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

• Published in: Cell metabolism 2017-03, Vol.25 (3), p.622-634
• Main Authors: Chakravarthy, Harini, Gu, Xueying, Enge, Martin, Dai, Xiaoqing, Wang, Yong, Damond, Nicolas, Downie, Carolina, Liu, Kathy, Wang, Jing, Xing, Yuan, Chera, Simona, Thorel, Fabrizio, Quake, Stephen, Oberholzer, Jose, MacDonald, Patrick E., Herrera, Pedro L., Kim, Seung K.
• Format: Article
• Language: English
• Subjects: Adult; Aging - metabolism; Calcium Signaling - drug effects; Cell Lineage - drug effects; Child; Child, Preschool; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; Electrophysiological Phenomena - drug effects; Female; Gene Deletion; Gene Expression Regulation - drug effects; Glucagon - metabolism; Glucagon-Secreting Cells - drug effects; Glucagon-Secreting Cells - metabolism; Glucose - pharmacology; Homeodomain Proteins - metabolism; Humans; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Medicin och hälsovetenskap; Sequence Analysis, RNA; Single-Cell Analysis; Transcription Factors - metabolism; Young Adult
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2017.01.009

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. [Display omitted] •Adult mouse islet α cells convert rapidly into β cells after Dnmt1 and Arx loss•RNA-seq reveals a strikingly similar gene expression in converted and native β cells•Converted α cells acquire hallmark functional features of native β cells•Glucagon+ cells lose DNMT1 and ARX and express β cell markers in human T1D islets Chakravarthy et al. dissect the mechanisms maintaining α cell identity and reveal that simultaneous inactivation of the DNA methyltransferase Dnmt1 and the transcription factor Arx in adult mice drives the conversion of α- to β-like cells. In human T1D islets, glucagon+ cells lose DNMT1 and ARX expression and express β cell markers.