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

被引:177
作者
Talele, Nilesh P. [1 ]
Fradette, Julie [2 ]
Davies, John E. [3 ]
Kapus, Andras [4 ,5 ]
Hinz, Boris [1 ]
机构
[1] Univ Toronto, Matrix Dynam Grp, Lab Tissue Repair & Regenerat, Fac Dent, Toronto, ON M5S 3E2, Canada
[2] Univ Laval, Ctr Rech Organogenese Expt, Div Regenerat Med, CHU Quebec Res Ctr,LOEX,Dept Surg,Fac Med, Quebec City, PQ G1J 1Z4, Canada
[3] Univ Toronto, Inst Biomat & Biomed Engn, Toronto, ON M5S 3G9, Canada
[4] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada
[5] Univ Toronto, Dept Surg, Toronto, ON M5B 1W8, Canada
基金
加拿大创新基金会; 加拿大健康研究院; 加拿大自然科学与工程研究理事会;
关键词
STEM-CELL; TGF-BETA; STRESS FIBERS; SELF-RENEWAL; MYOFIBROBLAST TRANSITION; TISSUE REGENERATION; MECHANICAL MEMORY; PROGENITOR CELLS; CLINICAL-TRIALS; IN-VIVO;
D O I
10.1016/j.stemcr.2015.05.004
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Pro-fibrotic microenvironments of scars and tumors characterized by increased stiffness stimulate mesenchymal stromal cells (MSCs) to express alpha-smooth muscle actin (alpha-SMA). We investigated whether incorporation of a-SMA into contractile stress fibers regulates human MSC fate. Sorted alpha-SMA-positive MSCs exhibited high contractile activity, low clonogenicity, and differentiation potential limited to osteogenesis. Knockdown of alpha-SMA was sufficient to restore clonogenicity and adipogenesis in MSCs. Conversely, a-SMA overexpression induced YAP translocation to the nucleus and reduced the high clonogenicity and adipogenic potential of alpha-SMA-negative MSCs. Inhibition of YAP rescued the decreased adipogenic differentiation potential induced by alpha-SMA, establishing a mechanistic link between matrix stiffness, alpha-SMA, YAP, and MSC differentiation. Consistent with in vitro findings, nuclear localization of YAP was positively correlated in a-SMA expressing stromal cells of adiposarcoma and osteosarcoma. We propose that a-SMA mediated contraction plays a critical role in mechanically regulating MSC fate by controlling YAP/TAZ activation.
引用
收藏
页码:1016 / 1030
页数:15
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