stubbs J, Anant S, Attard TM, Sampath V, Umar S. Dietary Interventions Ameliorate Infectious Colitis by Restoring the Microbiome and Promoting Stem Cell Proliferation in Mice. Int J Mol Sci 2021; 23:339. [PMID: 35008767 PMCID: PMC8745185 DOI: 10.3390/ijms23010339] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/21/2021] [Accepted: 12/25/2021] [Indexed: 12/15/2022] Open
Abstract
Decreases in short-chain-fatty-acids (SCFAs) are linked to inflammatory bowel disease (IBD). Yet, the mechanisms through which SCFAs promote wound healing, orchestrated by intestinal stem cells, are poorly understood. We discovered that, in mice with Citrobacter rodentium (CR)-induced infectious colitis, treatment with Pectin and Tributyrin diets reduced the severity of colitis by restoring Firmicutes and Bacteroidetes and by increasing mucus production. RNA-seq in young adult mouse colon (YAMC) cells identified higher expression of Lgr4, Lgr6, DCLK1, Muc2, and SIGGIR after Butyrate treatment. Lineage tracing in CR-infected Lgr5-EGFP-IRES-CreERT2/ROSA26-LacZ (Lgr5-R) mice also revealed an expansion of LacZ-labeled Lgr5(+) stem cells in the colons of both Pectin and Tributyrin-treated mice compared to control. Interestingly, gut microbiota was required for Pectin but not Tributyrin-induced Lgr5(+) stem cell expansion. YAMC cells treated with sodium butyrate exhibited increased Lgr5 promoter reporter activity due to direct Butyrate binding with Lgr5 at -4.0 Kcal/mol, leading to thermal stabilization. Upon ChIP-seq, H3K4me3 increased near Lgr5 transcription start site that contained the consensus binding motif for a transcriptional activator of Lgr5 (SPIB). Thus, a multitude of effects on gut microbiome, differential gene expression, and/or expansion of Lgr5(+) stem cells seem to underlie amelioration of colitis following dietary intervention.
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Affiliation(s)
- Ishfaq Ahmed
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
| | - Kafayat Yusuf
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
| | - Badal C. Roy
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
| | - Jason Stubbs
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Shrikant Anant
- Cancer Biology Department, University of Kansas Medical Center, Kansas City, KS 66160, USA;
| | - Thomas M. Attard
- Department of Pediatrics and Gastroenterology, Children’s Mercy Hospital, Kansas City, KS 66160, USA; (T.M.A.); (V.S.)
| | - Venkatesh Sampath
- Department of Pediatrics and Gastroenterology, Children’s Mercy Hospital, Kansas City, KS 66160, USA; (T.M.A.); (V.S.)
| | - Shahid Umar
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66160, USA; (I.A.); (K.Y.); (B.C.R.)
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Dou SD, Zhang JN, Xie XL, Liu T, Hu JL, Jiang XY, Wang MM, Jiang HD. MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1/parkin-mediated mitophagy. Open Med (Wars) 2021; 16:1718-1727. [PMID: 34825063 PMCID: PMC8590110 DOI: 10.1515/med-2021-0394] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 10/05/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
Mitophagy affects the activation of hepatic stellate cells (HSCs). Mitochondria-targeted ubiquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces the production of intracellular reactive oxygen species (ROS). However, its relationship with mitophagy remains unclear. This study evaluated mitophagy during HSC activation and the effects of MitoQ on mitophagy in cell culture and in an animal model of the activation of HSCs. We found that MitoQ reduced the activation of HSCs and alleviated hepatic fibrosis. PINK1 (PTEN-induced putative kinase 1) is a putative serine/threonine kinase located in the mitochondria’s outer membrane. While the activation of primary HSCs or LX-2 cells was associated with reduced PINK1/parkin-mediated mitophagy, MitoQ reduced intracellular ROS levels, enhanced PINK1/parkin-mediated mitophagy, and inhibited the activation of HSCs. After knocking down the key mitophagy-related protein, PINK1, in LX-2 cells to block mitophagy, MitoQ intervention failed to inhibit HSC activation. Our results showed that MitoQ inhibited the activation of HSCs and alleviated hepatic fibrosis by enhancing PINK1/parkin-mediated mitophagy.
