title: Expression of α-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 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.
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON M5S 3E2, Canada.
authors.forename: Nilesh P
authors.initials: NP
authors.lastname: Talele
authors.affiliation: Division of Regenerative Medicine, Department of Surgery, Centre de recherche en organogénèse expérimentale de l'Université Laval / LOEX, CHU de Québec Research Centre, Faculty of Medicine, Université Laval, Québec, QC G1J 1Z4, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Fradette
authors.affiliation: Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Davies
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON M5S 3E2, Canada. Electronic address: boris.hinz@utoronto.ca.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011166:Porphyrins / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors; D000077362:Verteporfin; D000091102:YAP-Signaling Proteins
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D011166:Porphyrins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000077362:Verteporfin