Vinculin and c-Cbl-associated protein (CAP) suppress Meflin expression to regulate stiffness-dependent osteogenic differentiation of mesenchymal stem cells

Vinculin and c-Cbl-associated protein (CAP) mediate the regulation of mesenchymal stem cell (MSC) differentiation depending on the stiffness of the extracellular matrix (ECM); however, the molecular mechanism downstream of vinculin-CAP is not fully elucidated. Here, we demonstrated that vinculin and CAP suppress Meflin expression, a factor crucial for maintaining MSCs in an undifferentiated state. Depletion of vinculin and CAP increases Meflin expression, particularly on rigid ECM substrates. This regulation occurs through Yes-associated protein, a transcriptional co-activator that influences cellular differentiation. Furthermore, CAP-mediated suppression of Meflin promotes osteoblast differentiation on rigid ECM. Overall, this study demonstrates that the vinculin-CAP-Meflin axis is involved in a complex regulatory mechanism that controls MSC differentiation into osteoblasts depending on ECM stiffness.