Wnt Signaling Modulates Routes of Retinoic Acid Induced Differentiation of Embryonic Stem Cells.

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.