Control of cellular phenotype in a human stem cell-derived smooth muscle cell model*

            Vascular smooth muscle cells (vSMCs) do not terminally differentiate and can switch between synthetic (proliferative) and contractile (mechanically active) phenotypes in response to environmental cues. The synthetic to contractile transition is important for mechanical adaptation of the vasculature during the perinatal period of development, but the mechanisms underlying this transition are not well understood, particularly in humans. To address mechanically induced modulation of vSMC phenotype switching, we have developed a human induced pluripotent stem (iPS) cell-derived vSMC model.  We have qualified this model through studies of cell surface chemistry, protein expression, proliferative activity, and contractile force in individual cells and in microtissue constructs, and through comparison with primary human vSMC lines. Notably, treatment with the MAP-kinase inhibitor MEKi causes increases in contractile markers and in generated force consistent with synthetic to contractile switching, but mTOR inhibition with rapamycin does not, in contrast to what is seen in animal models.  Human iPS-derived vSMCs systems thus are effective at uncovering how small molecules and mechanical cues affect phenotype switching and vSMC function in models of development.