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Miller PG, Huang E, Fisher R, Shuler ML. Development of a Microphysiological System to Model Human Cancer Metastasis From the Colon to the Liver. Biotechnol Bioeng 2025; 122:481-494. [PMID: 39587032 PMCID: PMC11810609 DOI: 10.1002/bit.28890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/05/2024] [Accepted: 11/10/2024] [Indexed: 11/27/2024]
Abstract
We describe a novel device to mimic the metastasis of cancer cells from the colon into the liver in a human model. The colon mimic is connected to the liver model by a gravity-driven recirculating unidirectional flow of a blood surrogate and can mimic the five steps of the metastatic cascade: invasion in the colon, intravasation into the bloodstream, systemic transportation, extravasation into the liver, and colonization in the liver. The colon mimic uses established normal colon epithelial organoid cells (NL) and human umbilical vein endothelial cells (HUVEC) plated on opposite sides of a membrane. To better mimic the colon structure the NL side of the membrane is exposed to air to establish an air-liquid interface. The liver mimic consists of human liver sinusoidal endothelial cells (HHSEC) and epithelial hepatic cells (HepG2 C3A) plated in Matrigel on opposite sides of a membrane. Labeled colorectal cancer cells/clusters (CA) from organoids are introduced into an established normal colon epithelial cell (NL) layer from the same patient before assembly of the system or alternatively NL organoids and fluorescently labeled CA organoids from the same patient were prepared as a ratio of 10:1 NL:CA and established together before assembly of the system. Cell viability is greater than 85% in this system. We demonstrate that over 5 days of operation that the five steps of the metastatic cascade are replicated. This novel device allows an in vitro estimate of metastatic capability (as measured by using percentages of the labeled areas per device through ImageJ) in response to selected variables. In this study, the metastatic capability depends on the source of cancer cells (e.g., the patient), the clumping of cancer cells, glucose concentration, and oxygen levels (hypoxia). For the first time, this new in vitro system mimics all five steps of the metastatic cascade in a single device and provides a new device to probe and observe the process of metastasis in a human-based model in only 5 days. The rapid observation is due to the use of a high concentration of cancer cells in the colon (e.g. 10%) and the absence of the immune system. Our device makes it possible to probe aspects of each step of metastasis and interactions between steps.
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Affiliation(s)
- Paula G. Miller
- Department of Biomedical Engineering, Cornell University, Weill Hall, Ithaca, NY 14883, USA
| | - Emina Huang
- Department of Surgery, UT Southwestern Medical Center, NB5.226, 5323 Harry Hines Blvd., Dallas, Texas 75390-8845
| | - Robert Fisher
- Department of Surgery, UT Southwestern Medical Center, NB5.226, 5323 Harry Hines Blvd., Dallas, Texas 75390-8845
| | - Michael L. Shuler
- Department of Biomedical Engineering, Cornell University, Weill Hall, Ithaca, NY 14883, USA
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Özkan A, Merry G, Chou DB, Posey RR, Stejskalova A, Calderon K, Sperry M, Horvath V, Ferri LE, Carlotti E, McDonald SAC, Winton DJ, Riccardi R, Bordeianou L, Hall S, Goyal G, Ingber DE. Inflammatory Bowel Disease Drivers Revealed in Human Organ Chips. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.12.05.24318563. [PMID: 39677416 PMCID: PMC11643285 DOI: 10.1101/2024.12.05.24318563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. Inflammation and fibrosis are accentuated by peristalsis-like motions in IBD Chips and when exposed to pregnancy-associated hormones in female IBD Chips. Carcinogen exposure also increases inflammation, gene mutations, and chromosome duplication in IBD Chips, but not in Healthy Chips. These data enabled by human Organ Chip technology suggest that the intestinal stroma and peristalsis-associated mechanical deformations play a key role in driving inflammation and disease progression in male and female IBD patients.
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Affiliation(s)
- Alican Özkan
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Gwenn Merry
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - David B. Chou
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Ryan R. Posey
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Anna Stejskalova
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Karina Calderon
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Megan Sperry
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Viktor Horvath
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Current address: Entact Bio, Watertown, MA
| | - Lorenzo E. Ferri
- Thoracic and Upper GI Cancer Research Laboratories, Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Department of Experimental Surgery and Department of Surgery, McGill University, Montreal, QC, Canada
| | - Emanuela Carlotti
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Stuart A. C. McDonald
- Clonal Dynamics in Epithelia Laboratory, Queen Mary University of London, London, United Kingdom
| | - Douglas J. Winton
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, United Kingdom
| | - Rocco Riccardi
- Department of Surgery, Massachusetts General Hospital, Boston, MA
| | | | - Sean Hall
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Current address: Iovance Therapeutics, Tampa, FL
| | - Girija Goyal
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
| | - Donald E. Ingber
- Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA
- Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA
- Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA
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Hartl K, Bayram Ş, Wetzel A, Harnack C, Lin M, Fischer AS, Liu L, Beccaceci G, Mastrobuoni G, Geisberger S, Forbes M, Monteiro BJE, Macino M, Flores RE, Engelmann C, Mollenkopf HJ, Schupp M, Tacke F, Sanders AD, Kempa S, Berger H, Sigal M. p53 terminates the regenerative fetal-like state after colitis-associated injury. SCIENCE ADVANCES 2024; 10:eadp8783. [PMID: 39453996 PMCID: PMC11506124 DOI: 10.1126/sciadv.adp8783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 09/20/2024] [Indexed: 10/27/2024]
Abstract
Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.
