title: De novo formation of insulin-producing "neo-β cell islets" from intestinal crypts.
abstract: The ability to interconvert terminally differentiated cells could serve as a powerful tool for cell-based treatment of degenerative diseases, including diabetes mellitus. To determine which, if any, adult tissues are competent to activate an islet β cell program, we performed an in vivo screen by expressing three β cell "reprogramming factors" in a wide spectrum of tissues. We report that transient intestinal expression of these factors-Pdx1, MafA, and Ngn3 (PMN)-promotes rapid conversion of intestinal crypt cells into endocrine cells, which coalesce into "neoislets" below the crypt base. Neoislet cells express insulin and show ultrastructural features of β cells. Importantly, intestinal neoislets are glucose-responsive and able to ameliorate hyperglycemia in diabetic mice. Moreover, PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into β-like cells. Our results thus demonstrate that the intestine is an accessible and abundant source of functional insulin-producing cells.
authors.affiliation: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Gastroenterology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Stacy R
authors.initials: SR
authors.lastname: Finkbeiner
authors.affiliation: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weinblatt
authors.affiliation: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Emmett
authors.affiliation: Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Feven
authors.initials: F
authors.lastname: Tameire
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Yousefi
authors.affiliation: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Yang
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, University of Massachusetts, Worcester, MA 01655, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Maehr
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Shemer
authors.affiliation: Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Gastroenterology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA; Center for Organogenesis, Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Spence
authors.affiliation: Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: bstanger@exchange.upenn.edu.
authors.forename: Ben Z
authors.initials: BZ
authors.lastname: Stanger
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D007328:Insulin