Furuyama, KenichiroChera, Simonavan Gurp, LéonOropeza, DanielGhila, LuizaDamond, NicolasVethe, HeidrunPaulo, Joao A.Joosten, Antoinette M.Berney, ThierryBosco, DomenicoDorrell, CraigGrompe, MarkusRæder, HelgeRoep, Bart O.Thorel, FabrizioHerrera, Pedro L.2022-08-252019-02-13Furuyama, Kenichiro, Simona Chera, Léon van Gurp, Daniel Oropeza, Luiza Ghila, Nicolas Damond, Heidrun Vethe et al. "Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells." Nature 567, no. 7746 (2019): 43-48. DOI: 10.1038/s41586-019-0942-80028-08361476-4687https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373047Authors: Kenichiro Furuyama, Simona Chera, Léon van Gurp, Daniel Oropeza, Luiza Ghila, Nicolas Damond, Heidrun Vethe, Joao A. Paulo, Antoinette M. Joosten, Thierry Berney, Domenico Bosco, Craig Dorrell, Markus Grompe, Helge Ræder, Bart O. Roep, Fabrizio Thorel and Pedro L. HerreraCell identity switches, where terminally-differentiated cells convert 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 α-cells and somatostatin-producing δ-cells become insulin expressers upon ablation of insulin-secreting β-cells, promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-β-cells, namely α-cells and PPY-producing γ–cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the β-cell Pdx1 and MafA transcription factors to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human α-cells reverse diabetes and remain producing insulin even after 6 months. Surprisingly, insulin-producing α-cells maintain α-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.en-USMultidisciplinaryJournal Article2022-08-2510.1038/s41586-019-0942-8