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

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

SUBMITTER: Talele NP 

PROVIDER: S-EPMC4471834 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other