Abstract
MG53 is an important membrane repair protein and partially protects bone marrow multipotent adult progenitor cells (MAPCs) against oxidized low‐density lipoprotein (ox‐LDL). The present study was to test the hypothesis that the limited protective effect of MG53 on MAPCs was due to ox‐LDL‐induced reduction of MG53. MAPCs were cultured with and without ox‐LDL (0‐20 μg/mL) for up to 48 hours with or without MG53 and antioxidant N‐acetylcysteine (NAC). Serum MG53 level was measured in ox‐LDL‐treated mice with or without NAC treatment. Ox‐LDL induced significant membrane damage and substantially impaired MAPC survival with selective inhibition of Akt phosphorylation. NAC treatment effectively prevented ox‐LDL‐induced reduction of Akt phosphorylation without protecting MAPCs against ox‐LDL. While having no effect on Akt phosphorylation, MG53 significantly decreased ox‐LDL‐induced membrane damage and partially improved the survival, proliferation and apoptosis of MAPCs in vitro. Ox‐LDL significantly decreased MG53 level in vitro and serum MG53 level in vivo without changing MG53 clearance. NAC treatment prevented ox‐LDL‐induced MG53 reduction both in vitro and in vivo. Combined NAC and MG53 treatment significantly improved MAPC survival against ox‐LDL. These data suggested that NAC enhanced the protective effect of MG53 on MAPCs against ox‐LDL through preventing ox‐LDL‐induced reduction of MG53.
Highlights
Bone marrow stem cells (BMSCs) are important sources for cell‐ based therapy that remains a viable and attractive option for tissue repair and regeneration.[1,2,3,4,5] one of the major challenges for cell‐based therapy with stem cells is the poor in vivo survival after delivery into target areas.[4,5] It has been shown that the number of mesenchymal stem cells (MSCs) in the cremaster decreased to 14% of the initial number 3 days after bolus injection into the ipsilateral common iliac artery in rats.[6]
A series of small blood samples were collected via tail vein at different time (0, 10, 30, 60 and 120 minutes and 4, 6 and 8 hours) after injection to measure serum MBP‐MG53 level using Western blot to determine the half‐ life of MBP‐MG53 as described above
Rat multipotent adult progenitor cells (MAPCs) were used as the source of BMSCs as BMSCs are a mixture of heterogeneous cells with very different phe‐ notypes and different capability of differentiating into multiple cell lineages.[28]
Summary
Bone marrow stem cells (BMSCs) are important sources for cell‐ based therapy that remains a viable and attractive option for tissue repair and regeneration.[1,2,3,4,5] one of the major challenges for cell‐based therapy with stem cells is the poor in vivo survival after delivery into target areas.[4,5] It has been shown that the number of mesenchymal stem cells (MSCs) in the cremaster decreased to 14% of the initial number 3 days after bolus injection into the ipsilateral common iliac artery in rats.[6] MSCs were initially accumulated in the lungs and did not reach the target sites after intravenous infusion, and many cells disappeared 2 hours after delivery in mice.[7] When the stem cells were injected into the left ventricular myocardium of mice, less than 1% of the delivered cells survived in the target areas 4 days after injection.[4]. Oxidized low‐density lipoproteins (ox‐LDLs) are naturally present in serum and an important source for reactive oxygen spe‐ cies (ROS) and oxidative stress.[8,9] Ox‐LDL has been shown to inhibit proliferation and endothelial differentiation of BMSCs, and induce apoptosis of BMSCs with both ROS‐dependent and ROS‐indepen‐ dent mechanisms.[10,11] Our previous study showed that ox‐LDL im‐ paired the survival of BMSCs in vitro partially through direct cell membrane damage independent of ROS formation.[12]
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