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Generation of pancreatic progenitors from human pluripotent stem cells by small molecules
Stem Cell Reports ( IF 5.9 ) Pub Date : 2021-08-26 , DOI: 10.1016/j.stemcr.2021.07.021
Yuqian Jiang 1 , Chuanxin Chen 2 , Lauren N Randolph 1 , Songtao Ye 3 , Xin Zhang 3 , Xiaoping Bao 4 , Xiaojun Lance Lian 5
Affiliation  

Human pluripotent stem cell (hPSC)-derived pancreatic progenitors (PPs) provide promising cell therapies for type 1 diabetes. Current PP differentiation requires a high amount of Activin A during the definitive endoderm (DE) stage, making it economically difficult for commercial ventures. Here we identify a dose-dependent role for Wnt signaling in controlling DE differentiation without Activin A. While high-level Wnt activation induces mesodermal formation, low-level Wnt activation by a small-molecule inhibitor of glycogen synthase kinase 3 is sufficient for DE differentiation, yielding SOX17+FOXA2+ DE cells. BMP inhibition further enhances this DE differentiation, generating over 87% DE cells. These DE cells could be further differentiated into PPs and functional β cells. RNA-sequencing analysis of PP differentiation from hPSCs revealed expected transcriptome dynamics and new gene regulators during our small-molecule PP differentiation protocol. Overall, we established a robust growth-factor-free protocol for generating DE and PP cells, facilitating scalable production of pancreatic cells for regenerative applications.



中文翻译:


通过小分子从人多能干细胞产生胰腺祖细胞



人类多能干细胞 (hPSC) 来源的胰腺祖细胞 (PP) 为 1 型糖尿病提供了有前景的细胞疗法。目前的 PP 分化在定形内胚层 (DE) 阶段需要大量的激活素 A,这使得商业投资在经济上变得困难。在这里,我们确定了 Wnt 信号在没有激活素 A 的情况下控制 DE 分化的剂量依赖性作用。虽然高水平的 Wnt 激活诱导中胚层形成,但糖原合酶激酶 3 的小分子抑制剂的低水平 Wnt 激活足以进行 DE 分化,产生 SOX17 + FOXA2 + DE 细胞。 BMP 抑制进一步增强了这种 DE 分化,产生了超过 87% 的 DE 细胞。这些DE细胞可以进一步分化为PPs和功能性β细胞。 hPSC 的 PP 分化的 RNA 测序分析揭示了我们的小分子 PP 分化方案中预期的转录组动态和新的基因调节因子。总的来说,我们建立了一个强大的无生长因子方案来生成 DE 和 PP 细胞,促进用于再生应用的胰腺细胞的规模化生产。

更新日期:2021-09-14
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