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Affiliation(s)
- Kimberly Hartl
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Şafak Bayram
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Alexandra Wetzel
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christine Harnack
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Manqiang Lin
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Anne-Sophie Fischer
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Lichao Liu
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Giulia Beccaceci
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Guido Mastrobuoni
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Sabrina Geisberger
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Martin Forbes
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Benedict J. E. Monteiro
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Martina Macino
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Roberto E. Flores
- Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Michael Schupp
- Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Frank Tacke
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ashley D. Sanders
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Kempa
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Hilmar Berger
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Michael Sigal
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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Ojo BA, Heo L, Fox SR, Waddell A, Moreno-Fernandez ME, Gibson M, Tran T, Dunn AL, Elknawy EIA, Saini N, López-Rivera JA, Divanovic S, de Jesus Perez VA, Rosen MJ. Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.22.609271. [PMID: 39229116 PMCID: PMC11370613 DOI: 10.1101/2024.08.22.609271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Background & Aims Ulcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Patient-derived organoids recapitulate complexities of the parent tissue in health and disease; however, whether colon organoids (colonoids) model metabolic impairments in the pediatric UC epithelium is unclear. This study determined the functional metabolic differences in the colon epithelia using epithelial colonoids from pediatric patients. Methods We developed biopsy-derived colonoids from pediatric patients with endoscopically active UC, inactive UC, and those without endoscopic or histologic evidence of colon inflammation (non-IBD controls). We extensively interrogated metabolic dysregulation through extracellular flux analyses and tested potential therapies that recapitulate or ameliorate such metabolic dysfunction. Results Epithelial colonoids from active UC patients exhibit elevated oxygen consumption and proton leak supported by enhanced glycolytic capacity and dysregulated lipid metabolism. The hypermetabolic features in active UC colonoids were associated with increased cellular stress and chemokine secretion, specifically during differentiation. Transcriptomic and pathway analyses indicated a role for PPAR-α in lipid-induced hypermetabolism in active UC colonoids, which was validated by PPAR-α activation in non-IBD colonoids. Accordingly, limiting neutral lipid accumulation in active UC colonoids through pharmacological inhibition of PPAR-α induced a metabolic shift towards glucose consumption, suppressed hypermetabolism and chemokine secretion, and improved cellular stress markers. Control and inactive UC colonoids had similar metabolic and transcriptomic profiles. Conclusions Our pediatric colonoids revealed significant lipid-related metabolic dysregulation in the pediatric UC epithelium that may be alleviated by PPAR-α inhibition. This study supports the advancement of colonoids as a preclinical human model for testing epithelial-directed therapies against such metabolic dysfunction. What You Need to Know Background and Context: Colon mucosa healing in pediatric UC requires reinstating normal epithelial function but a lack of human preclinical models of the diseased epithelium hinders the development of epithelial-directed interventions. New Findings Using colon biopsy-derived epithelial organoids, samples from pediatric patients with active UC show hyperactive metabolic function largely driven by enhanced lipid metabolism. Pharmacologic inhibition of lipid metabolism alleviates metabolic dysfunction, cellular stress, and chemokine production. Limitations Though our epithelial colon organoids from active UC patients show targetable metabolic and molecular features from non-IBD controls, they were cultured under sterile conditions, which may not fully capture any potential real-time contributions of the complex inflammatory milieu typically present in the disease. Clinical Research Relevance Current therapies for pediatric UC mainly target the immune system despite the need for epithelial healing to sustain remission. We identified a pharmacologic target that regulates epithelial metabolism and can be developed for epithelial-directed therapy in UC.Basic Research Relevance: Pediatric UC patient tissue adult stem cell-derived colon epithelial organoids retain disease-associated metabolic pathology and can serve as preclinical human models of disease. Excess reliance on lipids as an energy source leads to oxidative and inflammatory dysfunction in pediatric UC colon organoids. Preprint: This manuscript is currently on bioRxiv. doi: https://doi.org/10.1101/2024.08.22.609271 Lay Summary: Using patient tissue-derived colon epithelial organoids, the investigators identified epithelial metabolic dysfunction and inflammation in pediatric ulcerative colitis that can be alleviated by PPAR-a inhibition.
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Liu Y, Wang D, Luan Y, Tao B, Li Q, Feng Q, Zhou H, Mu J, Yu J. The application of organoids in colorectal diseases. Front Pharmacol 2024; 15:1412489. [PMID: 38983913 PMCID: PMC11231380 DOI: 10.3389/fphar.2024.1412489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 06/07/2024] [Indexed: 07/11/2024] Open
Abstract
Intestinal organoids are a three-dimensional cell culture model derived from colon or pluripotent stem cells. Intestinal organoids constructed in vitro strongly mimic the colon epithelium in cell composition, tissue architecture, and specific functions, replicating the colon epithelium in an in vitro culture environment. As an emerging biomedical technology, organoid technology has unique advantages over traditional two-dimensional culture in preserving parental gene expression and mutation, cell function, and biological characteristics. It has shown great potential in the research and treatment of colorectal diseases. Organoid technology has been widely applied in research on colorectal topics, including intestinal tumors, inflammatory bowel disease, infectious diarrhea, and intestinal injury regeneration. This review focuses on the application of organoid technology in colorectal diseases, including the basic principles and preparation methods of organoids, and explores the pathogenesis of and personalized treatment plans for various colorectal diseases to provide a valuable reference for organoid technology development and application.
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Affiliation(s)
- Yanxin Liu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Yanhong Luan
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Boqiang Tao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
| | - Qirong Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Qiang Feng
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Hengzong Zhou
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Jianfeng Mu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
| | - Jinhai Yu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, China
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Wang Z, Chen S, Guo Y, Zhang R, Zhang Q, Jiang X, Li M, Jiang Y, Ye L, Guo X, Li C, Zhang G, Li D, Chen L, Chen W. Intestinal carcinogenicity screening of environmental pollutants using organoid-based cell transformation assay. Arch Toxicol 2024; 98:1937-1951. [PMID: 38563870 DOI: 10.1007/s00204-024-03729-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 03/07/2024] [Indexed: 04/04/2024]
Abstract
The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.
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Affiliation(s)
- Ziwei Wang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
- Stony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA
| | - Shen Chen
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Yuzhi Guo
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Rui Zhang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Qi Zhang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Xinhang Jiang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Miao Li
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Yue Jiang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Lizhu Ye
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Xiaoyu Guo
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Chuang Li
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Guangtong Zhang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Daochuan Li
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Liping Chen
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China
| | - Wen Chen
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou, 510080, China.
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Xiong D, Wei X, Huang W, Zheng J, Feng R. Prediction significance of autophagy-related genes in survival probability and drug resistance in diffuse large B-cell lymphoma. Aging (Albany NY) 2024; 16:1049-1076. [PMID: 38240686 PMCID: PMC10866451 DOI: 10.18632/aging.205282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 10/15/2023] [Indexed: 02/06/2024]
Abstract
BACKGROUND/AIMS Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has significant prognostic heterogeneity. This study aimed to generate a prognostic prediction model based on autophagy-related genes for DLBCL patients. METHODS Utilizing bioinformatics techniques, we analyzed the clinical information and transcriptome data of DLBCL patients from the Gene Expression Omnibus (GEO) database. Through unsupervised clustering, we identified new autophagy-related molecular subtypes and pinpointed differentially expressed genes (DEGs) between these subtypes. Based on these DEGs, a prognostic model was constructed using Cox and Lasso regression. The effectiveness, accuracy, and clinical utility of this prognostic model were assessed using numerous independent validation cohorts, survival analyses, receiver operating characteristic (ROC) curves, multivariate Cox regression analysis, nomograms, and calibration curves. Moreover, functional analysis, immune cell infiltration, and drug sensitivity analysis were performed. RESULTS DLBCL patients with different clinical characterizations (age, molecular subtypes, ECOG scores, and stages) showed different expression features of autophagy-related genes. The prediction model was constructed based on the eight autophagy-related genes (ADD3, IGFBP3, TPM1, LYZ, AFDN, DNAJC10, GLIS3, and CCDC102A). The prognostic nomogram for overall survival of DLBCL patients incorporated risk level, stage, ECOG scores, and molecular subtypes, showing excellent agreement between observed and predicted outcomes. Differences were noted in the proportions of immune cells (native B cells, Treg cells, CD8+ T cell, CD4+ memory activated T cells, gamma delta T cells, macrophages M1, and resting mast cells) between high-risk and low-risk groups. LYZ and ADD3 exhibited correlations with drug resistance to most chemotherapeutic drugs. CONCLUSIONS This study established a novel prognostic assessment model based on the expression profile of autophagy-related genes and clinical characteristics of DLBCL patients, explored immune infiltration and predicted drug resistance, which may guide precise and individualized immunochemotherapy regimens.
