FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures

Ryotaro Bouchi, Kylie S. Foo, Haiqing Hua, Kyoichiro Tsuchiya, Yoshiaki Ohmura, P. Rodrigo Sandoval, Lloyd E. Ratner, Dieter Egli, Rudolph L. Leibel and Domenico Accili ()
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Ryotaro Bouchi: Columbia University College of Physicians and Surgeons
Kylie S. Foo: New York Stem Cell Foundation Research Institute
Haiqing Hua: New York Stem Cell Foundation Research Institute
Kyoichiro Tsuchiya: Tokyo Medical and Dental University
Yoshiaki Ohmura: Columbia University College of Physicians and Surgeons
P. Rodrigo Sandoval: Columbia University College of Physicians and Surgeons
Lloyd E. Ratner: Columbia University College of Physicians and Surgeons
Dieter Egli: New York Stem Cell Foundation Research Institute
Rudolph L. Leibel: Columbia University College of Physicians and Surgeons
Domenico Accili: Columbia University College of Physicians and Surgeons

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract 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 small hairpin RNA 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.

Date: 2014
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DOI: 10.1038/ncomms5242

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