MIF通过调控自噬年轻化衰老间充质干细胞治疗急性心肌梗死的机制研究

Mesenchymal stem cells (MSCs)- based therapies have had positive outcomes in treatment of acute myocardial infarction(AMI). However, the number and function of MSCs decline with age, reducing their ability to contribute to endogenous injury repair. Autophagy is closely related with cellular senescence, and decrease of autophagy causes dysfunction of senescent cells. Macrophage migration inhibitory factor(MIF) can induce autophagy to resist cellular senescence. In our previous experiments, we found that the expression of MIF, autophagy related protein, cell function, and treatment of AMI of the aged MSCs were decreased when compared with the young. Here, we suggest that exogenous MIF may ameliorate the aged MSCs cellular function through modulating cellular autophagy, and improve effect of therapy of AMI. We use rat AMI model to compare theraputic effect among aged MSCs, young MSCs, and aged MSCs pretreatment with MIF. In vitro, we culture rat MSCs to detect cell proliferation, paracrine, cellular apoptosis induced by hypoxia/serum deprivation, to reveal the mechanism underlying the rejuvenating function of MIF involves increased CD74- dependent AMPK-mTOR signaling pathway. Pretreatment of MSCs with MIF may have important therapeutic implications in restoration or rejuvenation of endogenous MSCs in AMI treatment.

间充质干细胞（MSCs）对急性心肌梗死（AMI）具有重要的治疗作用，但由于衰老个体来源MSCs生物学功能下降极大的降低了AMI移植治疗效果。自噬与细胞衰老关系密切，自噬作用减弱引起衰老细胞功能障碍。巨噬细胞迁移抑制因子（MIF）可明显诱导自噬进而发挥抗衰老作用。前期实验中，我们发现衰老个体较年轻个体来源MSCs：MIF表达、自噬相关蛋白、细胞功能、及AMI治疗能力均明显降低。我们推测MIF预处理衰老个体来源MSCs可以通过调节细胞自噬，改善细胞功能，进而提高AMI治疗效果。我们拟制备大鼠AMI模型，比较年轻个体来源MSCs、衰老个体来源MSCs、MIF预处理衰老个体来源MSCs对AMI治疗效果。同时离体培养衰老大鼠MSCs，以细胞增殖、旁分泌、抵抗缺血/缺氧诱导凋亡能力为主要指标，探究受体CD74依赖的 AMPK-mTOR信号通路的关键作用，为AMI干细胞移植治疗奠定理论基础。

骨髓间充质干细胞（BM-MSCs）在急性心肌梗死（AMI）治疗中发挥重要的治疗潜能，但由于衰老个体来源的MSCs生物学功能下降极大的限制了其自体移植治疗AMI的治疗效果。巨噬细胞迁移抑制因子（MIF）作为多种细胞信号通路调节因子，参与多种细胞增殖、存活、迁移等生命活动。本研究结果证实：MIF预处理衰老个体来源的MSCs可以改善其移植治疗AMI治疗效果。本研究离体培养衰老大鼠MSCs，给予外源性MIF预处理后，衰老个体来源的MSCs细胞增殖、细胞旁分泌功能、抵抗缺血/缺氧诱导凋亡能力均较未给予MIF处理的衰老个体来源的MSCs明显增强。同时本研究应用siRNA干扰技术沉默MIF受体CD74及 AMPK信号通路蛋白，结果提示：MIF/CD74/AMPK信号通路在MIF年轻化衰老细胞、改善细胞功能发挥关键作用，同时MIF预处理可以明显改善衰老相关性氧化应激反应，详细阐明MIF优化衰老个体来源的MSCs治疗AMI的分子机制。为探寻AMI干细胞移植治疗的新机制和新策略。