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Cell Rep. 2014 Mar 27;6(6):1046-1058. doi: 10.1016/j.celrep.2014.02.013. Epub 2014 Mar 6.

De novo formation of insulin-producing "neo-β cell islets" from intestinal crypts.

Author information

1
Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Gastroenterology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
3
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.
4
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Program in Molecular Medicine, University of Massachusetts Medical School, University of Massachusetts, Worcester, MA 01655, USA.
7
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
8
Department of Developmental Biology and Cancer Research, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
9
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
10
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.
11
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.

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.

PMID:
24613355
PMCID:
PMC4245054
DOI:
10.1016/j.celrep.2014.02.013
[Indexed for MEDLINE]
Free PMC Article

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