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Affiliation(s)
- Dan Xiong
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- Department of Hematology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan 528308, Guangdong, China
| | - Xiaolei Wei
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Weiming Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jingxia Zheng
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ru Feng
- Department of Hematology, Nanfang Hospital, Southern Medical University or the First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
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8
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Yan L, Gu C, Gao S, Wei B. Epigenetic regulation and therapeutic strategies in ulcerative colitis. Front Genet 2023; 14:1302886. [PMID: 38169708 PMCID: PMC10758477 DOI: 10.3389/fgene.2023.1302886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 12/07/2023] [Indexed: 01/05/2024] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease, and is characterized by the diffuse inflammation and ulceration in the colon and rectum mucosa, even extending to the caecum. Epigenetic modifications, including DNA methylations, histone modifications and non-coding RNAs, are implicated in the differentiation, maturation, and functional modulation of multiple immune and non-immune cell types, and are influenced and altered in various chronic inflammatory diseases, including UC. Here we review the relevant studies revealing the differential epigenetic features in UC, and summarize the current knowledge about the immunopathogenesis of UC through epigenetic regulation and inflammatory signaling networks, regarding DNA methylation, histone modification, miRNAs and lncRNAs. We also discuss the epigenetic-associated therapeutic strategies for the alleviation and treatment of UC, which will provide insights to intervene in the immunopathological process of UC in view of epigenetic regulation.
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Affiliation(s)
- Liwei Yan
- The First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, China
- Departments of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chao Gu
- Departments of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shanyu Gao
- Departments of Anorectal Surgery, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Benzheng Wei
- Center for Medical Artificial Intelligence, Shandong University of Traditional Chinese Medicine, Jinan, China
- Qingdao Academy of Chinese Medical Sciences, Shandong University of Traditional Chinese Medicine, Jinan, China
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9
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Huang R, Yao Y, Tong X, Wang L, Qian W, Lu J, Zhang W, Liu Y, Wang S, Xian S, Zhu Y, Huang J, Guo X, Gu M, Lv H, Bi W, Meng C, Chang Z, Zhang J, Xu D, Ji S. Tracing the evolving dynamics and research hotspots of microbiota and immune microenvironment from the past to the new era. Microbiol Spectr 2023; 11:e0013523. [PMID: 37768071 PMCID: PMC10581186 DOI: 10.1128/spectrum.00135-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 07/31/2023] [Indexed: 09/29/2023] Open
Abstract
Gut microbiota can regulate many physiological processes within gastrointestinal tract and other distal sites. Dysbiosis may not only influence chronic diseases like the inflammatory bowel disease (IBD), metabolic disease, tumor and its therapeutic efficacy, but also deteriorate acute injuries. This article aims to review the documents in this field and summarize the research hotspots as well as developing processes. Gut microbiota and immune microenvironment-related documents from 1976 to 2022 were obtained from the Web of Science Core Collection database. Bibliometrics was used to assess the core authors and journals, most contributive countries and affiliations together with hotspots in this field and keyword co-occurrence analysis. Data were visualized to help comprehension. Nine hundred and twelve documents about gut microbiota and immune microenvironment were retrieved, and the annual publications increased gradually. The most productive author, country, and affiliation were "Zitvogel L," USA and "UNIV TEXAS MD ANDERSON CANC CTR," respectively. FRONTIERS IN IMMUNOLOGY, CANCERS, and INTERNATIONAL JOURNAL OF MOLECULAR SCIENCE were the periodicals with most publications. Keyword co-occurrence analysis identified three clusters, including gut microbiota, inflammation, and IBD. Combined with the visualized analysis of documents and keyword co-occurrence as well as literature reading, we recognized three key topics of gut microbiota: cancer and therapy; immunity, inflammation and IBD; acute injuries and metabolic diseases. This article revealed researches on gut microbiota and immune microenvironment were growing. More attention should be given to the latest hotspots like gut microbiota, inflammation, IBD, cancer and immunotherapy, acute traumas, and metabolic diseases.IMPORTANCEGut microbiota can regulate many physiological processes within gastrointestinal tract and other distal sites. Dysbiosis may not only influence chronic diseases like inflammatory bowel disease (IBD), metabolic disease, tumor and its therapeutic efficacy, but also deteriorate acute injuries. While the application of bibliometrics in the field of gut microbiota and immune microenvironment still remains blank, which focused more on the regulation of the gut microbiota on the immune microenvironment of different kinds of diseases. Here, we intended to review and summarize the presented documents in gut microbiota and immune microenvironment field by bibliometrics. And we revealed researches on gut microbiota and immune microenvironment were growing. More attention should be given to the latest hotspots like gut microbiota, inflammation, IBD, cancer and immunotherapy, acute traumas, and metabolic diseases.
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Affiliation(s)
- Runzhi Huang
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Yuntao Yao
- Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xirui Tong
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Lei Wang
- Beijing Genomics Institute (BGI), Shenzhen, China
| | - Weijin Qian
- Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianyu Lu
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Wei Zhang
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Yifan Liu
- Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Siqiao Wang
- Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Shuyuan Xian
- Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Yushu Zhu
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Jie Huang
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Xinya Guo
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Minyi Gu
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Hanlin Lv
- Beijing Genomics Institute (BGI), Shenzhen, China
| | - Wenshuai Bi
- Beijing Genomics Institute (BGI), Shenzhen, China
| | - Chenwei Meng
- Beijing Genomics Institute (BGI), Shenzhen, China
| | - Zhengyan Chang
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Zhang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Dayuan Xu
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
| | - Shizhao Ji
- Department of Burn Surgery, First Affiliated Hospital of Naval Medical University, and Research Unit of Key Techniques for Treatment of Burns and Combined Burns and Trauma Injury, Chinese Academy of Medical Sciences, Shanghai, China
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10
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Chen Y, Ying Y, Wang M, Ma C, Jia M, Shi L, Wang S, Zheng X, Chen W, Shu XS. A distal super-enhancer activates oncogenic ETS2 via recruiting MECOM in inflammatory bowel disease and colorectal cancer. Cell Death Dis 2023; 14:8. [PMID: 36609474 PMCID: PMC9822945 DOI: 10.1038/s41419-022-05513-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 12/11/2022] [Accepted: 12/12/2022] [Indexed: 01/09/2023]
Abstract
Abnormal activities of distal cis-regulatory elements (CREs) contribute to the initiation and progression of cancer. Gain of super-enhancer (SE), a highly active distal CRE, is essential for the activation of key oncogenes in various cancers. However, the mechanism of action for most tumor-specific SEs still largely remains elusive. Here, we report that a candidate oncogene ETS2 was activated by a distal SE in inflammatory bowel disease (IBD) and colorectal cancer (CRC). The SE physically interacted with the ETS2 promoter and was required for the transcription activation of ETS2. Strikingly, the ETS2-SE activity was dramatically upregulated in both IBD and CRC tissues when compared to normal colon controls and was strongly correlated with the level of ETS2 expression. The tumor-specific activation of ETS2-SE was further validated by increased enhancer RNA transcription from this region in CRC. Intriguingly, a known IBD-risk SNP resides in the ETS2-SE and the genetic variant modulated the level of ETS2 expression through affecting the binding of an oncogenic transcription factor MECOM. Silencing of MECOM induced significant downregulation of ETS2 in CRC cells, and the level of MECOM and ETS2 correlated well with each other in CRC and IBD samples. Functionally, MECOM and ETS2 were both required for maintaining the colony-formation and sphere-formation capacities of CRC cells and MECOM was crucial for promoting migration. Taken together, we uncovered a novel disease-specific SE that distantly drives oncogenic ETS2 expression in IBD and CRC and delineated a mechanistic link between non-coding genetic variation and epigenetic regulation of gene transcription.
