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Cell Metab. 2017 Mar 7;25(3):622-634. doi: 10.1016/j.cmet.2017.01.009. Epub 2017 Feb 16.

Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.

Author information

1
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
3
Alberta Diabetes Institute, Department of Pharmacology, University of Alberta, Edmonton, AB T6G2E1, Canada.
4
Department of Surgery/Transplant, University of Illinois, Chicago, IL 60612, USA.
5
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.
6
Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
7
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
8
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: seungkim@stanford.edu.

Abstract

Insulin-producing pancreatic β cells in mice can slowly regenerate from glucagon-producing α cells in settings like β cell loss, but the basis of this conversion is unknown. Moreover, it remains unclear if this intra-islet cell conversion is relevant to diseases like type 1 diabetes (T1D). We show that the α cell regulators Aristaless-related homeobox (Arx) and DNA methyltransferase 1 (Dnmt1) maintain α cell identity in mice. Within 3 months of Dnmt1 and Arx loss, lineage tracing and single-cell RNA sequencing revealed extensive α cell conversion into progeny resembling native β cells. Physiological studies demonstrated that converted α cells acquire hallmark β cell electrophysiology and show glucose-stimulated insulin secretion. In T1D patients, subsets of glucagon-expressing cells show loss of DNMT1 and ARX and produce insulin and other β cell factors, suggesting that DNMT1 and ARX maintain α cell identity in humans. Our work reveals pathways regulated by Arx and Dnmt1 that are sufficient for achieving targeted generation of β cells from adult pancreatic α cells.

PMID:
28215845
PMCID:
PMC5358097
DOI:
10.1016/j.cmet.2017.01.009
[Indexed for MEDLINE]
Free PMC Article

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