Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction
Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction
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过度表达肝细胞生长因子的间充质干细胞增强的细胞存活和旁分泌作用促进心肌梗死的心脏保护作用
DOI：
10.1016/j.yexcr.2016.03.024
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发表时间：
2016
影响因子：
3.7
通讯作者：
Zhang Fengxiang
中科院分区：
文献类型：
--
作者：
Zhao Liyan;Liu Xiaolin;Zhang Yuelin;Liang Xiaoting;Ding Yue;Xu Yan;Fang Zhen;Zhang Fengxiang
移植后细胞存活不良影响了间充质干细胞(MSCs)对心肌梗死(MI)的治疗效果。肝细胞生长因子(HGF)是一种重要的血管生成、抗炎和抗细胞凋亡的细胞因子。本研究旨在评价高表达肝细胞生长因子的骨髓间充质干细胞对心肌梗死小鼠的心脏保护作用。检测脐血间充质干细胞(UC-MSCs)和肝细胞生长因子-UC-MSCs在常氧和低氧条件下的细胞凋亡率。在低氧条件下收集UC-MSCs和HGF-UC-MSCs的条件培养液(CDM)，观察其对缺氧条件下新生心肌细胞(NCMS)的保护作用。将UC-MSCs和HGF-UC-MSCs移植到心肌梗死小鼠的梗死灶周围，移植4周后进行心功能评估。缺氧条件下HGF-UC-MSCs的凋亡率明显低于UC-MSCs。HGF-UC-MSC低氧CDM组(HGF-UC-MSCs-hy-CDM)较UC-MSC低氧CDM组(UC-MSCs-hy-CDM)诱导的NCMS细胞凋亡率更低。HGF-UC-MSCs-hy-CDM可释放缺氧抑制的p-Akt，降低Bax/Bcl2的升高比例。HGF-UC-MSCs-hy-CDM较UC-MSCs-hy-CDM表达更高水平的HGF、EGF、bFGF和VEGF。移植HGF-UC-MSCs或UC-MSCs可显著改善心肌梗死小鼠的心功能。与UC-MSCs相比，移植HGF-UC-MSCs可减少心肌细胞的凋亡，促进血管生成，促进心肌细胞的增殖。本研究可能为心血管疾病的MSC治疗提供一种新的治疗策略。
Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted into the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.