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

ABSTRACT: Insulin-producing pancreatic ? cells in mice can slowly regenerate from glucagon-producing ? cells in settings like ? 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 ? cell regulators Aristaless-related homeobox (Arx) and DNA methyltransferase 1 (Dnmt1) maintain ? cell identity in mice. Within 3 months of Dnmt1 and Arx loss, lineage tracing and single-cell RNA sequencing revealed extensive ? cell conversion into progeny resembling native ? cells. Physiological studies demonstrated that converted ? cells acquire hallmark ? 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 ? cell factors, suggesting that DNMT1 and ARX maintain ? cell identity in humans. Our work reveals pathways regulated by Arx and Dnmt1 that are sufficient for achieving targeted generation of ? cells from adult pancreatic ? cells.

SUBMITTER: Chakravarthy H 

PROVIDER: S-EPMC5358097 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature