Alimperti Stella, You Hui, George Teresa, Agarwal Sandeep K, Andreadis Stelios T
Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Amherst, NY 14260-4200, USA.
Baylor College of Medicine, Department of Medicine, Section of Allergy, Immunology, and Rheumatology, Biology of Inflammation Center, One Baylor Plaza, Suite 672E, MS, BCM285, Houston, TX 77030, USA.
J Cell Sci. 2014 Jun 15;127(Pt 12):2627-38. doi: 10.1242/jcs.134833. Epub 2014 Apr 16.
Although soluble factors, such as transforming growth factor β1 (TGF-β1), induce mesenchymal stem cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage, the role of adherens junctions in this process is not well understood. In this study, we found that cadherin-11 but not cadherin-2 was necessary for MSC differentiation into SMCs. Cadherin-11 regulated the expression of TGF-β1 and affected SMC differentiation through a pathway that was dependent on TGF-β receptor II (TGFβRII) but independent of SMAD2 or SMAD3. In addition, cadherin-11 activated the expression of serum response factor (SRF) and SMC proteins through the Rho-associated protein kinase (ROCK) pathway. Engagement of cadherin-11 increased its own expression through SRF, indicative of the presence of an autoregulatory feedback loop that committed MSCs to the SMC fate. Notably, SMC-containing tissues (such as aorta and bladder) from cadherin-11-null (Cdh11(-/-)) mice showed significantly reduced levels of SMC proteins and exhibited diminished contractility compared with controls. This is the first report implicating cadherin-11 in SMC differentiation and contractile function in vitro as well as in vivo.
尽管诸如转化生长因子β1（TGF-β1）等可溶性因子可诱导间充质干细胞（MSC）向平滑肌细胞（SMC）谱系分化，但黏附连接在此过程中的作用尚未完全清楚。在本研究中，我们发现钙黏蛋白-11而非钙黏蛋白-2是MSC分化为SMC所必需的。钙黏蛋白-11调节TGF-β1的表达，并通过一条依赖于TGF-β受体II（TGFβRII）但不依赖于SMAD2或SMAD3的途径影响SMC分化。此外，钙黏蛋白-11通过Rho相关蛋白激酶（ROCK）途径激活血清反应因子（SRF）和SMC蛋白的表达。钙黏蛋白-11的结合通过SRF增加其自身的表达，这表明存在一个使MSC定向为SMC命运的自调节反馈环。值得注意的是，与对照组相比，来自钙黏蛋白-11基因敲除（Cdh11(-/-)）小鼠的含SMC组织（如主动脉和膀胱）显示SMC蛋白水平显著降低，收缩力减弱。这是首篇表明钙黏蛋白-11在体外和体内SMC分化及收缩功能中起作用的报道。