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Affiliation(s)
- Yongheng Chen
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Ying Ying
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
- Marshall Laboratory of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Maolin Wang
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
- Clinical Research Center, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515000, China
| | - Canjie Ma
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Min Jia
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Liang Shi
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Shilan Wang
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Xiangyi Zheng
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Wei Chen
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Xing-Sheng Shu
- Department of Physiology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
- Marshall Laboratory of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China.
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11
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Dotti I, Mayorgas A, Salas A. Generation of human colon organoids from healthy and inflammatory bowel disease mucosa. PLoS One 2022; 17:e0276195. [PMID: 36301950 PMCID: PMC9612551 DOI: 10.1371/journal.pone.0276195] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 10/01/2022] [Indexed: 11/05/2022] Open
Abstract
Ulcerative colitis and Crohn's disease are chronic inflammatory bowel diseases (IBD) of unknown cause characterized by a relapsing-remitting behavior. Growing evidence supports the idea that the epithelial barrier plays a central role in the pathogenesis of IBD as well as in its evolution over time, thus representing a potential target for novel therapeutic options. In the last decade, the introduction of 3D epithelial cultures from ex vivo-expanded intestinal adult stem cells (ASCs) has impacted our ability to study the function of the epithelium in several gastrointestinal disorders, including IBD. Here, we describe in detail a reproducible protocol to generate Matrigel-embedded epithelial organoids from ASCs of non-IBD and IBD donors using small colonic biopsies, including steps for its optimization. A slightly modified version of this protocol is also provided in case surgical samples are used. With this method, epithelial organoids can be expanded over several passages, thereby generating a large quantity of viable cells that can be used in multiple downstream analyses including genetic, transcriptional, proteomic and/or functional studies. In addition, 3D cultures generated using our protocol are suitable for the establishment of 2D cultures, which can model relevant cell-to-cell interactions that occur in IBD mucosa.
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Affiliation(s)
- Isabella Dotti
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
| | - Aida Mayorgas
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
| | - Azucena Salas
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBER-EHD, Barcelona, Spain
- * E-mail:
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12
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Sharma TT, Rabizadeh RR, Prabhakar VS, Bury MI, Sharma AK. Evolving Experimental Platforms to Evaluate Ulcerative Colitis. Adv Biol (Weinh) 2022; 6:e2200018. [PMID: 35866469 DOI: 10.1002/adbi.202200018] [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: 02/26/2022] [Revised: 05/06/2022] [Indexed: 01/28/2023]
Abstract
Ulcerative colitis (UC) is a multifactorial disease defined by chronic intestinal inflammation with idiopathic origins. It has a predilection to affect the mucosal lining of the large intestines and rectum. Management of UC depends upon numerous factors that include disease pathogenesis and severity that are maintained via medical or surgical means. Chronic inflammation that is left untreated or managed poorly from a clinical stance can result in intestinal ulceration accompanied by resulting physiological dysfunction. End-stage UC is mediated by surgical intervention with the resection of diseased tissue. This can lead to numerous health-related quality of life issues but is considered a curative approach. Regimens to treat UC are ever evolving and find their basis within various platforms to evaluate and treat UC. Numerous modeling systems have been examined to delineate potential mechanisms of action. However, UC is a heterogenous disease spanning unknown genetic origins coupled with environmental factors that can influence disease outcomes and related treatment procedures. Unfortunately, there is no one-size-fits-all model to fully assess all facets of UC. Within the context of this review article, the utility of various approaches that have been employed to gain insight into different aspects of UC will be investigated.
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Affiliation(s)
- Tiffany T Sharma
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA.,Stanley Manne Children's Research Institute, Chicago, IL, 60611, USA
| | - Rebecca R Rabizadeh
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA
| | - Vibhav S Prabhakar
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA
| | - Matthew I Bury
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA
| | - Arun K Sharma
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA.,Stanley Manne Children's Research Institute, Chicago, IL, 60611, USA.,Feinberg School of Medicine, Department of Urology, Northwestern University, Chicago, IL, 60611, USA.,McCormick School of Engineering, Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA.,Center for Advanced Regenerative Engineering (CARE), Northwestern University, Evanston, IL, 60208, USA.,Simpson Querrey Institute (SQI), Northwestern University, Chicago, IL, 60611, USA
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13
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Yan P, Li Z, Xian S, Wang S, Fu Q, Zhu J, Yue X, Zhang X, Chen S, Zhang W, Lu J, Yin H, Huang R, Huang Z. Construction of the prognostic enhancer RNA regulatory network in osteosarcoma. Transl Oncol 2022; 25:101499. [PMID: 36001923 PMCID: PMC9421318 DOI: 10.1016/j.tranon.2022.101499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/08/2022] [Accepted: 07/26/2022] [Indexed: 11/30/2022] Open
Abstract
Our enhancer RNAs-based prognostic model showed good predictive ability in osteosarcoma. CCAAT enhancer binding protein alpha (CEBPA) may regulate CD8A molecule (CD8A). CD8A activation may promote CD3E molecule (CD3E) expression and activate allograft rejection in CD8+ T cells. Above signal axis provided new insights in the mechanism of osteosarcoma tumorigenesis. Background Osteosarcoma (OS) is a common malignant tumor in osteoarticular system, the 5-year overall survival of which is poor. Enhancer RNAs (eRNAs) have been implicated in the tumorigenesis of various cancer types, whereas their roles in OS tumorigenesis remains largely unclear. Methods Differentially expressed eRNAs (DEEs), transcription factors (DETFs), target genes (DETGs) were identified using limma (Linear Models for Microarray Analysis) package. Prognosis-related DEEs were accessed by univariate Cox regression analysis. A multivariate model was constructed to evaluate the prognosis of OS samples. Prognosis-related DEEs, DETFs, DETGs, immune cells, and hallmark gene sets were co-analyzed to construct an regulatory network. Specific inhibitors were also filtered by connectivity Map analysis. External validation and scRNA-seq analysis were performed to verify our key findings. Results 3,981 DETGs, 468 DEEs, 51 DETFs, and 27 differentially expressed hallmark gene sets were identified. A total of Multivariate risk predicting model based on 18 prognosis-related DEEs showed a high accuracy (area under curve (AUC) = 0.896). GW-8510 was the candidate inhibitor targeting prognosis-related DEEs (mean = 0.670, p < 0.001). Based on the OS tumorigenesis-related regulation network, we identified that CCAAT enhancer binding protein alpha (CEBPA, DETF) may regulate CD8A molecule (CD8A, DEE), thereby promoting the transcription of CD3E molecule (CD3E, DETG), which may affect allograft rejection based on CD8+ T cells. Conclusion We constructed an eRNA-based prognostic model for predicting the OS patients’ prognosis and explored the potential regulation network for OS tumorigenesis by an integrated bioinformatics analysis, providing promising therapeutic targets for OS patients.
