Growth arrest-specific gene 6 transfer promotes mesenchymal stem cell survival and cardiac repair under hypoxia and ischemia via enhanced autocrine signaling and paracrine action
Growth arrest-specific gene 6 transfer promotes mesenchymal stem cell survival and cardiac repair under hypoxia and ischemia via enhanced autocrine signaling and paracrine action
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生长停滞特异性基因 6 转移通过增强的自分泌信号和旁分泌作用促进缺氧和缺血下间充质干细胞的存活和心脏修复
DOI：
10.1016/j.abb.2018.10.016
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发表时间：
2018
影响因子：
3.9
通讯作者：
Chengyun Liu
中科院分区：
文献类型：
--
作者：
Shengshuai Shan;Zhenyu Liu;Tangmeng Guo;Min Wang;Shaobo Tian;Yanqing Zhang;Kun Wang;Huabo Zheng;Xiaofang Zhao;Peiyuan Zuo;Yingxuan Wang;Dazhu Li;Chengyun Liu
移植后细胞活力差限制了间充质干细胞（MSCs）治疗心肌梗死（MI）后心功能障碍的能力。生长抑制特异性基因6 （Gas6）编码一种含有γ-羧谷氨酸（Gla）的分泌蛋白，在细胞生长、粘附、趋化、有丝分裂和细胞存活中起作用。在这项研究中，我们对MSCs进行了Gas6基因修饰，并通过心肌内输送评估了心肌梗死大鼠模型的细胞存活率、心功能和梗死面积。功能研究表明，Gas6的转移显著减少了MSC的凋亡，增加了MSCs在体外和体内的存活率，并且与对照MSCs （MSCNull）处理的动物相比，Gas6工程MSCs （MSCGas6）处理的动物具有更小的梗死面积和显著的功能恢复。在机制上，Gas6可以增强PI3K /Akt信号通路，并以axl依赖的自分泌方式改善缺氧诱导因子-1α (HIF-1α)驱动的MSCs中四种主要生长因子（VEGF、bFGF、SDF和IGF-1）的分泌。通过缺氧处理后的MSCGas6与条件培养基共培养新生大鼠心肌细胞，以及用VEGF、bFGF、SDF和IGF-1特异性受体抑制剂预处理心肌细胞，进一步验证了MSCGas6的旁分泌作用。总的来说，我们的数据表明，Gas6可能通过增强Gas6/Axl自分泌促生存信号和旁分泌细胞保护作用来提高MSC治疗梗死后心力衰竭的疗效。
Poor cell viability after transplantation has restricted the therapeutic capacity of mesenchymal stem cells (MSCs) for cardiac dysfunction after myocardial infarction (MI). Growth arrest-specific gene 6 (Gas6) encodes a secreted γ-carboxyglutamic acid (Gla)-containing protein that functions in cell growth, adhesion, chemotaxis, mitogenesis and cell survival. In this study, we genetically modified MSCs with Gas6 and evaluated cell survival, cardiac function, and infarct size in a rat model of MI via intramyocardial delivery. Functional studies demonstrated that Gas6 transfer significantly reduced MSC apoptosis, increased survival of MSCsin vitro and in vivo,and that Gas6-engineered MSCs (MSCGas6)-treated animals had smaller infarct size and showed remarkably functional recovery as compared with control MSCs (MSCNull)-treated animals. Mechanistically, Gas6 could enhance phosphatidylinositol 3-kinase (PI3K)/Akt signaling and improve hypoxia-inducible factor-1 alpha (HIF-1α)-driven secretion of four major growth factors (VEGF, bFGF, SDF and IGF-1) in MSCs under hypoxia in an Axl-dependent autocrine manner. The paracrine action of MSCGas6was further validated by coculture neonatal rat cardiomyocytes with conditioned medium from hypoxia-treated MSCGas6, as well as by pretreatment cardiomyocytes with the specific receptor inhibitors of VEGF, bFGF, SDF and IGF-1. Collectively, our data suggest that Gas6 may advance the efficacy of MSC therapy for post-infarcted heart failure via enhanced Gas6/Axl autocrine prosurvival signaling and paracrine cytoprotective action.