• ACS nano · Jan 2021

    Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Mitochondrial Damage and Inflammation by Stabilizing Mitochondrial DNA.

    • Meng Zhao, Shuyun Liu, Chengshi Wang, Yizhuo Wang, Meihua Wan, Fang Liu, Meng Gong, Yujia Yuan, Younan Chen, Jingqiu Cheng, Yanrong Lu, and Jingping Liu.
    • Key Laboratory of Transplant Engineering and Immunology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
    • ACS Nano. 2021 Jan 26; 15 (1): 1519-1538.

    AbstractMitochondrial 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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