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

Publication date: Available online 16 February 2017
Source:Cell Metabolism
Author(s): Harini Chakravarthy, Xueying Gu, Martin Enge, Xiaoqing Dai, Yong Wang, Nicolas Damond, Carolina Downie, Kathy Liu, Jing Wang, Yuan Xing, Simona Chera, Fabrizio Thorel, Stephen Quake, Jose Oberholzer, Patrick E. MacDonald, Pedro L. Herrera, Seung K. Kim
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.

Graphical abstract

Teaser

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.


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