Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells
Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells
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DOI：
10.1016/j.stemcr.2018.12.012
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发表时间：
2019-02-12
影响因子：
5.9
通讯作者：
Millman, Jeffrey R.
中科院分区：
文献类型：
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作者：
Velazco-Cruz, Leonardo;Song, Jiwon;Millman, Jeffrey R.
人类多能干细胞（hPSC）分化方案的最新进展已经产生了类似于胰腺β细胞的胰岛素产生细胞。虽然这些干细胞衍生的 β (SC-β) 细胞能够进行葡萄糖刺激的胰岛素分泌 (GSIS)，但与胰岛相比，每个细胞的胰岛素分泌仍然较低，并且细胞缺乏动态胰岛素释放。在此，我们报告了一种分化策略，重点是调节转化生长因子β（TGF-β）信号传导、控制细胞簇大小，并使用富集的无血清培养基生成表达β细胞标记物的SC-β细胞，并经历第一相和第二相动态胰岛素分泌的GSIS。将这些细胞移植到小鼠体内可以大大改善葡萄糖耐量。这些结果表明，在 SC-β 细胞分化过程中需要特定的时间范围来抑制和允许 TGF-β 信号传导，以实现动态功能。这些细胞经历 GSIS 并动态释放胰岛素的能力使它们成为糖尿病细胞治疗的有前途的细胞来源。
Recent advances in human pluripotent stem cell (hPSC) differentiation protocols have generated insulin-producing cells resembling pancreatic beta cells. While these stem cell-derived beta (SC-beta) cells are capable of undergoing glucose-stimulated insulin secretion (GSIS), insulin secretion per cell remains low compared with islets and cells lack dynamic insulin release. Herein, we report a differentiation strategy focused on modulating transforming growth factor beta (TGF-beta) signaling, controlling cellular cluster size, and using an enriched serum-free media to generate SC-beta cells that express beta cell markers and undergo GSIS with first-and second-phase dynamic insulin secretion. Transplantation of these cells into mice greatly improves glucose tolerance. These results reveal that specific time frames for inhibiting and permitting TGF-beta signaling are required during SC-beta cell differentiation to achieve dynamic function. The capacity of these cells to undergo GSIS with dynamic insulin release makes them a promising cell source for diabetes cellular therapy.