title: Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.
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.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Harini
authors.initials: H
authors.lastname: Chakravarthy
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Gu
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Enge
authors.affiliation: Alberta Diabetes Institute, Department of Pharmacology, University of Alberta, Edmonton, AB T6G2E1, Canada.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Surgery/Transplant, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Damond
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Downie
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery/Transplant, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Clinical Science, University of Bergen, 5021 Bergen, Norway.
authors.forename: Simona
authors.initials: S
authors.lastname: Chera
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Quake
authors.affiliation: Department of Surgery/Transplant, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Oberholzer
authors.affiliation: Alberta Diabetes Institute, Department of Pharmacology, University of Alberta, Edmonton, AB T6G2E1, Canada.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva 4, Switzerland.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: 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.
authors.forename: Seung K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000378:metabolism*; D055815:Young Adult
chemical_list: C469264:ARX protein, human; C469265:ARX protein, mouse; D018398:Homeodomain Proteins; D007328:Insulin; D014157:Transcription Factors; D005934:Glucagon; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D005947:Glucose