Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
Cell Rep. 2020 May 26;31(8):107687. doi: 10.1016/j.celrep.2020.107687.
Generation of insulin-secreting β cells in vitro is a promising approach for diabetes cell therapy. Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) are differentiated to β cells (SC-β cells) and mature to undergo glucose-stimulated insulin secretion, but molecular regulation of this defining β cell phenotype is unknown. Here, we show that maturation of SC-β cells is regulated by the transcription factor SIX2. Knockdown (KD) or knockout (KO) of SIX2 in SC-β cells drastically limits glucose-stimulated insulin secretion in both static and dynamic assays, along with the upstream processes of cytoplasmic calcium flux and mitochondrial respiration. Furthermore, SIX2 regulates the expression of genes associated with these key β cell processes, and its expression is restricted to endocrine cells. Our results demonstrate that expression of SIX2 influences the generation of human SC-β cells in vitro.
体外生成胰岛素分泌β细胞是糖尿病细胞治疗的一种很有前途的方法。人胚胎干细胞（hESCs）和人诱导多能干细胞（hiPSCs）可分化为β细胞（SC-β细胞）并成熟以进行葡萄糖刺激的胰岛素分泌，但这种定义明确的β细胞表型的分子调控尚不清楚。在这里，我们表明转录因子 SIX2 调节 SC-β细胞的成熟。SC-β 细胞中 SIX2 的敲低（KD）或敲除（KO）极大地限制了静态和动态测定中的葡萄糖刺激胰岛素分泌，以及细胞质钙流和线粒体呼吸的上游过程。此外，SIX2 调节与这些关键β细胞过程相关的基因的表达，其表达仅限于内分泌细胞。我们的结果表明，SIX2 的表达影响了体外人 SC-β 细胞的生成。
