Diabetes relief in mice by glucose-sensing insulin-secreting human ?-cells.

ABSTRACT: Cell-identity switches, in which terminally differentiated cells are converted into different cell types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic ?-cells and somatostatin-producing ?-cells become insulin-expressing cells after the ablation of insulin-secreting ?-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-?-cells, namely ?-cells and pancreatic polypeptide (PPY)-producing ?-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human ?-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing ?-cells maintain expression of ?-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases.

SUBMITTER: Furuyama K 

PROVIDER: S-EPMC6624841 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature