Bone Marrow Mesenchymal Stem Cells and Their Derived Extracellular Vesicles Attenuate Non-Alcoholic Steatohepatitis-Induced Cardiotoxicity via Modulating Cardiac Mechanisms

Abstract

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 × 106 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.

Secretome-based acellular therapy of bone marrow-derived mesenchymal stem cells in degenerative and immunological disorders: A narrative review

“…Increased Parkin, PINK1, ULK1, BNIP3L, FUNDC1, LC3B, UCP2, and MnSOD genes in cardiac muscles 2. Regulated the pAKT, PI3K, hypoxia, VEGF, and NF-κβ signaling pathways Non-alcoholic steatohepatitis-cardiotoxicities [ 13 ] miR-199b-3p miR-125a-5p 1. Induction of M2 macrophage-mediated angiogenesis 2.…”

“…Exosomal miRNAs may also mitigate non-alcoholic steatohepatitis-induced cardiotoxicity. These microRNAs increased Parkin, PTEN-induced kinase 1 (PINK1), uncoupling protein 2 (UCP2), FUN14 domain-containing protein 1 (FUNDC1), Unc-51-like kinase 1 (ULK1), BCL2/adenovirus E1B 19-kDa-interacting protein 3-like (BNIP3L/NIX), microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B), and manganese superoxide dismutase (MnSOD) genes, thereby modifying cardiotoxicity by regulating pAKT, VEGF, PI3K, hypoxia, and NF-kβ signalling pathways and restoring mitochondrial antioxidant status and Parkin-dependent and -independent mitophagy [ 13 ].…”

“…Therefore, BMSC-secretome, as a golden cell-free therapy, is being studied in the treatment of dermatological diseases (hair loss/alopecia, skin wounds, antimicrobial effects on skin wounds) [ 3 ], skeletal muscle degeneration (atrophic muscle disorders and muscle injuries) [ 4 ], intervertebral disc changes caused by trauma and degeneration [ 5 ], sepsis-induced cardiomyopathy [ 6 ], chemobrain/chemofog [ 7 ], spinal cord injury [ 8 ], neurodegenerative diseases [ 9 ], premature ovarian failure (POF) [ 10 ], liver diseases [ 11 ], cardiovascular diseases [ 12 , 13 ], and bone diseases [ 14 ].…”

Possible Ameliorative Effects of Different Treatment Regimens Using Bone Marrow-mesenchymal Stem Cells of Doxorubicin-induced Toxicity in Female Wistar Rats

“…After centrifugation at (2400 rpm for 20 min) and pellet to culture, cells are suspended in DMEM and FBS and incubated in another culture flask, the resulting culture is considered the 1 st passage. In our study, 2 nd passage is used in which a purified population of BM-MSCs can be obtained 2 weeks after the commencement of culture [16].…”