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

Kenichiro Furuyama, Simona Chera, Léon 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. Herrera ()
Additional contact information
Kenichiro Furuyama: University of Geneva
Simona Chera: University of Geneva
Léon Gurp: University of Geneva
Daniel Oropeza: University of Geneva
Luiza Ghila: University of Geneva
Nicolas Damond: University of Geneva
Heidrun Vethe: University of Bergen
Joao A. Paulo: Harvard Medical School
Antoinette M. Joosten: Leiden University Medical Center
Thierry Berney: Geneva University Hospitals, University of Geneva
Domenico Bosco: Geneva University Hospitals, University of Geneva
Craig Dorrell: Oregon Health & Science University
Markus Grompe: Oregon Health & Science University
Helge Ræder: University of Bergen
Bart O. Roep: Leiden University Medical Center
Fabrizio Thorel: University of Geneva
Pedro L. Herrera: University of Geneva

Nature, 2019, vol. 567, issue 7746, 43-48

Abstract: 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 α-cells and somatostatin-producing δ-cells become insulin-expressing cells after the ablation of insulin-secreting β-cells, thus 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 pancreatic polypeptide (PPY)-producing γ-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 α-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing α-cells maintain expression of 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.

Date: 2019
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DOI: 10.1038/s41586-019-0942-8

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