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Affiliation(s)
- Shi-Ding Dou
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China.,Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jiu-Na Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Xiao-Li Xie
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Ting Liu
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Jun-Li Hu
- Emergency Department, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiao-Yu Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
| | - Miao-Miao Wang
- Department of Infectious Diseases, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Hui-Ding Jiang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Hebei Clinical Research Center for Digestive Disease, Hebei, China
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Chen S, Wang W, Tan HY, Lu Y, Li Z, Qu Y, Wang N, Wang D. Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action. Front Cell Dev Biol 2021; 9:715200. [PMID: 34414192 PMCID: PMC8369482 DOI: 10.3389/fcell.2021.715200] [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: 05/26/2021] [Accepted: 07/15/2021] [Indexed: 01/07/2023] Open
Abstract
Autophagy is an intracellular scavenging mechanism induced to eliminate damaged, denatured, or senescent macromolecular substances and organelles in the body. The regulation of autophagy plays essential roles in the processes of cellular homeostasis and senescence. Dysregulated autophagy is a common feature of several human diseases, including cancers and neurodegenerative disorders. The initiation and development of these disorders have been shown to be associated with the maintenance of disease-specific stem cell compartments. In this review, we summarize recent advances in our understanding of the role of autophagy in the maintenance of stemness. Specifically, we focus on the intersection between autophagy and adult stem cells in the initiation and progression of specific diseases. Accordingly, this review highlights the role of autophagy in stemness maintenance from the perspective of disease-associated mechanisms, which may be fundamental to our understanding of the pathogeneses of human diseases and the development of effective therapies.
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Affiliation(s)
- Shanshan Chen
- School of Life Sciences, Jilin University, Changchun, China
| | - Wenqi Wang
- School of Life Sciences, Jilin University, Changchun, China
| | - Hor-Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhiping Li
- School of Life Sciences, Jilin University, Changchun, China
| | - Yidi Qu
- School of Life Sciences, Jilin University, Changchun, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun, China
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun, China
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Li P, Chang M. Roles of PRR-Mediated Signaling Pathways in the Regulation of Oxidative Stress and Inflammatory Diseases. Int J Mol Sci 2021; 22:ijms22147688. [PMID: 34299310 PMCID: PMC8306625 DOI: 10.3390/ijms22147688] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress is a major contributor to the pathogenesis of various inflammatory diseases. Accumulating evidence has shown that oxidative stress is characterized by the overproduction of reactive oxygen species (ROS). Previous reviews have highlighted inflammatory signaling pathways, biomarkers, molecular targets, and pathogenetic functions mediated by oxidative stress in various diseases. The inflammatory signaling cascades are initiated through the recognition of host cell-derived damage associated molecular patterns (DAMPs) and microorganism-derived pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). In this review, the effects of PRRs from the Toll-like (TLRs), the retinoic acid-induced gene I (RIG-I)-like receptors (RLRs) and the NOD-like (NLRs) families, and the activation of these signaling pathways in regulating the production of ROS and/or oxidative stress are summarized. Furthermore, important directions for future studies, especially for pathogen-induced signaling pathways through oxidative stress are also reviewed. The present review will highlight potential therapeutic strategies relevant to inflammatory diseases based on the correlations between ROS regulation and PRRs-mediated signaling pathways.
