Title | Discovery of a drug candidate for GLIS3-associated diabetes. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Amin S, Cook B, Zhou T, Ghazizadeh Z, Lis R, Zhang T, Khalaj M, Crespo M, Perera M, Xiang JZhaoying, Zhu Z, Tomishima M, Liu C, Naji A, Evans T, Huangfu D, Chen S |
Journal | Nat Commun |
Volume | 9 |
Issue | 1 |
Pagination | 2681 |
Date Published | 2018 Jul 11 |
ISSN | 2041-1723 |
Keywords | Animals, Cell Differentiation, Cell Line, Diabetes Mellitus, DNA-Binding Proteins, Drug Discovery, Gene Expression Profiling, Human Embryonic Stem Cells, Humans, Hypoglycemic Agents, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, SCID, Mutation, Pyrazoles, Quinolines, Repressor Proteins, Trans-Activators, Transcription Factors, Transplantation, Heterologous |
Abstract | <p>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.</p> |
DOI | 10.1038/s41467-018-04918-x |
Alternate Journal | Nat Commun |
PubMed ID | 29992946 |
PubMed Central ID | PMC6041295 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States R01 DK096239 / DK / NIDDK NIH HHS / United States DP3 DK111907-01 / / U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) / International |