ESPEYB16 10. Type 1 Diabetes Mellitus (1) (20 abstracts)
10.19. Diabetes relief in mice by glucose-sensing insulin-secreting human [alpha]-cells
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 & Pedro L Herrera
Department of Genetic Medicine and Development, iGE3 and Centre Facultaire du Diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
To read the full abstract: Nature 567, 43–48 (2019)
Cell engineering might be a way to reinstall insulin-production in the pancreas of people with autoimmune diabetes. This experimental mouse study achieved to switch human alpha cells to secrete insulin.
Cell-identity switches, in which terminally differentiated cells are converted into different cell types, 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 cells also display this plasticity, especially in diabetic conditions, was not previously shown.
This study shows 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 reversed diabetes and continued to produce insulin even after six months. Notably, insulin-producing α-cells maintained expression of α-cell markers, as seen by deep transcriptomic and proteomic characterization.
These findings provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a potential future treatment for diabetes and other degenerative diseases. Applying such approaches might even bring cure for diabetes within reach. A major challenge to such therapeutic approaches is to prevent disrupted autoimmune processes in the T1D human host from attacking newly built beta-cells – this might be possible as the cells still appeared from the outside to look like α-cells.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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