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Affiliation(s)
- Pengwei Li
- State Key Laboratory of Freshwater Ecology and Biotechnology, Key Laboratory of Aquaculture Disease Control, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;
| | - Mingxian Chang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Key Laboratory of Aquaculture Disease Control, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China;
- Innovation Academy for Seed Design, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Correspondence: ; Tel.: +86-027-6878-0760
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Li H, Jiang M, Zhao SY, Zhang SQ, Lu L, He X, Feng GX, Wu X, Fan SJ. Exosomes are involved in total body irradiation-induced intestinal injury in mice. Acta Pharmacol Sin 2021; 42:1111-1123. [PMID: 33637947 PMCID: PMC8209125 DOI: 10.1038/s41401-021-00615-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/15/2021] [Indexed: 12/16/2022]
Abstract
Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy. Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo, but its effects on ionizing radiation-induced intestinal damage are undetermined. In this study we investigated the roles of exosomes during total body irradiation (TBI)-induced intestinal injury in vivo and in vitro. We isolated exosomes from serum of donor mice 24 h after lethal dose (9 Gy) TBI (Exo-IR-24h), then intravenously injected the exosomes into receipt mice, and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss, but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice. Moreover, Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure. In murine intestinal epithelial MODE-K cells, treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis, resulting in decreased cell vitality. We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells. In addition, TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, injection of GW4869 (an inhibitor of exosome biogenesis and release, 1.25 mg·kg-1·d-1, ip, for 5 consecutive days starting 3 days before radiation exposure) was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage. Collectively, this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.
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Affiliation(s)
- Hang Li
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.
| | - Mian Jiang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Shu-Ya Zhao
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Shu-Qin Zhang
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Lu Lu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Xin He
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Guo-Xing Feng
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Xin Wu
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China
| | - Sai-Jun Fan
- Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.
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Ouladan S, Gregorieff A. Taking a Step Back: Insights into the Mechanisms Regulating Gut Epithelial Dedifferentiation. Int J Mol Sci 2021; 22:ijms22137043. [PMID: 34208872 PMCID: PMC8268356 DOI: 10.3390/ijms22137043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/15/2021] [Accepted: 06/27/2021] [Indexed: 01/22/2023] Open
Abstract
Despite the environmental constraints imposed upon the intestinal epithelium, this tissue must perform essential functions such as nutrient absorption and hormonal regulation, while also acting as a critical barrier to the outside world. These functions depend on a variety of specialized cell types that are constantly renewed by a rapidly proliferating population of intestinal stem cells (ISCs) residing at the base of the crypts of Lieberkühn. The niche components and signals regulating crypt morphogenesis and maintenance of homeostatic ISCs have been intensely studied over the last decades. Increasingly, however, researchers are turning their attention to unraveling the mechanisms driving gut epithelial regeneration due to physical damage or infection. It is now well established that injury to the gut barrier triggers major cell fate changes, demonstrating the highly plastic nature of the gut epithelium. In particular, lineage tracing and transcriptional profiling experiments have uncovered several injury-induced stem-cell populations and molecular markers of the regenerative state. Despite the progress achieved in recent years, several questions remain unresolved, particularly regarding the mechanisms driving dedifferentiation of the gut epithelium. In this review, we summarize the latest studies, primarily from murine models, that define the regenerative processes governing the gut epithelium and discuss areas that will require more in-depth investigation.
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Affiliation(s)
- Shaida Ouladan
- Department of Pathology, McGill University, Montréal, QC H3A 2B4, Canada;
- McGill Regenerative Medicine Network, Montréal, QC H3A 1A3, Canada
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
| | - Alex Gregorieff
- Department of Pathology, McGill University, Montréal, QC H3A 2B4, Canada;
- McGill Regenerative Medicine Network, Montréal, QC H3A 1A3, Canada
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
- Correspondence:
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Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids. Int J Mol Sci 2021; 22:ijms22126431. [PMID: 34208517 PMCID: PMC8233984 DOI: 10.3390/ijms22126431] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 01/08/2023] Open
Abstract
Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.
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Harris M, Potgieter J, Ishfaq K, Shahzad M. Developments for Collagen Hydrolysate in Biological, Biochemical, and Biomedical Domains: A Comprehensive Review. MATERIALS (BASEL, SWITZERLAND) 2021; 14:2806. [PMID: 34070353 PMCID: PMC8197487 DOI: 10.3390/ma14112806] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/19/2021] [Accepted: 05/19/2021] [Indexed: 01/11/2023]
Abstract
The collagen hydrolysate, a proteinic biopeptide, is used for various key functionalities in humans and animals. Numerous reviews explained either individually or a few of following aspects: types, processes, properties, and applications. In the recent developments, various biological, biochemical, and biomedical functionalities are achieved in five aspects: process, type, species, disease, receptors. The receptors are rarely addressed in the past which are an essential stimulus to activate various biomedical and biological activities in the metabolic system of humans and animals. Furthermore, a systematic segregation of the recent developments regarding the five main aspects is not yet reported. This review presents various biological, biochemical, and biomedical functionalities achieved for each of the beforementioned five aspects using a systematic approach. The review proposes a novel three-level hierarchy that aims to associate a specific functionality to a particular aspect and its subcategory. The hierarchy also highlights various key research novelties in a categorical manner that will contribute to future research.
