Year: 2018
Type: article
Abstract: GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic β-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3−/− β-like cells have been unsuccessful. Here, we develop a “minimal component” protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono-hormonal glucose-responding β-like (PP2-β) cells. Using this differentiation platform, we discover that GLIS3−/− hESCs show impaired differentiation, with significant death of PP2 and PP2-β cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3-associated β-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes β-cell death, by activating the TGFβ pathway. This study establishes an optimized directed differentiation protocol for modeling human β-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients.
Source: Nature Communications
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, American Diabetes Association, New York State Department of Health, Icahn School of Medicine at Mount Sinai, New York State Stem Cell Science, National Institutes of Health, Weill Cornell Medical College, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G3718456196, G5370700109, G609382939, G616303020, G6575443754, Discovery of T1DM Associated Functional Variants in Human Pancreatic Beta Cell Development and Survival, G7721124235, Cell Sorter, Understanding human pancreas development for diabetes cell-replacement therapy, G8993662893, Cancer Center Support Grant
OpenAlex ID: W2827733148