PDF(Pubmed)
Abstract：
One of the largest challenges to the implementation of cardiac cell therapy is identifying selective reparative targets to enhance stem/progenitor cell therapeutic efficacy. In this work, we hypothesized that such a target could be an urokinase-type plasminogen activator receptor (uPAR)-a glycosyl-phosphatidyl-inositol-anchored membrane protein, interacting with urokinase. uPAR is able to form complexes with various transmembrane proteins such as integrins, activating intracellular signaling pathway and thus regulating multiple cell functions. We focused on studying the CD117+ population of cardiac mesenchymal progenitor cells (MPCs), expressing uPAR on their surface. It was found that the number of CD117+ MPCs in the heart of the uPAR-/- mice is lower, as well as their ability to proliferate in vitro compared with cells from wild-type animals. Knockdown of uPAR in CD117+ MPCs of wild-type animals was accompanied by a decrease in survival rate and Akt signaling pathway activity and by an increase in the level of caspase activity in these cells. That suggests the role of uPAR in supporting cell survival. After intramyocardial transplantation of uPAR(-) MPCs, reduced cell retention and angiogenesis stimulation were observed in mice with myocardial infarction model compared to uPAR(+) cells transplantation. Taken together, the present results appear to prove a novel mechanism of uPAR action in maintaining the survival and angiogenic properties of CD117+ MPCs. These results emphasize the importance of the uPAR as a potential pharmacological target for the regulation of reparative properties of myocardial mesenchymal progenitor cells.
摘要：
实施心脏细胞疗法的最大挑战之一是鉴定选择性修复靶标以增强干/祖细胞治疗功效。在这项工作中,我们假设这样的靶标可能是尿激酶型纤溶酶原激活物受体（uPAR）-糖基磷脂酰肌醇锚定膜蛋白，与尿激酶相互作用。uPAR能够与各种跨膜蛋白如整合素形成复合物，激活细胞内信号通路，从而调节多种细胞功能。我们专注于研究心脏间充质祖细胞（MPCs）的CD117+群体，在其表面表达uPAR。发现uPAR-/-小鼠心脏中CD117+MPCs的数量较低，以及它们与野生型动物细胞相比在体外增殖的能力。野生型动物的CD117+MPC中uPAR的敲低伴随着存活率和Akt信号传导途径活性的降低以及这些细胞中的半胱天冬酶活性水平的增加。这表明uPAR在支持细胞存活中的作用。心肌内移植uPAR(-)MPCs后，与uPAR（）细胞移植相比，在心肌梗死模型小鼠中观察到细胞保留和血管生成刺激减少。一起来看,本结果似乎证明了uPAR作用在维持CD117+MPCs的存活和血管生成特性方面的新机制。这些结果强调了uPAR作为调节心肌间充质祖细胞修复特性的潜在药理学靶标的重要性。
