El-Derany Marwa O, AbdelHamid Sherihan G
Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.
Life (Basel). 2022 Feb 28;12(3):355. doi: 10.3390/life12030355.
Cardiovascular-disease (CVD)-related mortality has been fueled by the upsurge of non-alcoholic steatohepatitis (NASH). Mesenchymal stem cells (MSCs) were extensively studied for their reparative power in ameliorating different CVDs via direct and paracrine effects. Several reports pointed to the importance of bone marrow mesenchymal stem cells (BM-MSCs) as a reliable therapeutic approach for several CVDs. Nevertheless, their therapeutic potential has not yet been investigated in the cardiotoxic state that is induced by NASH. Thus, this study sought to investigate the molecular mechanisms associated with cardiotoxicity that accompany NASH. Besides, we aimed to comparatively study the therapeutic effects of bone-marrow mesenchymal-stem-cell-derived extracellular vesicles (BM-MSCs-EV) and BM-MSCs in a cardiotoxic model that is induced by NASH in rats. Rats were fed with high-fat diet (HFD) for 12 weeks. At the seventh week, BM-MSCs-EV were given a dose of 120 µg/kg i.v., twice a week for six weeks (12 doses per 6 weeks). Another group was treated with BM-MSCs at a dose of 1 × 10 cell i.v., per rat once every 2 weeks for 6 weeks (3 doses per 6 weeks). BM-MSCs-EV demonstrated superior cardioprotective effects through decreasing serum cardiotoxic markers, cardiac hypoxic state (HIF-1) and cardiac inflammation (NF-κB p65, TNF-α, IL-6). This was accompanied by increased vascular endothelial growth factor (VEGF) and improved cardiac histopathological alterations. Both BM-MSCs-EV and BM-MSCs restored the mitochondrial antioxidant state through the upregulation of UCP2 and MnSOD genes. Besides, mitochondrial Parkin-dependent and -independent mitophagies were regained through the upregulation of (Parkin, PINK1, ULK1, BNIP3L, FUNDC1) and (LC3B). These effects were mediated through the regulation of pAKT, PI3K, Hypoxia, VEGF and NF-κB signaling pathways by an array of secreted microRNAs (miRNAs). Our findings unravel the potential ameliorative effects of BM-MSCs-EV as a comparable new avenue for BM-MSCs for modulating cardiotoxicity that is induced by NASH.
非酒精性脂肪性肝炎（NASH）的激增加剧了心血管疾病（CVD）相关的死亡率。间充质干细胞（MSCs）因其通过直接和旁分泌作用改善不同CVD的修复能力而受到广泛研究。几份报告指出骨髓间充质干细胞（BM-MSCs）作为几种CVD可靠治疗方法的重要性。然而，它们在NASH诱导的心脏毒性状态下的治疗潜力尚未得到研究。因此，本研究旨在探讨与NASH伴随的心脏毒性相关的分子机制。此外,我们旨在比较研究骨髓间充质干细胞衍生的细胞外囊泡（BM-MSCs-EV）和BM-MSCs在大鼠NASH诱导的心脏毒性模型中的治疗效果。大鼠喂食高脂饮食（HFD）12周。在第7周，静脉注射剂量为120μg/kg的BM-MSCs-EV，每周两次，共六周（每6周12剂）。另一组以每只大鼠静脉注射1×10个细胞的剂量用BM-MSCs治疗，每2周一次，共六周（每6周3剂）。BM-MSCs-EV通过降低血清心脏毒性标志物、心脏缺氧状态（HIF-1）和心脏炎症（NF-κB p65、TNF-α、IL-6）表现出卓越的心脏保护作用。这伴随着血管内皮生长因子（VEGF）增加和心脏组织病理学改变改善。BM-MSCs-EV和BM-MSCs均通过上调UCP2和MnSOD基因恢复线粒体抗氧化状态。此外，通过上调（Parkin、PINK1、ULK1、BNIP3L、FUNDC1）和（LC3B）恢复线粒体Parkin依赖性和非依赖性线粒体自噬。这些作用是通过一系列分泌的微小RNA（miRNAs）对pAKT、PI3K、缺氧、VEGF和NF-κB信号通路的调节介导的。我们的研究结果揭示了BM-MSCs-EV作为BM-MSCs调节NASH诱导的心脏毒性的可比新途径的潜在改善作用。
