美国斯坦福大学医学院的Sean M. Wu研究组取得一项新突破。他们的最新研究表明，Wnt激活与细胞接触降低能够协同实现对人类iPSC来源的心肌细胞进行大规模扩增。2020年7月2日，《细胞—干细胞》发表了这一成果。

据研究人员介绍，调节包括Wnt和Hippo在内的信号通路可以在体内诱导心肌细胞增殖。在体外将这些信号调节剂应用于人诱导型多能干细胞来源的心肌细胞（hiPSC-CM）可使CM适度扩增（低于5倍）。

Author: Jan W. Buikema, Soah Lee, William R. Goodyer, Renee G. Maas, Orlando Chirikian, Guang Li, Yi Miao, Sharon L. Paige, Daniel Lee, Haodi Wu, David T. Paik, Siyeon Rhee, Lei Tian, Francisco X. Galdos, Nazan Puluca, Benjamin Beyersdorf, James Hu, Aimee Beck, Sneha Venkamatran, Srilatha Swami, Paul Wijnker, Maike Schuldt, Larissa M. Dorsch, Alain van Mil, Kristy Red-Horse, Joy Y. Wu, Caroline Geisen, Michael Hesse, Vahid Serpooshan, Stefan Jovinge, Bernd K. Fleischmann, Pieter A. Doevendans, Jolanda van der Velden, K. Christopher Garcia, Joseph C. Wu, Joost P.G. Sluijter, Sean M. Wu

Issue&Volume: 2020/07/02

Abstract: Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferationin vivo. Applying these signaling modulators to human induced pluripotent stem cell-derivedcardiomyocytes (hiPSC-CMs) in vitro can expand CMs modestly (<5-fold). Here, we demonstrate massive expansion of hiPSC-CMsin vitro (i.e., 100- to 250-fold) by glycogen synthase kinase-3β (GSK-3β) inhibition usingCHIR99021 and concurrent removal of cell-cell contact. We show that GSK-3β inhibitionsuppresses CM maturation, while contact removal prevents CMs from cell cycle exit.Remarkably, contact removal enabled 10 to 25 times greater expansion beyond GSK-3βinhibition alone. Mechanistically, persistent CM proliferation required both LEF/TCFactivity and AKT phosphorylation but was independent from yes-associated protein (YAP)signaling. Engineered heart tissues from expanded hiPSC-CMs showed comparable contractilityto those from unexpanded hiPSC-CMs, demonstrating uncompromised cellular functionalityafter expansion. In summary, we uncovered a molecular interplay that enables massivehiPSC-CM expansion for large-scale drug screening and tissue engineering applications.

DOI: 10.1016/j.stem.2020.06.001

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30268-X