Influence of extracellular matrix components on cardiac progenitor cell-mediated myocardial regeneration

在西方国家，心力衰竭是导致死亡的主要原因。在哺乳动物成年心脏中发现了驻留的多能心血管祖细胞（CPCs），为自体细胞治疗带来了希望。在啮齿类动物心肌梗死边界区注射体外扩张CPCs可改善心脏功能，可能与瘢痕组织内新生心肌和血管的形成有关。进一步的改善是通过过继转移的CPCs中Pim-1的过表达介导的。PI3K/Akt/Pim-1信号轴是许多细胞系统的关键保护通路。在非心脏细胞中，来自细胞外基质（ECM）的整合素介导的信号导致Akt的激活。到目前为止，我们对这些导致心肌细胞中Akt/Pim-1级联激活的信号知之甚少。该提案的目的是详细研究ECM和cpc之间的串扰。研究人员提出，对心肌细胞中Akt/Pim-1信号的ECM成分进行系统分析可能会通过改善细胞存活和对心源谱系的承诺来促进心肌再生。体外ECM处理后，观察CPC的增殖、凋亡、粘附和转运功能。在确定最佳ECM操作后，将使用小鼠心肌梗死模型对体外结果进行体内测试。这些研究将对未来通过细胞疗法治疗心力衰竭具有潜在的相关性。

Heart failure is the leading cause of mortality in western countries. Discovery of resident multipotent cardiovascular progenitor cells (CPCs) in mammalian adult heart raises hope for autologous cell therapy. Injection of ex vivo expanded CPCs in border zones of myocardial infarcts in rodents improves cardiac function possibly related with formation of de novo cardiac muscle and blood vessels within scar tissue. Further improvement is mediated by over-expression of Pim-1 in adoptively transferred CPCs. The PI3K/Akt/Pim-1 signaling axis is a pivotal protective pathway in many cell systems. In non-cardiac cells integrin-mediated signals from the extracellular matrix (ECM) lead to Akt activation. So far little is known about these signals leading to activation of the Akt/Pim-1 cascade in CPCs. Goal of the proposal is to investigate in detail the crosstalk between ECM and CPCs. It is proposed that a systematic analysis of ECM components on Akt/Pim-1 signaling in CPCs may improve myocardial regeneration through improved cellular survival and commitment to cardiogenic lineages. CPC functions as proliferation, apoptosis, adhesion and transmigration will be determined after ECM treatment in vitro. After optimal ECM manipulations are determined, in vitro findings will be tested in vivo, using a mouse myocardial infarction model. These studies will have potential relevance for future treatment of heart failure through cell-based therapies.