Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair
Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair
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DOI：
10.18632/aging.102592
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发表时间：
2019-12
期刊：
影响因子：
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通讯作者：
Yuelin Zhang;Wenwu Zhu;Haiwei He;B. Fan;R. Deng;Yimei Hong;Xiaoting Liang;Hongyan Zhao;Xin L
中科院分区：
文献类型：
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作者：
Yuelin Zhang;Wenwu Zhu;Haiwei He;B. Fan;R. Deng;Yimei Hong;Xiaoting Liang;Hongyan Zhao;Xin L
间充质干细胞（MSCs）的有益功能随着年龄的增长而下降，限制了其对心肌梗死（MI）的治疗效果。巨噬细胞迁移抑制因子（Macrophage migration inhibitory factor， MIF）促进细胞增殖和存活。我们研究了MIF过表达是否能使衰老的MSCs恢复活力并提高其治疗心肌梗死的疗效。我们从年轻和老年供者的骨髓中分离出年轻和年老的MSCs。在大鼠心肌梗死模型中，将年轻MSCs、年老MSCs和过表达mif的年老MSCs移植到梗死周围区域。与年轻MSCs相比，衰老MSCs表现出较低的增殖能力、较低的MIF水平、较大的细胞大小、较高的衰老相关-β-半乳糖苷酶活性和较弱的旁分泌效应。在年轻间充质干细胞中敲低MIF可诱导细胞衰老，而在老年间充质干细胞中过表达MIF可减少细胞衰老。MIF通过激活自噬使衰老的MSCs恢复活力，这一作用在很大程度上被自噬抑制剂3-甲基腺嘌呤逆转。MIF过表达的衰老MSCs比衰老MSCs更能诱导血管生成和阻止心肌细胞凋亡，并且在心肌梗死4周后比衰老MSCs更有效地改善心功能和细胞存活。因此，MIF通过激活自噬来恢复衰老MSCs的活力，并增强其在心肌梗死中的治疗效果，提示了一种新的基于MIF的老年心血管疾病治疗策略。
The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in MI. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat MI model. Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine. MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after MI. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in MI, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.