Reichman David E, Park Laura, Man Limor, Redmond David, Chao Kenny, Harvey Richard P, Taketo Makoto M, Rosenwaks Zev, James Daylon
Center for Reproductive Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
Development. 2018 Jan 8;145(1):dev159905. doi: 10.1242/dev.159905.
Several studies have demonstrated a multiphasic role for Wnt signaling during embryonic cardiogenesis and developed protocols that enrich for cardiac derivatives during differentiation of human pluripotent stem cells (hPSCs). However, few studies have investigated the role of Wnt signaling in the specification of cardiac progenitor cells (CPCs) toward downstream fates. Using transgenic mice and hPSCs, we tracked endothelial cells (ECs) that originated from CPCs expressing NKX2.5. Analysis of EC-fated CPCs at discrete phenotypic milestones during hPSC differentiation identified reduced Wnt activity as a hallmark of EC specification, and the enforced activation or inhibition of Wnt reduced or increased, respectively, the degree of vascular commitment within the CPC population during both hPSC differentiation and mouse embryogenesis. Wnt5a, which has been shown to exert an inhibitory influence on Wnt signaling during cardiac development, was dynamically expressed during vascular commitment of hPSC-derived CPCs, and ectopic Wnt5a promoted vascular specification of hPSC-derived and mouse embryonic CPCs.
多项研究已证明Wnt信号在胚胎心脏发生过程中具有多相作用，并开发了在人多能干细胞（hPSC）分化过程中富集心脏衍生物的方案。然而，很少有研究调查Wnt信号在心脏祖细胞（CPC）向下游命运特化中的作用。利用转基因小鼠和hPSC，我们追踪了源自表达NKX2.5的CPC的内皮细胞（EC）。在hPSC分化过程中，对处于离散表型里程碑的EC命运CPC进行分析，发现Wnt活性降低是EC特化的标志，在hPSC分化和小鼠胚胎发育过程中，Wnt的强制激活或抑制分别降低或增加了CPC群体内血管定向分化的程度。Wnt5a在心脏发育过程中已被证明对Wnt信号发挥抑制作用，在hPSC来源的CPC的血管定向分化过程中动态表达，异位表达的Wnt5a促进了hPSC来源和小鼠胚胎CPC的血管特化。
