GW24-e3739 MiR-210 Over-expression Enhances Mesenchymal Stromal Cells Survival in an Oxidative Stress Circumstance though Anti-oxidation and c-Met Pathways Activation

Objectives We aimed to investigate whether over-expression of miR-210, an oxide-related miR, could protect mesenchymal stromal cells (MSCs) against apoptosis induced by oxidative stress, and if so, what the potential mechanisms involved. Methods MSCs, derived from male SD rats, with forced expression of miR-210 or miR-null by lentivirus infection was incubated with or without Peroxide hydrogen (H2O2). The reactive oxygen species (ROS) accumulation in MSCs was detected by immunofluoresence probes; cellular survival was measured by MTT assay, Hochest staining and TUNEL examination; superoxidedismutase (SOD) activity and adecreaseinmalonaldehyde (MDA) content were analysed by ELISA assay; and the activation of c-Met pathway was quantified by immunoblot. After application of Crizotinib, an inhibitor specific to c-Met pathway, the above detections were investigated to clarify the mechanisms involved. In an in vivo experiment, the expression of sry gene was checked by quantitative PCR to compare the survival of MSCs-miR-210 and MSCs-miR-null in the infarcted myocardium of female rats on day 4 after transplantation; afterwards, echocardiology was applied to assess the cardiac remodelling and myocardial function in a 4-week follow-up. Results It was revealed that forced expression of miR-210 significantly decreased the apoptosis of MSCs against H2O2 compared with that of miR-null, indicated as follows: a notable decreases in ROS generation (2.34 ± 0.62 vs. 3.98 ± 0.57, P<0.05) and apoptotic indices [(15.3 ± 3.87)% vs. (33.8 ± 2.67)%, P<0.05]; a dramatic increase in cell viability (2.98 ± 0.67 vs. 1.00 ± 0.74, P<0.05), SOD activity (3.91 ± 0.28 vs. 1.00 ± 0.38, P<0.05) and MDA content (2.95 ± 0.41 vs. 1.00 ± 0.36, P<0.05), which was companied by a remarkable activation of c-Met pathway (2.87 ± 0.34 vs. 1.00 ± 0.52, P<0.05). Most importantly, each of the above beneficial effects was attenuated by Crizotinib (P all <0.05). Furthermore, transplantation of MSCs-miR-210 resulted in higher cell survival rates (2.86 ± 0.33 vs. 1.00 ± 0.37, P<0.05), therefore significantly improved cardiac remodelling [LVIDd: (5.38 ± 0.61) mm vs. (6.39 ± 0.67) mm, P<0.05; LVIDs: (4.92 ± 0.52) mm vs. (5.89 ± 0.51) mm, P<0.05;] and statistically ameliorated myocardial function [LVEF: (62.3 ± 5.32)% vs. (42.6 ± 4.38)%, P<0.05] than that of MSCs-miR-null. Conclusions MiR-210 over-expression may improve MSCs survival in an oxidative stress circumstances through anti-oxidation and c-Met pathways activation, thus enhances their therapeutic effect on myocardial infarction, suggesting that miR-210 was a potential intervention target in the cell-based treatment.