SOD2 overexpression in bone marrow‑derived mesenchymal stem cells ameliorates hepatic ischemia/reperfusion injury

Abstract

Hepatic ischemia/reperfusion injury (HIRI) is a complex pathophysiological process that may develop after liver transplantation and resection surgery, as well as in uncontrolled clinical conditions. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are potential targets for liver diseases. Thus, the present study aimed to investigate the effects of superoxide dismutase 2 (SOD2) overexpression in BM-MSCs on HIRI by constructing a HIRI rat model. The adenoviral vector containing SOD2 and the corresponding control vector were designed and constructed, and SOD2-overexpressing BM-MSCs were injected into the tail vein of the rats. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, as well as pathological changes and the remnant liver regeneration rate were determined. The activities of SOD and glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) content were measured. Reactive oxygen species (ROS) were determined with 2',7'-dichlorofluorescein diacetate and measured via fluorescence microscopy. Cell apoptosis was assessed using TUNEL staining. Moreover, the expression levels of Bax, Bcl-2 and caspase-3 were detected via western blotting. SOD2-overexpressing BM-MSCs significantly reduced the elevation of serum AST and ALT levels. Furthermore, SOD2-overexpressing BM-MSCs enhanced SOD and GSH-Px activities, and suppressed the production of MDA and ROS. Histopathological findings revealed that SOD2-overexpressing BM-MSCs decreased the number of TUNEL-positive cells in the liver. It was also found that SOD2-overexpressing BM-MSCs promoted Bcl-2 expression, but inhibited Bax and caspase-3 expression in HIRI. Collectively, these findings suggest that SOD2-overexpressing BM-MSCs may provide therapeutic support in HIRI by inhibiting oxidative stress and hepatocyte apoptosis.

MSC based gene delivery methods and strategies improve the therapeutic efficacy of neurological diseases

“…Many studies have reported on developing MSCs expressing antiapoptotic genes to promote cell survival and inhibit apoptosis induced by hypoxia or ROS, including superoxide dismutase 2 (SOD2) [ 238 ], Bcl-2 [ 239 ], and adrenomedullin (ADM) [ 240 ]. In addition, the co-overexpression of VEGF and Bcl-2 genes not only reduced apoptosis and decreased autophagy but also promoted more rapid proliferation in vitro under OGD [ 241 ].…”

Immunomodulatory Role of Mesenchymal Stem Cells in Liver Transplantation: Status and Prospects

“…For instance, Wang et al [42] indicated that BM-MSCs could protect the rats against IRI by enhancing the autophagy mediated by HO-1 (heme oxygenase-1). In addition, Li et al [43] reported that BM-MSCs with overexpression of superoxide dismutase 2 could attenuate hepatic IRI through inhibiting oxidative stress and apoptosis of hepatocytes. Nowadays, there are two types of immune rejection, including host-versus-graft reaction and graft-versus-host reaction.…”

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

“…This has been supported by the following observations. First, overexpression of antioxidants such as glutathione peroxidase 1 (GPX1) in ECs [ 142 ], HO-1 [ 143 ] and SOD [ 144 ] reduced the Bax/Bcl-2 ratio in I/R injury of other types of cells. In addition, meldonium, which functions as an antioxidant, decreased the ratio of Bax/Bcl-2, ameliorating I/R-induced kidney injury [ 121 ].…”

“…As discussed earlier, antioxidants inhibit ceramide-producing enzymes, and conversely the inhibition of antioxidants by ROS activates these enzymes ( Section 4.3 and Section 4.4 ). In addition, overexpression of antioxidants [ 142 , 143 , 144 ] reduced apoptotic-Bcl-2 family proteins that activate ceramide-producing enzymes and increased anti-apoptotic Bcl-2 family proteins that inhibit ceramide-producing enzymes ( Section 5.2 ). Furthermore, a rheostat of ROS-antioxidants can regulate the activity of SphKs ( Section 7.2 ).…”