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3 results on '"Olfm4, olfactomedin 4"'

1. A Novel Organoid Model of Damage and Repair Identifies HNF4α as a Critical Regulator of Intestinal Epithelial RegenerationSummary

Author

Sander Meisner, Agnès Ribeiro, Vanesa Muncan, Manon E. Wildenberg, Jarom Heijmans, Christine Jones, Jan Koster, Gijs R. van den Brink, Jacqueline L.M. Vermeulen, Jonathan H. M. van der Meer, François Boudreau, Paula S. Montenegro-Miranda, Gastroenterology and Hepatology, Graduate School, Tytgat Institute for Liver and Intestinal Research, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Oncogenomics, and General Internal Medicine

Subjects
0301 basic medicine, Male, qRT-PCR, quantitative reverse transcription polymerase chain reaction, Primary Cell Culture, Regulator, EdU, 5-ethynyl-2’-deoxyuridine, PBS, phosphate-buffered saline, Transcript profiling, Biology, Lgr5, leucine-rich repeat-containing G-protein–coupled receptor 5, HNF4α, hepatocyte nuclear factor 4α, BrdU, bromodeoxyuridine, 03 medical and health sciences, Mice, 0302 clinical medicine, Intestine, Small, Organoid, Animals, Regeneration, Olfm4, olfactomedin 4, Intestinal Mucosa, lcsh:RC799-869, Cells, Cultured, Original Research, Epithelial barrier, Mice, Knockout, Hepatology, Regeneration (biology), Gastroenterology, Intestinal organoids, IPA, ingenuity pathway analysis, ENR, epidermal growth factor, Noggin, and R-spondin, Cell biology, Organoids, Hepatocyte nuclear factors, Radiation Injuries, Experimental, 030104 developmental biology, Hepatocyte Nuclear Factor 4, 030211 gastroenterology & hepatology, TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling, Irradiation, lcsh:Diseases of the digestive system. Gastroenterology
Abstract

Background & Aims Recent evidence has suggested that the intact intestinal epithelial barrier protects our body from a range of immune-mediated diseases. The epithelial layer has an impressive ability to reconstitute and repair upon damage and this process of repair increasingly is seen as a therapeutic target. In vitro models to study this process in primary intestinal cells are lacking. Methods We established and characterized an in vitro model of intestinal damage and repair by applying γ-radiation on small-intestinal organoids. We then used this model to identify novel regulators of intestinal regeneration. Results We identified hepatocyte nuclear factor 4α (HNF4α) as a pivotal upstream regulator of the intestinal regenerative response. Organoids lacking Hnf4a were not able to propagate in vitro. Importantly, intestinal Hnf4a knock-out mice showed impaired regeneration after whole-body irradiation, confirming intestinal organoids as a valuable alternative to in vivo studies. Conclusions In conclusion, we established and validated an in vitro damage–repair model and identified HNF4α as a crucial regulator of intestinal regeneration. Transcript profiling: GSE141515 and GSE141518., Graphical abstract

Published
2020

2. Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice.

Author

Nakanishi A, Toyama S, Onozato D, Watanabe C, Hashita T, Iwao T, and Matsunaga T

Abstract

Introduction: Ulcerative colitis (UC) is an inflammatory bowel disease characterized by repeated remissions and relapses. Immunosuppressive drugs have facilitated the induction and maintenance of remission in many patients with UC. However, immunosuppressive drugs cannot directly repair impaired intestinal mucosa and are insufficient for preventing relapse. Therefore, new treatment approaches to repair the damaged epithelium in UC have been attempted through the transplantation of intestinal organoids, which can be differentiated into mucosa by embedding in Matrigel, generated from patient-derived intestinal stem cells. The method, however, poses the challenge of yielding sufficient cells for UC therapy, and patient-derived cells might already have acquired pathological changes. In contrast, human induced pluripotent stem (iPS) cells generated from healthy individuals are infinitely proliferated and can be differentiated into target cells. Recently developed human iPS cell-derived intestinal organoids (HIOs) aim to generate organoids that closely resemble the adult intestine. However, no study till date has reported HIOs injected into in vivo inflammatory models, and it remains unclear whether HIOs with cells that closely resemble the adult intestine or with intestinal stem cells retain the better ability to repair tissue in colitis., Methods: We generated two types of HIOs via suspension culture with and without small-molecule compounds: HIOs that include predominantly more intestinal stem cells [HIO (A)] and those that include predominantly more intestinal epithelial and secretory cells [HIO (B)]. We examined whether the generated HIOs engrafted in vivo and compared their ability to accelerate recovery of the damaged tissue., Results: Findings showed that the HIOs expressed intestinal-specific markers such as caudal-type homeobox 2 ( CDX2 ) and villin, and HIOs engrafted under the kidney capsules of mice. We then injected HIOs into colitis-model mice and found that the weight and clinical score of the mice injected with HIO (A) recovered earlier than that of the mice in the sham group. Further, the production of mucus and the expression of cell proliferation markers and tight junction proteins in the colon tissues of the HIO (A) group were restored to levels similar to those observed in healthy mice. However, neither HIO (A) nor HIO (B) could be engrafted into the colon., Conclusions: Effective cell therapy should directly repair tissue by engraftment at the site of injury. However, the difference in organoid property impacting the rate of tissue repair in transplantation without engraftment observed in the current study should be considered a critical consideration in the development of regenerative medicine using iPS-derived organoids., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Published
2022
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3. GATA4 Regulates Epithelial Cell Proliferation to Control Intestinal Growth and Development in Mice

