Weill Graduate School of Medical Sciences of Cornell University, 1300 York Avenue, New York, NY, 10065, USA.
Department of Surgery, 1300 York Avenue, New York, NY, 10065, USA.
Nat Commun. 2018 Jul 11;9(1):2681. doi: 10.1038/s41467-018-04918-x.
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.
GLIS3 突变与 1 型、2 型和新生儿糖尿病有关，反映了该基因在胰腺 β 细胞生物学中的关键功能。以前试图在 GLIS3 β 样细胞中重现与疾病相关的表型的尝试都没有成功。在这里，我们开发了一种“最小成分”方案来生成晚期胰腺祖细胞 (PP2)，这些祖细胞分化为单激素葡萄糖反应性 β 样 (PP2-β) 细胞。使用这种分化平台，我们发现 GLIS3 hESC 显示出分化受损，PP2 和 PP2-β 细胞大量死亡，而不会影响总内分泌池。此外，我们进行了高通量化学筛选，并确定了一种候选药物，该药物可在体外和体内挽救突变 GLIS3 相关的 β 细胞死亡。最后，我们发现 GLIS3 的缺失通过激活 TGFβ 途径导致 β 细胞死亡。这项研究建立了一种优化的定向分化方案，用于模拟人类 β 细胞疾病，并确定了一种候选药物，用于治疗广泛的 GLIS3 相关糖尿病患者。
