The Institute of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, China.
Key Laboratory of Organ Development and Regeneration of Zhejiang Province, College of Life Sciences, Hangzhou Normal University, Zhejiang, China.
Stem Cells Dev. 2019 Oct 1;28(19):1334-1345. doi: 10.1089/scd.2019.0065. Epub 2019 Aug 27.
Smooth muscle cells (SMCs) are important cell type for regenerative medicine. Previous studies showed that retinoic acid (RA) induces differentiation of SMCs from monolayer-cultured embryonic stem cells (ESCs) with high efficiency. However, the underlying mechanisms are still poorly defined. Here, we identified Wnt signaling as a primary regulator for RA-induced ESC differentiation. The activation of Wnt signaling inhibited the epithelial-mesenchymal transition during ESC differentiation, leading to inhibition of RA-induced SMC differentiation and promoting differentiation of ESCs toward primitive endoderm (PrE) lineage instead, while the inhibition of Wnt signaling promoted RA-induced SMC differentiation. Loss-of-function studies revealed that 7-like 2 (Tcf7l2) was the key transcription factor that Wnt operate through during RA-induced differentiation. Thus, this study revealed that the Tcf7l2-mediated Wnt signaling is a switch in determining the mesoderm/PrE fates in RA-induced ESC differentiation.
平滑肌细胞（SMCs）是再生医学中的重要细胞类型。先前的研究表明，视黄酸（RA）能够高效诱导单层培养的胚胎干细胞（ESCs）分化为 SMCs。然而，其潜在的机制仍不清楚。在这里，我们发现 Wnt 信号是 RA 诱导 ESC 分化的主要调控因子。Wnt 信号的激活抑制了 ESC 分化过程中的上皮-间充质转化，导致 RA 诱导的 SMC 分化受到抑制，并促进 ESC 向原始内胚层（PrE）谱系分化，而 Wnt 信号的抑制则促进了 RA 诱导的 SMC 分化。功能丧失研究表明，7 类类似物 2（Tcf7l2）是 Wnt 在 RA 诱导分化过程中通过的关键转录因子。因此，本研究揭示了 Tcf7l2 介导的 Wnt 信号是决定 RA 诱导的 ESC 分化中中胚层/PrE 命运的关键开关。
