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Nature. 2019 Mar;567(7746):43-48. doi: 10.1038/s41586-019-0942-8. Epub 2019 Feb 13.

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

Author information

1
Department of Genetic Medicine and Development, iGE3 and Centre Facultaire du Diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
2
Department of Clinical Science, University of Bergen, Bergen, Norway.
3
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
4
Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
5
Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, University of Geneva, Geneva, Switzerland.
6
Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR, USA.
7
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
8
Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA.
9
Department of Genetic Medicine and Development, iGE3 and Centre Facultaire du Diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland. pedro.herrera@unige.ch.

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.

PMID:
30760930
DOI:
10.1038/s41586-019-0942-8

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