Author

Michele A. Battle, Emily M. Walker, Bridget M. Kohlnhofer, and Cayla A. Thompson

Subjects
EdU, 5-ethynyl-2'deoxyuridine, 0301 basic medicine, Prdm1, PR domain containing 1, endocrine system, Frizzled, Morphogenesis, Biology, Pdgfa, platelet-derived growth factor α, Villus Morphogenesis, Bio-ChIP-Seq, biotin-mediated chromatin immunoprecipitation with high-throughput sequencing, cKO, conditional knockout, SBS, short-bowel syndrome, PDGFRA, platelet-derived growth factor receptor α, 03 medical and health sciences, PCR, polymerase chain reaction, Cyclin D2, medicine, Olfm4, olfactomedin 4, lcsh:RC799-869, Sonic hedgehog, reproductive and urinary physiology, Original Research, Transcriptional Regulation, Hes1/6, hairy and enhancer of split-1/6, E, embryonic day, Hepatology, WNT Signaling, Ccnd1/2, cyclin D1/2, Cdk6, cyclin-dependent kinase 6, Atoh, atonal homolog 1, Gastroenterology, Wnt signaling pathway, Fzd5, frizzled 5, respiratory system, Intestinal epithelium, Molecular biology, Epithelium, 030104 developmental biology, medicine.anatomical_structure, Wnt, wingless type MMTV integration site family, embryonic structures, Shh, sonic hedgehog, cardiovascular system, biology.protein, lcsh:Diseases of the digestive system. Gastroenterology, Endoderm
Abstract

Background & Aims: The embryonic small intestinal epithelium is highly proliferative, and although much is known about mechanisms regulating proliferation in the adult intestine, the mechanisms controlling epithelial cell proliferation in the developing intestine are less clear. GATA4, a transcription factor that regulates proliferation in other developing tissues, is first expressed early in the developing gut in midgut endoderm. GATA4 function within midgut endoderm and the early intestinal epithelium is unknown. Methods: By using Sonic Hedgehog Cre to eliminate GATA4 in the midgut endoderm of mouse embryos, we determined the impact of loss of GATA4 on intestinal development, including epithelial cell proliferation, between embryonic day (E)9.5 and E18.5. Results: We found that intestinal length and width were decreased in GATA4 mutants compared with controls. GATA4-deficient intestinal epithelium contained fewer cells, and epithelial girth was decreased. We further observed a decreased proportion of proliferating epithelial cells at E10.5 and E11.5 in GATA4 mutants. We showed that GATA4 binds to chromatin containing GATA4 consensus binding sites within cyclin D2 (Ccnd2), cyclin-dependent kinase 6 (Cdk6), and frizzled 5 (Fzd5). Moreover, Ccnd2, Cdk6, and Fzd5 transcripts were reduced at E11.5 in GATA4 mutant tissue. Villus morphogenesis was delayed, and villus structure was abnormal in GATA4 mutant intestine. Conclusions: Our data identify GATA4 as an essential regulator of early intestinal epithelial cell proliferation. We propose that GATA4 controls proliferation in part by directly regulating transcription of cell-cycle mediators. Our data further suggest that GATA4 affects proliferation through transcriptional regulation of Fzd5, perhaps by influencing the response of the epithelium to WNT signaling. Keywords: Transcriptional Regulation, WNT Signaling, Villus Morphogenesis

Published
2016
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