MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation
MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation
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MSC 通过 AMPK α 激活改善肝脏缺血/再灌注损伤中 PINK1 依赖性线粒体自噬介导的肝细胞凋亡
DOI：
10.1038/s41419-020-2424-1
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发表时间：
2020-04-20
影响因子：
9
通讯作者：
Yang Yang
中科院分区：
文献类型：
--
作者：
Zheng Jun;Chen Liang;Yang Yang
肝细胞凋亡是肝脏缺血再灌注损伤的主要病理生理过程。线粒体异常在肝细胞损伤中起着至关重要的作用。间充质干细胞(MSCs)的肝脏保护作用已被证实。本研究旨在探讨骨髓间充质干细胞抗肝脏I/R损伤的作用及其可能机制。在小鼠肝脏I/R损伤模型和L02肝细胞缺氧/复氧(H/R)模型中观察MSCs的作用。研究了MSCs在体内和体外诱导的肝细胞I/R凋亡模型中的作用机制。随着肝脏损伤程度的改善，MSCs表现出控制线粒体质量的能力，表现为减少线粒体活性氧自由基(MtROS)的过量产生，减少线粒体碎片的积累，恢复ATP合成，上调线粒体吞噬功能。此外，我们还描述了MSCs上调丝裂原吞噬功能的可能机制，发现在I/R模型中，肝组织中Parkin和PINK1表达减少，AMPKα通路失活。这些效应可被MSCs治疗逆转。体外研究表明，MSC条件培养液(MSC-CM)可抑制H/R环境中肝细胞的凋亡和mtROS积聚。转染PINK1 siRNA或加入多索吗啡后，MSC-CM的上述作用被部分阻断。总之，我们的发现提供了一种新的药理学机制，即MSCs通过上调PINK1依赖的有丝分裂吞噬作用在肝脏I/R损伤中发挥保护肝脏的作用。此外，这种作用可能归因于AMPKα激活的调制。
Hepatocyte apoptosis is the main pathophysiological process underlying liver ischemia/reperfusion (I/R) injury. Mitochondrial abnormalities have a vital role in hepatocellular damage. The hepatoprotective effects of mesenchymal stem cells (MSCs) have been previously demonstrated. In this study, we aim to investigate the effect and potential mechanism of MSCs against liver I/R injury. Effects of MSCs were studied in mice liver I/R injury model and in a hypoxia/reoxygenation (H/R) model of L02 hepatocytes. The potential mechanisms of MSCs on these in vivo and in vitro I/R-induced hepatocellular apoptosis models were studies. Accompanied by the improvement of hepatic damage, MSCs exhibited capabilities of controlling mitochondrial quality, shown by reduced mitochondrial reactive oxygen species (mtROS) overproduction, decreased the accumulation of mitochondrial fragmentation, restored ATP generation and upregulated mitophagy. Furthermore, we descripted a potential mechanism of MSCs on upregulating mitophagy and found that the reduced Parkin and PINK1 expression and inactivated AMPK alpha pathway were observed in the liver tissue in I/R model. These effects were reversed by MSCs treatment. In vitro study showed that MSC-conditioned medium (MSC-CM) suppressed hepatocellular apoptosis and inhibited mtROS accumulation in the H/R environment. And these effects of MSC-CM were partially blocked after the cells were transfected with PINK1 siRNA or added with dorsomorphin. Collectively, our findings provide a novel pharmacological mechanism that MSCs exert hepatoprotective effect in liver I/R injury via upregulating PINK1-dependent mitophagy. In addition, this effect might be attributed to the modulation of AMPK alpha activation.