Expression of α-Smooth Muscle Actin Determines the Fate of Mesenchymal Stromal Cells

摘要

Summary Pro-fibrotic microenvironments of scars and tumors characterized by increased stiffness stimulate mesenchymal stromal cells (MSCs) to express α-smooth muscle actin (α-SMA). We investigated whether incorporation of α-SMA into contractile stress fibers regulates human {MSC} fate. Sorted α-SMA-positive {MSCs} exhibited high contractile activity, low clonogenicity, and differentiation potential limited to osteogenesis. Knockdown of α-SMA was sufficient to restore clonogenicity and adipogenesis in MSCs. Conversely, α-SMA overexpression induced {YAP} translocation to the nucleus and reduced the high clonogenicity and adipogenic potential of α-SMA-negative MSCs. Inhibition of {YAP} rescued the decreased adipogenic differentiation potential induced by α-SMA, establishing a mechanistic link between matrix stiffness, α-SMA, YAP, and {MSC} differentiation. Consistent with in?vitro findings, nuclear localization of {YAP} was positively correlated in α-SMA expressing stromal cells of adiposarcoma and osteosarcoma. We propose that α-SMA mediated contraction plays a critical role in mechanically regulating {MSC} fate by controlling YAP/TAZ activation.