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Affiliation(s)
- Penghui Yan
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zhenyu Li
- Tongji University School of Medicine, Shanghai 200092, China
| | - Shuyuan Xian
- Tongji University School of Medicine, Shanghai 200092, China
| | - Siqiao Wang
- Tongji University School of Medicine, Shanghai 200092, China; Division of Spine, Department of Orthopedics, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai 200065, China
| | - Qing Fu
- Tongji University School of Medicine, Shanghai 200092, China
| | - Jiwen Zhu
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xi Yue
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Xinkun Zhang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
| | - Shaofeng Chen
- Department of Orthopedics, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Wei Zhang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Jianyu Lu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Huabin Yin
- Department of Orthopedics, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200065, China.
| | - Runzhi Huang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Tongji University School of Medicine, Shanghai 200092, China; Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China.
| | - Zongqiang Huang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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14
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Hautefort I, Poletti M, Papp D, Korcsmaros T. Everything You Always Wanted to Know About Organoid-Based Models (and Never Dared to Ask). Cell Mol Gastroenterol Hepatol 2022; 14:311-331. [PMID: 35643188 PMCID: PMC9233279 DOI: 10.1016/j.jcmgh.2022.04.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 12/12/2022]
Abstract
Homeostatic functions of a living tissue, such as the gastrointestinal tract, rely on highly sophisticated and finely tuned cell-to-cell interactions. These crosstalks evolve and continuously are refined as the tissue develops and give rise to specialized cells performing general and tissue-specific functions. To study these systems, stem cell-based in vitro models, often called organoids, and non-stem cell-based primary cell aggregates (called spheroids) appeared just over a decade ago. These models still are evolving and gaining complexity, making them the state-of-the-art models for studying cellular crosstalk in the gastrointestinal tract, and to investigate digestive pathologies, such as inflammatory bowel disease, colorectal cancer, and liver diseases. However, the use of organoid- or spheroid-based models to recapitulate in vitro the highly complex structure of in vivo tissue remains challenging, and mainly restricted to expert developmental cell biologists. Here, we condense the founding knowledge and key literature information that scientists adopting the organoid technology for the first time need to consider when using these models for novel biological questions. We also include information that current organoid/spheroid users could use to add to increase the complexity to their existing models. We highlight the current and prospective evolution of these models through bridging stem cell biology with biomaterial and scaffold engineering research areas. Linking these complementary fields will increase the in vitro mimicry of in vivo tissue, and potentially lead to more successful translational biomedical applications. Deepening our understanding of the nature and dynamic fine-tuning of intercellular crosstalks will enable identifying novel signaling targets for new or repurposed therapeutics used in many multifactorial diseases.
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Affiliation(s)
- Isabelle Hautefort
- Earlham Institute, Organisms and Ecosystems Programme, Norwich, United Kingdom
| | - Martina Poletti
- Earlham Institute, Organisms and Ecosystems Programme, Norwich, United Kingdom; Quadram Institute Bioscience, Gut Microbes and Health Programme, Norwich, United Kingdom
| | - Diana Papp
- Quadram Institute Bioscience, Gut Microbes and Health Programme, Norwich, United Kingdom
| | - Tamas Korcsmaros
- Earlham Institute, Organisms and Ecosystems Programme, Norwich, United Kingdom; Quadram Institute Bioscience, Gut Microbes and Health Programme, Norwich, United Kingdom; Imperial College London, Department of Metabolism, Digestion and Reproduction, London, United Kingdom.
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15
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Boye TL, Steenholdt C, Jensen KB, Nielsen OH. Molecular manipulations and intestinal stem cell-derived organoids in inflammatory bowel disease. Stem Cells 2022; 40:447-457. [DOI: 10.1093/stmcls/sxac014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 02/15/2022] [Indexed: 11/13/2022]
Abstract
Abstract
The pathogenesis of inflammatory bowel diseases (IBD) involves genetic predisposition, environmental factors, and a broadly dysregulated intestinal immune response to the commensal intestinal microflora. The interface between genetic predisposition and environmental factors is reflected in the epigenetic regulation at the transcriptional level. Treatment targets now involve mucosal and histological healing, but the future might additionally include normalization of intestinal cellular functions also at the molecular level, for example comprising complete restoration of phenotypic, genotypic, and epigenetic states. Recent developments in patient-derived epithelial intestinal stem cell (ISC) organoid technologies have opened exciting new therapeutic opportunities to potentially attain molecular healing by combining stem cell therapy with molecular manipulations using (epi)drugs and/or CRISPR/Cas9 genome editing. Here, we are the first to discuss the possibility for phenotypic, genotypic, and epigenetic restoration via molecular manipulations and stem cell therapy in IBD from a clinical perspective.
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Affiliation(s)
- Theresa Louise Boye
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark
| | - Casper Steenholdt
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark
| | - Kim Bak Jensen
- Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, DK-2200 Copenhagen N, Denmark
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark
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16
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Ojo BA, VanDussen KL, Rosen MJ. The Promise of Patient-Derived Colon Organoids to Model Ulcerative Colitis. Inflamm Bowel Dis 2022; 28:299-308. [PMID: 34251431 PMCID: PMC8804507 DOI: 10.1093/ibd/izab161] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Indexed: 12/11/2022]
Abstract
Physiologic, molecular, and genetic findings all point to impaired intestinal epithelial function as a key element in the multifactorial pathogenesis of ulcerative colitis (UC). The lack of epithelial-directed therapies is a conspicuous weakness of our UC therapeutic armamentarium. However, a critical barrier to new drug discovery is the lack of preclinical human models of UC. Patient tissue-derived colon epithelial organoids (colonoids) are primary epithelial stem cell-derived in vitro structures capable of self-organization and self-renewal that hold great promise as a human preclinical model for UC drug development. Several single and multi-tissue systems for colonoid culture have been developed, including 3-dimensional colonoids grown in a gelatinous extracellular matrix, 2-dimensional polarized monolayers, and colonoids on a chip that model luminal and blood flow and nutrient delivery. A small number of pioneering studies suggest that colonoids derived from UC patients retain some disease-related transcriptional and epigenetic changes, but they also raise questions regarding the persistence of inflammatory transcriptional programs in culture over time. Additional research is needed to fully characterize the extent to which and under what conditions colonoids accurately model disease-associated epithelial molecular and functional aberrations. With further advancement and standardization of colonoid culture methodology, colonoids will likely become an important tool for realizing precision medicine in UC.
