Massive Expansion of Functional Human iPSC-derived Cardiomyocytes by Concomitant Glycogen Synthase Kinase-3 Beta Inhibition and Removal of Cell-Cell Contact
收藏干细胞与再生医学数据中心2022-02-20 更新2024-03-06 收录
下载链接：
http://data.iscr.ac.cn/Article?id=5ff208af5c56aeac1534a1633e2e4812
下载链接
链接失效反馈官方服务：
资源简介：
Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs only to modest extent (< 5-fold). Here, we demonstrate massive expansion of hiPSC-CMs in vitro (i.e. 100-250-fold) by glycogen synthase kinase-3β (GSK-3β) inhibition using CHIR99021 and concurrent removal of cell-cell contact. We show GSK-3β inhibition suppresses CM maturation while contact removal prevents CMs from cell cycle exit. Remarkably, contact removal enabled 10-to-25-times greater expansion beyond GSK-3β inhibition alone. Mechanistically, cell cycle re-activation required both LEF/TCF activity and AKT phosphorylation, but it was independent from Yes associated protein (YAP) activity. Engineered heart tissues from expanded hiPSC-CMs showed the comparable contractility to those from unexpanded hiPSC-CMs, demonstrating uncompromised cellular functionality after expansion. In sum, we uncovered a molecular interplay that enables massive expansion hiPSC-CMs for large-scale drug screening and tissue engineering.
提供机构：
Stanford University
创建时间：
2022-02-20