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Affiliation(s)
- Muhammad Harris
- Massey Agrifood (MAF) Digital Labs, Massey University, Palmerston North 4410, New Zealand;
- Industrial and Manufacturing Engineering Department, Rachna College of Engineering and Technology, Gujranwala 52250, Pakistan;
| | - Johan Potgieter
- Massey Agrifood (MAF) Digital Labs, Massey University, Palmerston North 4410, New Zealand;
| | - Kashif Ishfaq
- Industrial and Manufacturing Engineering Department, University of Engineering and Technology, Lahore 54890, Pakistan;
| | - Muhammad Shahzad
- Industrial and Manufacturing Engineering Department, Rachna College of Engineering and Technology, Gujranwala 52250, Pakistan;
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Ferguson M, Foley E. Microbial recognition regulates intestinal epithelial growth in homeostasis and disease. FEBS J 2021; 289:3666-3691. [PMID: 33977656 DOI: 10.1111/febs.15910] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/06/2021] [Accepted: 04/30/2021] [Indexed: 12/13/2022]
Abstract
The intestine is constantly exposed to a dynamic community of microbes. Intestinal epithelial cells respond to microbes through evolutionarily conserved recognition pathways, such as the immune deficiency (IMD) pathway of Drosophila, the Toll-like receptor (TLR) response of flies and vertebrates, and the vertebrate nucleotide-binding oligomerization domain (NOD) pathway. Microbial recognition pathways are tightly controlled to respond effectively to pathogens, tolerate the microbiome, and limit intestinal disease. In this review, we focus on contributions of different model organisms to our understanding of how epithelial microbe recognition impacts intestinal proliferation and differentiation in homeostasis and disease. In particular, we compare how microbes and subsequent recognition by the intestine influences barrier integrity, intestinal repair and tumorigenesis in Drosophila, zebrafish, mice, and organoids. In addition, we discuss the importance of microbial recognition in homeostatic intestinal growth and discuss how immune pathways directly impact stem cell and crypt dynamics.
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Affiliation(s)
- Meghan Ferguson
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Edan Foley
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Liput M, Magliaro C, Kuczynska Z, Zayat V, Ahluwalia A, Buzanska L. Tools and approaches for analyzing the role of mitochondria in health, development and disease using human cerebral organoids. Dev Neurobiol 2021; 81:591-607. [PMID: 33725382 DOI: 10.1002/dneu.22818] [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: 10/03/2020] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 12/16/2022]
Abstract
Mitochondria are cellular organelles involved in generating energy to power various processes in the cell. Although the pivotal role of mitochondria in neurogenesis was demonstrated (first in animal models), very little is known about their role in human embryonic neurodevelopment and its pathology. In this respect human-induced pluripotent stem cells (hiPSC)-derived cerebral organoids provide a tractable, alternative model system of the early neural development and disease that is responsive to pharmacological and genetic manipulations, not possible to apply in humans. Although the involvement of mitochondria in the pathogenesis and progression of neurodegenerative diseases and brain dysfunction has been demonstrated, the precise role they play in cell life and death remains unknown, compromising the development of new mitochondria-targeted approaches to treat human diseases. The cerebral organoid model of neurogenesis and disease in vitro provides an unprecedented opportunity to answer some of the most fundamental questions about mitochondrial function in early human neurodevelopment and neural pathology. Largely an unexplored territory due to the lack of tools and approaches, this review focuses on recent technological advancements in fluorescent and molecular tools, imaging systems, and computational approaches for quantitative and qualitative analyses of mitochondrial structure and function in three-dimensional cellular assemblies-cerebral organoids. Future developments in this direction will further facilitate our understanding of the important role or mitochondrial dynamics and energy requirements during early embryonic development. This in turn will provide a further understanding of how dysfunctional mitochondria contribute to disease processes.
