Differentiation of bone marrow mesenchymal stem cells towards the smooth muscle cell lineage by blocking Elk‐1 signaling and overexpression of myocardin

Abstract

Objective: Smooth muscle cells (SMC) are major components of blood vessels, with their differentiation being driven by myocardin and antagonized by Elk-1 transcription factors. This study aims to evaluate whether adult bone marrow-derived mesenchymal stem cells (BMMSC) can be converted into SMC by modulating these two transcription factors. Methods: We employed PD98059, an inhibitor of MEK to block Elk-1 activation. TAT-myocardin protein expression vector was constructed for myocardin overexpression. We evaluated SMC specific marker gene expression by RT-PCR and immuno-detection. Results: Undifferentiated BMMSC express most SMC marker genes, albeit sometimes at low levels, except smooth muscle myosin heavy chain (SMMHC), the most definitive marker of differentiated SMC. PD98059 blocked Elk-1 phosphorylation in BMMSC in low serum condition and induced SMMHC expression in BMMSC. Myocardin overexpression also induced SMMHC expression. Conclusions: Inhibition of Elk-1 signaling and/or overexpression of myocardin drives BMMSC into SMC lineage. Further studies will determine if this is sufficient for SMC functioning or if additional cellular conditions is needed. These findings provide impetus for rationale bioengineering of blood vessels. Study supported by CAP Foundation (K.T.) and NIGMS (A.W.)