TY - JOUR
T1 - Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells
AU - Furuyama, Kenichiro
AU - Chera, Simona
AU - van Gurp, Léon
AU - Oropeza, Daniel
AU - Ghila, Luiza
AU - Damond, Nicolas
AU - Vethe, Heidrun
AU - Paulo, Joao A.
AU - Joosten, Antoinette M.
AU - Berney, Thierry
AU - Bosco, Domenico
AU - Dorrell, Craig
AU - Grompe, Markus
AU - Ræder, Helge
AU - Roep, Bart O.
AU - Thorel, Fabrizio
AU - Herrera, Pedro L.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/3/7
Y1 - 2019/3/7
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-019-0942-8
DO - 10.1038/s41586-019-0942-8
M3 - Article
C2 - 30760930
AN - SCOPUS:85062639517
SN - 0028-0836
VL - 567
SP - 43
EP - 48
JO - Nature
JF - Nature
IS - 7746
ER -