粒体自噬
间充质干细胞
生物
褪黑素
细胞生物学
衰老
线粒体
基因敲除
干细胞
下调和上调
细胞凋亡
自噬
内分泌学
生物化学
基因
作者
Jun Hee Lee,Yeo Min Yoon,Keon‐Hyoung Song,Hyunjin Noh,Sang Hun Lee
出处
期刊:Aging Cell
[Wiley]
日期:2020-01-22
卷期号:19 (3)
被引量:82
摘要
Abstract Mesenchymal stem cells (MSCs) are a popular cell source for stem cell‐based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs. In senescent MSCs (late passage), replicative senescence decreased mitophagy by inhibiting mitofission, resulting in the augmentation of mitochondrial dysfunction. Treatment with melatonin rescued replicative senescence by enhancing mitophagy and mitochondrial function through upregulation of heat shock 70 kDa protein 1L (HSPA1L). More specifically, we found that melatonin‐induced HSPA1L binds to cellular prion protein (PrP C ), resulting in the recruitment of PrP C into the mitochondria. The HSPA1L‐PrP C complex then binds to COX4IA, which is a mitochondrial complex IV protein, leading to an increase in mitochondrial membrane potential and anti‐oxidant enzyme activity. These protective effects were blocked by knockdown of HSPA1L. In a murine hindlimb ischemia model, melatonin‐treated senescent MSCs enhanced functional recovery by increasing blood flow perfusion, limb salvage, and neovascularization. This study, for the first time, suggests that melatonin protects MSCs against replicative senescence during ex vivo expansion for clinical application via mitochondrial quality control.
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