Cell membrane damage is involved in the impaired survival of bone marrow stem cells by oxidized low‐density lipoprotein

Abstract

Cell therapy with bone marrow stem cells (BMSCs) remains a viable option for tissue repair and regeneration. A major challenge for cell therapy is the limited cell survival after implantation. This study was to investigate the effect of oxidized low-density lipoprotein (ox-LDL, naturally present in human blood) on BMSC injury and the effect of MG53, a tissue repair protein, for the improvement of stem cell survival. Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox-LDL, which caused significant cell death as reflected by the increased LDH release to the media. Exposure of MAPCs to ox-LDL led to entry of fluorescent dye FM1-43 measured under confocal microscope, suggesting damage to the plasma membrane. Ox-LDL also generated reactive oxygen species (ROS) as measured with electron paramagnetic resonance spectroscopy. While antioxidant N-acetylcysteine completely blocked ROS production from ox-LDL, it failed to prevent ox-LDL-induced cell death. When MAPCs were treated with the recombinant human MG53 protein (rhMG53) ox-LDL induced LDH release and FM1-43 dye entry were significantly reduced. In the presence of rhMG53, the MAPCs showed enhanced cell survival and proliferation. Our data suggest that membrane damage induced by ox-LDL contributed to the impaired survival of MAPCs. rhMG53 treatment protected MAPCs against membrane damage and enhanced their survival which might represent a novel means for improving efficacy for stem cell-based therapy for treatment of diseases, especially in setting of hyperlipidemia.

N‐acetylcysteine prevents oxidized low‐density lipoprotein‐induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells

“…It is known that excessive amount of ROS is produced in hyperlipidemic states and associated with increased oxidative stress . A significant amount of ROS could be generated from ox‐LDL both in vitro and in vivo that could be effectively inhibited with NAC . The data from the present study showed that ox‐LDL treatment significantly decreased MG53 levels both in vitro and in vivo that was effectively prevented with antioxidant NAC (Figure ).…”

Probucol Protects Endothelial Progenitor Cells Against Oxidized Low-Density Lipoprotein via Suppression of Reactive Oxygen Species Formation In Vivo

“…Ox-LDL induces senescence [54], accelerates the ageing of hematopoietic stem cells in vivo [55], and inhibits their proliferation, migration, adhesion and differentiation [17,30,53,56,57]. Previous studies showed that the number of circulating EPCs was inversely correlated with total cholesterol, LDL-cholesterol and ox-LDL levels [11,[58][59][60].…”

“…It was demonstrated that a significant amount of ROS was produced spontaneously from ox-LDL at clinically relevant concentrations, and was involved in the action of ox-LDL on human umbilical vein endothelial cells [28,29], bone marrow (BM) stem cells [30], vascular smooth muscle cells [31], monocytes [32], macrophage [33] and foam cells [34]. Treatment with ox-LDL increased intracellular ROS generation in cultured endothelial cells [35].…”

Mitsugumin-53: Potential biomarker and therapeutic for myocardial ischemic injury?

“…In addition to protective effects observed in the myocardium, the authors have also demonstrated that rhMG53 administration can facilitate the repair of damaged skeletal muscle membranes, particularly in the setting of muscular dystrophy [24]. Additionally, rhMG53-depedendent protection has also been observed in other cell types, including rat bone marrow-derived stem cells [26]. The fact that mitsugumin-53 can elicit protective effects in multiple cells types clearly broadens the therapeutic potential beyond that of myocardial injury.…”