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

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 int...

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Autores principales: Nakanishi, Anna, Toyama, Satoshi, Onozato, Daichi, Watanabe, Chihiro, Hashita, Tadahiro, Iwao, Takahiro, Matsunaga, Tamihide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Japanese Society for Regenerative Medicine 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9471335/
https://www.ncbi.nlm.nih.gov/pubmed/36161099
http://dx.doi.org/10.1016/j.reth.2022.08.004
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author Nakanishi, Anna
Toyama, Satoshi
Onozato, Daichi
Watanabe, Chihiro
Hashita, Tadahiro
Iwao, Takahiro
Matsunaga, Tamihide
author_facet Nakanishi, Anna
Toyama, Satoshi
Onozato, Daichi
Watanabe, Chihiro
Hashita, Tadahiro
Iwao, Takahiro
Matsunaga, Tamihide
author_sort Nakanishi, Anna
collection PubMed
description 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.
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spelling pubmed-94713352022-09-22 Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice Nakanishi, Anna Toyama, Satoshi Onozato, Daichi Watanabe, Chihiro Hashita, Tadahiro Iwao, Takahiro Matsunaga, Tamihide Regen Ther Original Article 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. Japanese Society for Regenerative Medicine 2022-09-09 /pmc/articles/PMC9471335/ /pubmed/36161099 http://dx.doi.org/10.1016/j.reth.2022.08.004 Text en © 2022 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Nakanishi, Anna
Toyama, Satoshi
Onozato, Daichi
Watanabe, Chihiro
Hashita, Tadahiro
Iwao, Takahiro
Matsunaga, Tamihide
Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice
title Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice
title_full Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice
title_fullStr Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice
title_full_unstemmed Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice
title_short Effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice
title_sort effects of human induced pluripotent stem cell-derived intestinal organoids on colitis-model mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9471335/
https://www.ncbi.nlm.nih.gov/pubmed/36161099
http://dx.doi.org/10.1016/j.reth.2022.08.004
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