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Affiliation(s)
- Babajide A Ojo
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
| | - Kelli L VanDussen
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
| | - Michael J Rosen
- Divisions of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
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17
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Rana N, Privitera G, Kondolf HC, Bulek K, Lechuga S, De Salvo C, Corridoni D, Antanaviciute A, Maywald RL, Hurtado AM, Zhao J, Huang EH, Li X, Chan ER, Simmons A, Bamias G, Abbott DW, Heaney JD, Ivanov AI, Pizarro TT. GSDMB is increased in IBD and regulates epithelial restitution/repair independent of pyroptosis. Cell 2022; 185:283-298.e17. [PMID: 35021065 PMCID: PMC8879997 DOI: 10.1016/j.cell.2021.12.024] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 10/09/2021] [Accepted: 12/16/2021] [Indexed: 02/08/2023]
Abstract
Gasdermins are a family of structurally related proteins originally described for their role in pyroptosis. Gasdermin B (GSDMB) is currently the least studied, and while its association with genetic susceptibility to chronic mucosal inflammatory disorders is well established, little is known about its functional relevance during active disease states. Herein, we report increased GSDMB in inflammatory bowel disease, with single-cell analysis identifying epithelial specificity to inflamed colonocytes/crypt top colonocytes. Surprisingly, mechanistic experiments and transcriptome profiling reveal lack of inherent GSDMB-dependent pyroptosis in activated epithelial cells and organoids but instead point to increased proliferation and migration during in vitro wound closure, which arrests in GSDMB-deficient cells that display hyper-adhesiveness and enhanced formation of vinculin-based focal adhesions dependent on PDGF-A-mediated FAK phosphorylation. Importantly, carriage of disease-associated GSDMB SNPs confers functional defects, disrupting epithelial restitution/repair, which, altogether, establishes GSDMB as a critical factor for restoration of epithelial barrier function and the resolution of inflammation.
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Affiliation(s)
- Nitish Rana
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Departments of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Giuseppe Privitera
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Hannah C Kondolf
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Katarzyna Bulek
- Department of Inflammation & Immunity, Learner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Susana Lechuga
- Department of Inflammation & Immunity, Learner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Carlo De Salvo
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Daniele Corridoni
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Agne Antanaviciute
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Rebecca L Maywald
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alexander M Hurtado
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Junjie Zhao
- Department of Inflammation & Immunity, Learner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Emina H Huang
- Departments of Cancer Biology and Colon & Rectal Surgery, Learner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Xiaoxia Li
- Department of Inflammation & Immunity, Learner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - E Ricky Chan
- Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Alison Simmons
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Giorgos Bamias
- Academic Department of Gastroenterology, Ethnikon & Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
| | - Derek W Abbott
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Jason D Heaney
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Andrei I Ivanov
- Department of Inflammation & Immunity, Learner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Theresa T Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
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18
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Girish N, Liu CY, Gadeock S, Gomez ML, Huang Y, Sharifkhodaei Z, Washington MK, Polk DB. Persistence of Lgr5+ colonic epithelial stem cells in mouse models of inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2021; 321:G308-G324. [PMID: 34260310 PMCID: PMC8461791 DOI: 10.1152/ajpgi.00248.2020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/02/2021] [Accepted: 07/12/2021] [Indexed: 02/08/2023]
Abstract
Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells. Whether this paradigm applies to mouse models of IBD remains unknown. In contrast to previously tested models, IBD models involve an inflammatory response rooted in the loss of immunologic tolerance to intestinal luminal contents including the microbiome. Here, we show the persistence of Lgr5+ cells in oxazolone, 2,4,6-trinitrobenzene sulfonic acid (TNBS), and Il10-/-, and Il10-/- Tnfr1-/- IBD models. This contrasts with results obtained from DSS-induced injury. Through high-throughput expression profiling, we find that these colitis models were associated with distinct patterns of cytokine expression. Direct exposure of colonic epithelial organoids to DSS, oxazolone, or TNBS resulted in increased apoptosis and loss of Lgr5+ cells. Targeted ablation of Lgr5+ cells resulted in severe exacerbation of chronic, antibody-induced IL-10-deficient colitis, but had only modest effects in TNBS-induced colitis. These results show that distinct mouse models of IBD-like colitis induce different patterns of Lgr5+ stem cell retention and function.NEW & NOTEWORTHY Acute intestinal injury and epithelial repair are associated with the loss of fast-cycling Lgr5+ stem cells and plasticity in the activation of formerly quiescent cell populations. In contrast, here we show in murine inflammatory bowel disease the persistence of the Lgr5+ stem cell population and its essential role in restricting the severity of chronic colitis. This demonstrates a diversity of stem cell responses to colitis.
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Affiliation(s)
- Nandini Girish
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
| | - Cambrian Y Liu
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Department of Medicine, The University of Chicago, Chicago, Illinois
| | - Safina Gadeock
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
| | - Marie L Gomez
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Ying Huang
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
| | - Zohreh Sharifkhodaei
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
| | - M Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - D Brent Polk
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Division of Pediatric Gastroenterology, Hepatology, & Nutrition, Department of Pediatrics, UC University of California San Diego School of Medicine, San Diego, California
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California
- Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, California
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19
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Neyazi M, Bharadwaj SS, Bullers S, Varenyiova Z, Travis S, Arancibia-Cárcamo CV, Powrie F, Geremia A. Overexpression of Cancer-Associated Stem Cell Gene OLFM4 in the Colonic Epithelium of Patients With Primary Sclerosing Cholangitis. Inflamm Bowel Dis 2021; 27:1316-1327. [PMID: 33570127 PMCID: PMC8314119 DOI: 10.1093/ibd/izab025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND To examine immune-epithelial interactions and their impact on epithelial transformation in primary sclerosing cholangitis-associated ulcerative colitis (PSC-UC) using patient-derived colonic epithelial organoid cultures (EpOCs). METHODS The EpOCs were originated from colonic biopsies from patients with PSC-UC (n = 12), patients with UC (n = 14), and control patients (n = 10) and stimulated with cytokines previously associated with intestinal inflammation (interferon (IFN) γ and interleukin (IL)-22). Markers of cytokine downstream pathways, stemness, and pluripotency were analyzed by real-time quantitative polymerase chain reaction and immunofluorescence. The OLFM4 expression in situ was assessed by RNAscope and immunohistochemistry. RESULTS A distinct expression of stem cell-associated genes was observed in EpOCs derived from patients with PSC-UC, with lower expression of the classical stem-cell marker LGR5 and overexpression of OLFM4, previously associated with pluripotency and early stages of neoplastic transformation in the gastrointestinal and biliary tracts. High levels of OLFM4 were also found ex vivo in colonic biopsies from patients with PSC-UC. In addition, IFNγ stimulation resulted in the downregulation of LGR5 in EpOCs, whereas higher expression of OLFM4 was observed after IL-22 stimulation. Interestingly, expression of the IL-22 receptor, IL22RA1, was induced by IFNγ, suggesting that a complex interplay between these cytokines may contribute to carcinogenesis in PSC-UC. CONCLUSIONS Higher expression of OLFM4, a cancer stemness gene induced by IL-22, is present in PSC-UC, suggesting that IL-22 responses may result in alterations of the intestinal stem-cell niche in these patients.
