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FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures
Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor ce...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083475/ https://www.ncbi.nlm.nih.gov/pubmed/24979718 http://dx.doi.org/10.1038/ncomms5242 |
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author | Bouchi, Ryotaro Foo, Kylie S. Hua, Haiqing Tsuchiya, Kyoichiro Ohmura, Yoshiaki Sandoval, P. Rodrigo Ratner, Lloyd E. Egl, Dieter Leibel, Rudolph L. Accili, Domenico |
author_facet | Bouchi, Ryotaro Foo, Kylie S. Hua, Haiqing Tsuchiya, Kyoichiro Ohmura, Yoshiaki Sandoval, P. Rodrigo Ratner, Lloyd E. Egl, Dieter Leibel, Rudolph L. Accili, Domenico |
author_sort | Bouchi, Ryotaro |
collection | PubMed |
description | Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor cells of mice can be differentiated into glucose-responsive, insulin-producing cells by ablation of transcription factor Foxo1. Here we show that FOXO1 is present in human gut endocrine progenitor and serotonin-producing cells. Using gut organoids derived from human iPS cells, we show that FOXO1 inhibition using a dominant-negative mutant or lentivirus-encoded shRNA promotes generation of insulin-positive cells that express all markers of mature pancreatic β-cells, release C-peptide in response to secretagogues, and survive in vivo following transplantation into mice. The findings raise the possibility of using gut-targeted FOXO1 inhibition or gut organoids as a source of insulin-producing cells to treat human diabetes. |
format | Online Article Text |
id | pubmed-4083475 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-40834752014-12-30 FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures Bouchi, Ryotaro Foo, Kylie S. Hua, Haiqing Tsuchiya, Kyoichiro Ohmura, Yoshiaki Sandoval, P. Rodrigo Ratner, Lloyd E. Egl, Dieter Leibel, Rudolph L. Accili, Domenico Nat Commun Article Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor cells of mice can be differentiated into glucose-responsive, insulin-producing cells by ablation of transcription factor Foxo1. Here we show that FOXO1 is present in human gut endocrine progenitor and serotonin-producing cells. Using gut organoids derived from human iPS cells, we show that FOXO1 inhibition using a dominant-negative mutant or lentivirus-encoded shRNA promotes generation of insulin-positive cells that express all markers of mature pancreatic β-cells, release C-peptide in response to secretagogues, and survive in vivo following transplantation into mice. The findings raise the possibility of using gut-targeted FOXO1 inhibition or gut organoids as a source of insulin-producing cells to treat human diabetes. 2014-06-30 /pmc/articles/PMC4083475/ /pubmed/24979718 http://dx.doi.org/10.1038/ncomms5242 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Bouchi, Ryotaro Foo, Kylie S. Hua, Haiqing Tsuchiya, Kyoichiro Ohmura, Yoshiaki Sandoval, P. Rodrigo Ratner, Lloyd E. Egl, Dieter Leibel, Rudolph L. Accili, Domenico FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures |
title | FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures |
title_full | FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures |
title_fullStr | FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures |
title_full_unstemmed | FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures |
title_short | FOXO1 Inhibition Yields Functional Insulin-Producing Cells In Human Gut Organoid Cultures |
title_sort | foxo1 inhibition yields functional insulin-producing cells in human gut organoid cultures |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083475/ https://www.ncbi.nlm.nih.gov/pubmed/24979718 http://dx.doi.org/10.1038/ncomms5242 |
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