(656d) OB-Cadherin Regulates Mesenchymal Stem Cell Differentiation Into Smooth Muscle Cells and Development of Contractile Function in Vivo

Mesenchymal stem cells are multi-potent cells that can be differentiated into fat, bone, cartilage and muscle. Although soluble factors (e.g. TGF-β1) induced mesenchymal stem cell (MSC) differentiation toward smooth muscle (SMC) lineage, the role of adherent junctions in this process is not well understood.  To this end, we examined how cell-cell communication controls the fate of MSC towards smooth muscle cells (SMC). Specifically, we identified the molecular mechanism of MSC differentiation into vascular fate during cell-cell contact through a molecule called OB-cadherin. We further applied this study in-vivo and we confirmed our hypothesis in a mice model. Initially, we observed that increased cell density increased adherens junction (AJ) formation and at the same time, high cell density increased expression of myogenic markers such as αSMA as well as N-cadherin and OB-cadherin. Interestingly, we found that OB-cadherin mediated SMC differentiation through activation of serum response factor (SRF) via ROCK pathway. Also, myogenic differentiation proceeded even in the absence of TGF-β receptor, while exogenous TGF-β1 failed to promote SMC differentiation in the absence of OB-cadherin. Engagement of OB-cadherin increased its own expression through SRF, suggesting the presence of an auto regulatory feedback loop that regulated SMC differentiation. Notably, SMC-containing tissues such as bladder and arteries from OB^-/- mice showed significantly reduced levels of SMC proteins and exhibited diminished contractility and mechanical properties. To conclude, we revealed a previously unknown role of OB-cadherin based AJs in the process of SMC regeneration and shed light into the mechanism of MSC differentiation with potential implications for the development of strategies to understand and control stem cell fate decisions.