Discovery of a drug candidate for GLIS3-associated diabetes.
Sadaf AminBrandoch CookTing ZhouZaniar GhazizadehRaphael LisTuo ZhangMona KhalajMiguel CrespoManuradhi PereraJenny Zhaoying XiangZengrong ZhuMark TomishimaChengyang LiuAli NajiTodd EvansDanwei HuangfuShuibing ChenPublished in: Nature communications (2018)
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.
Keyphrases
- cell death
- cell cycle arrest
- induced apoptosis
- type diabetes
- high throughput
- single cell
- cardiovascular disease
- randomized controlled trial
- genome wide
- endothelial cells
- signaling pathway
- cell therapy
- small molecule
- glycemic control
- adverse drug
- pi k akt
- endoplasmic reticulum stress
- gene expression
- emergency department
- blood glucose
- oxidative stress
- bone marrow
- metabolic syndrome
- polycystic ovary syndrome
- skeletal muscle
- induced pluripotent stem cells