Diabetes relief in mice by glucose-sensing insulin-secreting human [alpha]-cells

• Published in: Nature (London) Vol. 567; no. 7746; pp. 43 - 48
• Main Authors: Furuyama, Kenichiro, Chera, Simona, van Gurp, Léon, Oropeza, Daniel, Ghila, Luiza, Damond, Nicolas, Vethe, Heidrun
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01.03.2019
• Subjects: Care and treatment; Diabetes mellitus; Diabetes research; Displays (Marketing); DNA binding proteins; Glucagon; Glucose; Insulin; Pancreatic beta cells
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-0942-8

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 [alpha]-cells and somatostatin-producing [delta]-cells become insulin-expressing cells after the ablation of insulin-secreting [beta]-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-[beta]-cells, namely [alpha]-cells and pancreatic polypeptide (PPY)-producing [gamma]-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 [alpha]-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing [alpha]-cells maintain expression of [alpha]-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.