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Affiliation(s)
- Mastura Neyazi
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Sraddha S Bharadwaj
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Samuel Bullers
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
| | - Zofia Varenyiova
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Oxford IBD Cohort Study Investigators
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Simon Travis
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Carolina V Arancibia-Cárcamo
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Fiona Powrie
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Oxford, UK
| | - Alessandra Geremia
- Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Services Foundation Trust, John Radcliffe Hospital, University of Oxford, Oxford, UK
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20
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Idris M, Alves MM, Hofstra RMW, Mahe MM, Melotte V. Intestinal multicellular organoids to study colorectal cancer. Biochim Biophys Acta Rev Cancer 2021; 1876:188586. [PMID: 34216725 DOI: 10.1016/j.bbcan.2021.188586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 06/10/2021] [Accepted: 06/28/2021] [Indexed: 02/08/2023]
Abstract
Modeling colorectal cancer (CRC) using organoids has burgeoned in the last decade, providing enhanced in vitro models to study the development and possible treatment options for this type of cancer. In this review, we describe both normal and CRC intestinal organoid models and their utility in the cancer research field. Besides highlighting studies that develop epithelial CRC organoid models, i.e. organoids without tumor microenvironment (TME) cellular components, we emphasize on the need for TME in CRC modeling, to help reduce translational disparities in this area. Also, we discuss the utilization of CRC organoids derived from pluripotent stem cells, as well as their potential to be used in cancer research. Finally, limitations and challenges in the current CRC organoids field, are discussed.
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Affiliation(s)
- Musa Idris
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Robert M W Hofstra
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Maxime M Mahe
- Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, OH, USA; TENS - Inserm UMR 1235, INSERM, University of Nantes, Nantes, France
| | - Veerle Melotte
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
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21
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Pieters VM, Co IL, Wu NC, McGuigan AP. Applications of Omics Technologies for Three-Dimensional In Vitro Disease Models. Tissue Eng Part C Methods 2021; 27:183-199. [PMID: 33406987 DOI: 10.1089/ten.tec.2020.0300] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Omics technologies, such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, multiomics, and integrated modalities, have greatly contributed to our understanding of various diseases by enabling researchers to probe the molecular wiring of cellular systems in a high-throughput and precise manner. With the development of tissue-engineered three-dimensional (3D) in vitro disease models, such as organoids and spheroids, there is potential of integrating omics technologies with 3D disease models to elucidate the complex links between genotype and phenotype. These 3D disease models have been used to model cancer, infectious disease, toxicity, neurological disorders, and others. In this review, we provide an overview of omics technologies, highlight current and emerging studies, discuss the associated experimental design considerations, barriers and challenges of omics technologies, and provide an outlook on the future applications of omics technologies with 3D models. Overall, this review aims to provide a valuable resource for tissue engineers seeking to leverage omics technologies for diving deeper into biological discovery. Impact statement With the emergence of three-dimensional (3D) in vitro disease models, tissue engineers are increasingly interested to investigate these systems to address biological questions related to disease mechanism, drug target discovery, therapy resistance, and more. Omics technologies are a powerful and high-throughput approach, but their application for 3D disease models is not maximally utilized. This review illustrates the achievements and potential of using omics technologies to leverage the full potential of 3D in vitro disease models. This will improve the quality of such models, advance our understanding of disease, and contribute to therapy development.
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Affiliation(s)
- Vera M Pieters
- Institute of Biomedical Engineering, University of Toronto, Toronto, Canada
| | - Ileana L Co
- Institute of Biomedical Engineering, University of Toronto, Toronto, Canada
| | - Nila C Wu
- Institute of Biomedical Engineering, University of Toronto, Toronto, Canada
| | - Alison P McGuigan
- Institute of Biomedical Engineering, University of Toronto, Toronto, Canada.,Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada
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22
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Sarvestani SK, Signs S, Hu B, Yeu Y, Feng H, Ni Y, Hill DR, Fisher RC, Ferrandon S, DeHaan RK, Stiene J, Cruise M, Hwang TH, Shen X, Spence JR, Huang EH. Induced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity. Nat Commun 2021; 12:262. [PMID: 33431859 PMCID: PMC7801686 DOI: 10.1038/s41467-020-20351-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/30/2020] [Indexed: 02/08/2023] Open
Abstract
The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient.
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Affiliation(s)
- Samaneh K Sarvestani
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Steven Signs
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Bo Hu
- Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Yunku Yeu
- Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Hao Feng
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Ying Ni
- Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - David R Hill
- Department of Internal Medicine, Gastroenterology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Robert C Fisher
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Sylvain Ferrandon
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Reece K DeHaan
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Jennifer Stiene
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Michael Cruise
- Department of Pathology, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Tae Hyun Hwang
- Department of Quantitative Health Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA
| | - Xiling Shen
- Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA
| | - Jason R Spence
- Department of Internal Medicine, Gastroenterology, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Emina H Huang
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, 44195, USA.
- Department of Colorectal Surgery, Cleveland Clinic, Cleveland, OH, 44195, USA.
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23
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Mo BY, Li GS, Huang SN, Wei ZX, Su YS, Dai WB, Ruan L. Laryngeal Squamous Cell Carcinoma: Potential Molecular Mechanism and Prognostic Signature Based on Immune-Related Genes. Med Sci Monit 2020; 26:e928185. [PMID: 33361747 PMCID: PMC7772955 DOI: 10.12659/msm.928185] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Immune-related genes (IRGs) are closely related to the incidence and progression of tumors, potentially indicating that IRGs play an important role in laryngeal squamous cell carcinoma (LSCC). MATERIAL AND METHODS An RNA sequencing dataset containing 123 samples was collected from The Cancer Genome Atlas. Based on immune-related differentially expressed genes (IRDEGs), a potential molecular mechanism of LSCC was explored through analysis of information in the Gene Ontology (GO) resource and the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interactions (PPIs). A regulatory network of transcriptional regulators and IRDEGs was constructed to explore the underlying molecular mechanism of LSCC at the upstream level. Candidates from IRDEGs for signature were screened via univariate Cox analysis and using the least absolute shrinkage and selection operator (LASSO) technique. The IRDEG signature of LSCC was constructed by using a multivariate Cox proportional hazards model. RESULTS GO and KEGG analysis showed that IRDEGs may participate in the progression of LSCC through immune-related reactions. PPI analysis demonstrated that, among the IRDEGs in LSCC, the Kininogen 1; C-X-X motif chemokine ligand 10; elastase, neutrophil expressed; and LYZ genes are hub genes in the development of LSCC. At the upstream level, SPI1, SP140, signal transducer and activator of transcription 4, zinc finger E-box binding homeobox, and Ikaros family zinc finger 2 are the hub transcriptional regulators of IRDEGs. The risk score based on the IRDEG signature was able to distinguish prognosis in patients with LSCC and represents an independent prognostic risk factor for LSCC. CONCLUSIONS From the perspective of IRGs, we first constructed an IRDEG signature related to the prognosis of LSCC, which can be used as a novel marker to predict prognosis in patients with LSCC.
