TFAM公司
细胞生物学
线粒体
线粒体DNA
间充质干细胞
癌症研究
干细胞
生物
线粒体生物发生
生物化学
基因
作者
Meng Zhao,Shuyun Liu,Chengshi Wang,Yizhuo Wang,Meihua Wan,Fang Liu,Meng Gong,Yujia Yuan,Younan Chen,Jingqiu Cheng,Yanrong Lu,Jingping Liu
出处
期刊:ACS Nano
[American Chemical Society]
日期:2020-12-28
卷期号:15 (1): 1519-1538
被引量:178
标识
DOI:10.1021/acsnano.0c08947
摘要
Mitochondrial dysfunction is a key feature of injury to numerous tissues and stem cell aging. Although the tissue regenerative role of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) is well known, their specific role in regulating mitochondrial function in target cells remains elusive. Here, we report that MSC-EVs attenuated mtDNA damage and inflammation after acute kidney injury (AKI) and that this effect was at least partially dependent on the mitochondrial transcription factor A (TFAM) pathway. In detail, TFAM and mtDNA were depleted by oxidative stress in MSCs from aged or diabetic donors. Higher levels of TFAM mRNA and mtDNA were detected in normal control (NC) MSC-EVs than in TFAM-knockdown (TFAM-KD) and aged EVs. EV-mediated TFAM mRNA transfer in recipient cells was unaffected by transcriptional inhibition. Accordingly, the application of MSC-EVs restored TFAM protein and TFAM-mtDNA complex (nucleoid) stability, thereby reversing mtDNA deletion and mitochondrial oxidative phosphorylation (OXPHOS) defects in injured renal tubular cells. Loss of TFAM also led to downregulation of multiple anti-inflammatory miRNAs and proteins in MSC-EVs. In vivo, intravenously injected EVs primarily accumulated in the liver, kidney, spleen, and lung. MSC-EVs attenuated renal lesion formation, mitochondrial damage, and inflammation in mice with AKI, whereas EVs from TFAM-KD or aged MSCs resulted in poor therapeutic outcomes. Moreover, TFAM overexpression (TFAM-OE) improved the rescue effect of MSC-EVs on mitochondrial damage and inflammation to some extent. This study suggests that MSC-EVs are promising nanotherapeutics for diseases characterized by mitochondrial damage, and TFAM signaling is essential for maintaining their regenerative capacity.
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