title: FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures.
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.
authors: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Ryotaro
authors: R
authors: Bouchi
authors: 1] New York Stem Cell Foundation Research Institute, New York, New York 10032, USA [2] Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Kylie S
authors: KS
authors: Foo
authors: 1] New York Stem Cell Foundation Research Institute, New York, New York 10032, USA [2] Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Haiqing
authors: H
authors: Hua
authors: Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors: Kyoichiro
authors: K
authors: Tsuchiya
authors: Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Yoshiaki
authors: Y
authors: Ohmura
authors: Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: P Rodrigo
authors: PR
authors: Sandoval
authors: Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Lloyd E
authors: LE
authors: Ratner
authors: 1] New York Stem Cell Foundation Research Institute, New York, New York 10032, USA [2] Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Dieter
authors: D
authors: Egli
authors: Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Rudolph L
authors: RL
authors: Leibel
authors: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Domenico
authors: D
authors: Accili
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009940:Organoids / Q000166:cytology / Q000378:metabolism*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin