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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

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

Talele Nilesh P NP Fradette Julie J Davies John E JE Kapus Andras A Hinz Boris B

Stem cell reports 20150528 6

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. ...[more]

PMID: 26028530

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Project description:IntroductionObliterative vasculopathy and fibrosis are hallmarks of systemic sclerosis (SSc), a severe systemic autoimmune disease. Bone marrow-derived mesenchymal stromal cells (MSCs) from SSc patients may harbor disease-specific abnormalities. We hypothesized disturbed vascular smooth muscle cell (VSMC) differentiation with increased propensity towards myofibroblast differentiation in response to SSc-microenvironment defining growth factors and determined responsible mechanisms.MethodsWe studied responses of multipotent MSCs from SSc-patients (SSc-MSCs) and healthy controls (H-MSCs) to long-term exposure to CTGF, b-FGF, PDGF-BB or TGF-β1. Differentiation towards VSMC and myofibroblast lineages was analyzed on phenotypic, biochemical, and functional levels. Intracellular signaling studies included analysis of TGF-β receptor regulation, SMAD, AKT, ERK1/2 and autocrine loops.ResultsVSMC differentiation towards both, contractile and synthetic VSMC phenotypes in response to CTGF and b-FGF was disturbed in SSc-MSCs. H-MSCs and SSc-MSCs responded equally to PDGF-BB with prototypic fibroblastic differentiation. TGF-β1 initiated myofibroblast differentiation in both cell types, yet with striking phenotypic and functional differences: In relation to H-MSC-derived myofibroblasts induced by TGF-β1, those obtained from SSc-MSCs expressed more contractile proteins, migrated towards TGF-β1, had low proliferative capacity, and secreted higher amounts of collagen paralleled by reduced MMP expression. Higher levels of TGF-β receptor 1 and enhanced canonical and noncanonical TGF-β signaling in SSc-MSCs accompanied aberrant differentiation response of SSc-MSCs in comparison to H-MSCs.ConclusionsDeregulated VSMC differentiation with a shift towards myofibroblast differentiation expands the concept of disturbed endogenous regenerative capacity of MSCs from SSc patients. Disease related intrinsic hyperresponsiveness to TGF-β1 with increased collagen production may represent one responsible mechanism. Better understanding of repair barriers and harnessing beneficial differentiation processes in MSCs could widen options of autologous MSC application in SSc patients.

Dataset Information

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

Publications

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

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