mTORC2-mediated cell-cell interactions promote BMP4-induced WNT activation and mesoderm differentiation

The mechanistic target of rapamycin complex 2 (mTORC2) is essential for embryonic development but its underlying molecular mechanisms remain unclear. Here we show that disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the Rho/Rac signaling dynamics and reduces cell adhesion. Despite this, mTORC2-deficient hESCs maintain self-renewal and expression of pluripotent markers when cultured in mouse-embryonic fibroblast conditioned medium supplemented with bFGF (MEF-CM). However, these hESCs exhibit significantly impaired mesoderm and endoderm differentiation in response to BMP4 and Activin, respectively, due to reduced WNT activation mediated by cell-cell interactions. Direct activation of the WNT pathway by a GSK3 inhibitor restores mesendoderm differentiation in mTORC2-deficient hESCs. Our study uncovers a novel mechanism by which mTORC2 regulates cell fate determination and highlights a critical link between the intercellular adhesion and the activation of canonical WNT genes.