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Affiliation(s)
- Michał Liput
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
| | - Chiara Magliaro
- Research Centre "E. Piaggio", and Department of Information Engineering, University of Pisa, Pisa, Italy
| | - Zuzanna Kuczynska
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
| | - Valery Zayat
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
| | - Arti Ahluwalia
- Research Centre "E. Piaggio", and Department of Information Engineering, University of Pisa, Pisa, Italy
| | - Leonora Buzanska
- Department of Stem Cell Bioengineering, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
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Han X, Mslati MA, Davies E, Chen Y, Allaire JM, Vallance BA. Creating a More Perfect Union: Modeling Intestinal Bacteria-Epithelial Interactions Using Organoids. Cell Mol Gastroenterol Hepatol 2021; 12:769-782. [PMID: 33895425 PMCID: PMC8273413 DOI: 10.1016/j.jcmgh.2021.04.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 02/08/2023]
Abstract
Intestinal organoids have become indispensable tools for many gastrointestinal researchers, advancing their studies of nontransformed intestinal epithelial cells, and their roles in an array of diseases, including inflammatory bowel disease and colon cancer. In many cases. these diseases, as well as many enteric infections, reflect pathogenic interactions between bacteria and the gut epithelium. The complexity of studying this microbe-epithelial interface in vivo has led to significant focus on modeling this cross-talk using organoid models. Considering how quickly the organoid field is advancing, it can be difficult to keep up to date with the latest techniques, as well as their respective strengths and weaknesses. This review addresses the advantages of using organoids derived from adult stem cells and the recently identified differences that biopsy location and patient age can have on organoids and their interactions with microbes. Several approaches to introducing bacteria in a relevant (apical) manner (ie, microinjecting 3-dimensional spheroids, polarity-reversed organoids, and 2-dimensional monolayers) also are addressed, as are the key readouts that can be obtained using these models. Lastly, the potential for new approaches, such as air-liquid interface, to facilitate studying bacterial interactions with important but understudied epithelial subsets such as goblet cells and their products, is evaluated.
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Affiliation(s)
- Xiao Han
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Matthias A Mslati
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Emily Davies
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Yan Chen
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Joannie M Allaire
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Bruce A Vallance
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
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Kayisoglu Ö, Schlegel N, Bartfeld S. Gastrointestinal epithelial innate immunity-regionalization and organoids as new model. J Mol Med (Berl) 2021; 99:517-530. [PMID: 33538854 PMCID: PMC8026474 DOI: 10.1007/s00109-021-02043-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 12/18/2020] [Accepted: 01/19/2021] [Indexed: 12/27/2022]
Abstract
The human gastrointestinal tract is in constant contact with microbial stimuli. Its barriers have to ensure co-existence with the commensal bacteria, while enabling surveillance of intruding pathogens. At the centre of the interaction lies the epithelial layer, which marks the boundaries of the body. It is equipped with a multitude of different innate immune sensors, such as Toll-like receptors, to mount inflammatory responses to microbes. Dysfunction of this intricate system results in inflammation-associated pathologies, such as inflammatory bowel disease. However, the complexity of the cellular interactions, their molecular basis and their development remains poorly understood. In recent years, stem cell-derived organoids have gained increasing attention as promising models for both development and a broad range of pathologies, including infectious diseases. In addition, organoids enable the study of epithelial innate immunity in vitro. In this review, we focus on the gastrointestinal epithelial barrier and its regional organization to discuss innate immune sensing and development.
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Affiliation(s)
- Özge Kayisoglu
- Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany
| | - Nicolas Schlegel
- Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Oberduerrbacher Strasse 6, Wuerzburg, Germany
| | - Sina Bartfeld
- Research Centre for Infectious Diseases, Institute for Molecular Infection Biology, Julius Maximilians University of Wuerzburg, Wuerzburg, Germany.
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