期刊
NATURE
卷 567, 期 7746, 页码 43-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-0942-8
关键词
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资金
- JDRF [31-2008-416]
- NIDDK [DK098085]
- Research Council of Norway [NFR 247577]
- Novo Nordisk Foundation [NNF15OC0015054, NNF17OC0027258]
- NIH/NIDDK [DK098285]
- Bergen Forskningsstiftelse [BFS2014REK02]
- Western Norway Regional Health Authority (Bergen Stem Cell Consortium)
- NIH/NIDDK (Human Islet Research Network) [DK104209, DK108132]
- Juvenile Diabetes Research Foundation [SRA-2015-67-Q-R]
- Fondation Privee des HUG - Confirm Award
- Fondation Aclon
- Swiss National Science Foundation [406340-128056, 310030_152965]
- Bonus of Excellence [310030B_173319]
- Swiss National Science Foundation (SNF) [310030_152965, 406340_128056, 310030B_173319] Funding Source: Swiss National Science Foundation (SNF)
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.
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