miR-155-5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction
miR-155-5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction
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miR-155-5p 抑制可使衰老的间充质干细胞恢复活力并增强梗死后的心脏保护作用
DOI：
10.1111/acel.13128
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发表时间：
2020-03-20
期刊：
影响因子：
7.8
通讯作者：
Zhang, Yuelin
中科院分区：
文献类型：
--
作者：
Hong, Yimei;He, Haiwei;Zhang, Yuelin
衰老损害了人类间充质干细胞（MSC）的功能，从而严重降低了它们对心肌梗死（MI）的有益作用。microRNAs（miRNAs）在调控MSCs衰老过程中发挥重要作用，但其机制尚不清楚。在这里，我们研究了miR-155- 5 p在调节MSC衰老中的意义，以及miR-155- 5 p的抑制是否可以使衰老的MSC（AMSC）恢复活力，以增强其对MI的治疗效果。分别从年轻和老年供体中分离年轻MSC（YMSC）和AMSC。通过衰老相关β-半乳糖苷酶（SA-β-gal）染色评价MSC的细胞衰老。与YMSC相比，AMSC表现出增加的细胞衰老，如增加的SA-β-gal活性和降低的增殖能力和旁分泌效应所证明的。miR-155- 5 p在老年供体的血清和MSC中的表达均远高于年轻供体。miR-155- 5 p在YMSC中的上调导致细胞衰老增加，而miR-155- 5 p的下调降低AMSC衰老。从机制上讲，miR-155- 5 p通过AMPK信号通路抑制MSC中的线粒体分裂并增加线粒体融合，从而通过抑制Cab 39的表达导致细胞衰老。这些作用通过AMPK激活剂或mitofusin 2特异性siRNA（Mfn 2-siRNA）处理而部分逆转。通过增强血管生成和促进细胞存活，与AMSC移植相比，抗miR-155- 5 p-AMSC移植导致MI老年小鼠模型中心脏功能改善。总之，我们的研究表明，miR-155- 5 p通过调节Cab 39/AMPK信号通路介导MSC衰老，miR-155- 5 p是再生AMSC并增强其心脏保护作用的新靶点。
Aging impairs the functions of human mesenchymal stem cells (MSCs), thereby severely reducing their beneficial effects on myocardial infarction (MI). MicroRNAs (miRNAs) play crucial roles in regulating the senescence of MSCs; however, the underlying mechanisms remain unclear. Here, we investigated the significance of miR-155-5p in regulating MSC senescence and whether inhibition of miR-155-5p could rejuvenate aged MSCs (AMSCs) to enhance their therapeutic efficacy for MI. Young MSCs (YMSCs) and AMSCs were isolated from young and aged donors, respectively. The cellular senescence of MSCs was evaluated by senescence-associated beta-galactosidase (SA-beta-gal) staining. Compared with YMSCs, AMSCs exhibited increased cellular senescence as evidenced by increased SA-beta-gal activity and decreased proliferative capacity and paracrine effects. The expression of miR-155-5p was much higher in both serum and MSCs from aged donors than young donors. Upregulation of miR-155-5p in YMSCs led to increased cellular senescence, whereas downregulation of miR-155-5p decreased AMSC senescence. Mechanistically, miR-155-5p inhibited mitochondrial fission and increased mitochondrial fusion in MSCs via the AMPK signaling pathway, thereby resulting in cellular senescence by repressing the expression of Cab39. These effects were partially reversed by treatment with AMPK activator or mitofusin2-specific siRNA (Mfn2-siRNA). By enhancing angiogenesis and promoting cell survival, transplantation of anti-miR-155-5p-AMSCs led to improved cardiac function in an aged mouse model of MI compared with transplantation of AMSCs. In summary, our study shows that miR-155-5p mediates MSC senescence by regulating the Cab39/AMPK signaling pathway and miR-155-5p is a novel target to rejuvenate AMSCs and enhance their cardioprotective effects.