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Affiliation(s)
- Bin-Yu Mo
- Department of Otolaryngology, Liuzhou People's Hospital of Guangxi, Liuzhou, Guangxi, China (mainland)
| | - Guo-Sheng Li
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Su-Ning Huang
- Department of Radiotherapy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China (mainland)
| | - Zhu-Xin Wei
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
| | - Ya-Si Su
- Department of Pathology, Liuzhou People's Hospital, Liuzhou, Guangxi, China (mainland)
| | - Wen-Bin Dai
- Department of Pathology, Liuzhou People's Hospital, Liuzhou, Guangxi, China (mainland)
| | - Lin Ruan
- Department of Radiotherapy, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China (mainland)
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24
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van der Hee B, Madsen O, Vervoort J, Smidt H, Wells JM. Congruence of Transcription Programs in Adult Stem Cell-Derived Jejunum Organoids and Original Tissue During Long-Term Culture. Front Cell Dev Biol 2020; 8:375. [PMID: 32714922 PMCID: PMC7343960 DOI: 10.3389/fcell.2020.00375] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 04/27/2020] [Indexed: 12/20/2022] Open
Abstract
The emergence of intestinal organoids, as a stem cell-based self-renewable model system, has led to many studies on intestinal development and cell-cell signaling. However, potential issues regarding the phenotypic stability and reproducibility of the methodology during culture still needs to be addressed for different organoids. Here we investigated the transcriptomes of jejunum organoids derived from the same pig as well as batch-to-batch variation of organoids derived from different pigs over long-term passage. The set of genes expressed in organoids closely resembled that of the tissue of origin, including small intestine specific genes, for at least 17 passages. Minor differences in gene expression were observed between individual organoid cultures. In contrast, most small intestine-specific genes were not expressed in the jejunum cell line IPEC-J2, which also showed gene expression consistent with cancer phenotypes. We conclude that intestinal organoids provide a robust and stable model for translational research with clear advantages over transformed cells.
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Affiliation(s)
- Bart van der Hee
- Host-Microbe Interactomics Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands.,Laboratory of Microbiology, Wageningen University & Research, Wageningen, Netherlands
| | - Ole Madsen
- Animal Breeding and Genomics, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands
| | - Jacques Vervoort
- Laboratory of Biochemistry, Wageningen University & Research, Wageningen, Netherlands
| | - Hauke Smidt
- Laboratory of Microbiology, Wageningen University & Research, Wageningen, Netherlands
| | - Jerry M Wells
- Host-Microbe Interactomics Group, Department of Animal Sciences, Wageningen University & Research, Wageningen, Netherlands
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25
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Mizoguchi E, Low D, Ezaki Y, Okada T. Recent updates on the basic mechanisms and pathogenesis of inflammatory bowel diseases in experimental animal models. Intest Res 2020; 18:151-167. [PMID: 32326669 PMCID: PMC7206339 DOI: 10.5217/ir.2019.09154] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/10/2020] [Indexed: 12/19/2022] Open
Abstract
The specific pathogenesis underlining inflammatory bowel disease (IBD) is very complicated, and it is further more difficult to clearly explain the pathophysiology of 2 major forms of IBD, Crohn’s disease (CD) and ulcerative colitis (UC), and both disorders affect individuals throughout life. Despite every extensive effort, the interplay among genetic factors, immunological factors, environmental factors and intestinal microbes is still completely unrevealed. Animal models are indispensable to find out mechanistic details that will facilitate better preclinical setting to target specific components involved in the pathogenesis of IBD. Based on many recent reports, dysbiosis of the commensal microbiota is implicated in the pathogenesis of several diseases, not only IBD but also colon cancer, obesity, psoriasis as well as allergic disorders, in both human and animal models. Advanced technologies including cell-specific and inducible knockout systems, which are recently employed to mouse IBD models, have further enhanced the ability of developing new therapeutic strategies for IBD. Furthermore, data from these mouse models highlight the critical involvement of dysregulated immune responses and impaired colonic epithelial defense system in the pathogenesis of IBD. In this review, we will explain from the history of animal models of IBD to the recent reports of the latest compounds, therapeutic strategies, and approaches tested on IBD animal models.
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Affiliation(s)
- Emiko Mizoguchi
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan.,Department of Molecular Microbiology and Immunology, Brown University Warren Alpert Medical School, Providence, RI, USA
| | - Daren Low
- Crohn's & Colitis Society of Singapore, Singapore
| | - Yui Ezaki
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan
| | - Toshiyuki Okada
- Department of Immunology, Kurume University School of Medicine, Kurume, Japan
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Yang ZH, Dang YQ, Ji G. Role of epigenetics in transformation of inflammation into colorectal cancer. World J Gastroenterol 2019; 25:2863-2877. [PMID: 31249445 PMCID: PMC6589733 DOI: 10.3748/wjg.v25.i23.2863] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/24/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
Molecular mechanisms associated with inflammation-promoted tumorigenesis have become an important topic in cancer research. Various abnormal epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA regulation, occur during the transformation of chronic inflammation into colorectal cancer (CRC). These changes not only accelerate transformation but also lead to cancer progression and metastasis by activating carcinogenic signaling pathways. The NF-κB and STAT3 signaling pathways play a particularly important role in the transformation of inflammation into CRC, and both are critical to cellular signal transduction and constantly activated in cancer by various abnormal changes including epigenetics. The NF-κB and STAT3 signals contribute to the microenvironment for tumorigenesis through secretion of a large number of pro-inflammatory cytokines and their crosstalk in the nucleus makes it even more difficult to treat CRC. Compared with gene mutation that is irreversible, epigenetic inheritance is reversible or can be altered by the intervention. Therefore, understanding the role of epigenetic inheritance in the inflammation-cancer transformation may elucidate the pathogenesis of CRC and promote the development of innovative drugs targeting transformation to prevent and treat this malignancy. This review summarizes the literature on the roles of epigenetic mechanisms in the occurrence and development of inflammation-induced CRC. Exploring the role of epigenetics in the transformation of inflammation into CRC may help stimulate futures studies on the role of molecular therapy in CRC.
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Affiliation(s)
- Zhen-Hua Yang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
- Digestive Endoscopy Department, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Yan-Qi Dang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
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Intestinal Epithelial Organoids as Tools to Study Epigenetics in Gut Health and Disease. Stem Cells Int 2019; 2019:7242415. [PMID: 30809264 PMCID: PMC6369455 DOI: 10.1155/2019/7242415] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 01/15/2019] [Indexed: 11/30/2022] Open
Abstract
The intestinal epithelium forms the inner layer of the human intestine and serves a wide range of diverse functions. Its constant exposure to a vast amount of complex microbiota highlights the critical interface that this single-cell layer forms between the host and our environment. Importantly, the well-documented contribution of environmental factors towards the functional development of the human intestinal epithelium directly implies epigenetic mechanisms in orchestrating this complex interplay. The development of intestinal epithelial organoid culture systems that can be generated from human tissue provides researchers with unpresented opportunities to study functional aspects of human intestinal epithelial pathophysiology. In this brief review, we summarise existing evidence for the role of epigenetics in regulating intestinal epithelial cell function and highlight the great potential for human gut organoids as translational research tools to investigate these mechanisms in vitro.
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