Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.
- Chakravarthy H Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Gu X Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Enge M Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
- Dai X Alberta Diabetes Institute, Department of Pharmacology, University of Alberta, Edmonton, AB T6G2E1, Canada.
- Wang Y Department of Surgery/Transplant, University of Illinois, Chicago, IL 60612, USA.
- Damond N Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.
- Downie C Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Liu K Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Wang J Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
- Xing Y Department of Surgery/Transplant, University of Illinois, Chicago, IL 60612, USA.
- Chera S Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
- Thorel F Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.
- Quake S Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
- Oberholzer J Department of Surgery/Transplant, University of Illinois, Chicago, IL 60612, USA.
- MacDonald PE Alberta Diabetes Institute, Department of Pharmacology, University of Alberta, Edmonton, AB T6G2E1, Canada.
- Herrera PL Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.
- Kim SK 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.
- 2017-02-21
Published in:
- Cell metabolism. - 2017
Adult
Aging
Calcium Signaling
Cell Lineage
Child
Child, Preschool
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
Diabetes Mellitus, Type 1
Electrophysiological Phenomena
Female
Gene Deletion
Gene Expression Regulation
Glucagon
Glucagon-Secreting Cells
Glucose
Homeodomain Proteins
Humans
Insulin
Insulin Secretion
Insulin-Secreting Cells
Male
Sequence Analysis, RNA
Single-Cell Analysis
Transcription Factors
Young Adult
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.cmet.2017.01.009
- PMID 28215845
- Persistent URL
- https://sonar.ch/global/documents/138118
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