Institute of Experimental Cardiology Named after Academician V.N. Smirnov, Federal State Budgetary Institution National Medical Research Center of Cardiology Named after Academician E.I. Chazov, Ministry of Health of the Russian Federation, 121552 Moscow, Russia.
Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia.
Int J Mol Sci. 2023 Oct 25;24(21):15554. doi: 10.3390/ijms242115554.
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.
心脏细胞治疗实施面临的最大挑战之一是确定选择性修复靶点，以增强干细胞/祖细胞治疗效果。在这项工作中，我们假设该靶点可以是尿激酶型纤溶酶原激活物受体 (uPAR)-一种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 (MPC) 中表达 uPAR 的 CD117+ 群体。结果发现，uPAR-/- 小鼠心脏中的 CD117+MPC 数量较少，其体外增殖能力也低于野生型动物的细胞。在野生型动物的 CD117+MPC 中敲低 uPAR 后，这些细胞的存活率和 Akt 信号通路活性降低，caspase 活性水平升高。这表明 uPAR 在支持细胞存活方面发挥作用。在心肌梗死模型小鼠中进行 uPAR(-)MPC 心肌内移植后，与 uPAR(+)细胞移植相比，观察到细胞保留减少和血管生成刺激减弱。总之，这些结果似乎证明了 uPAR 在维持 CD117+MPC 存活和血管生成特性中的新作用机制。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点的重要性。
