Intravenous Delivery Of Genetically Modified MiR-211Over-expressing Mesenchymal Stem Cells Improves Therapeutic Efficacy In A Rat Myocardial Infarction Model

AIMS:Bone marrow-derived mesenchymal stem cells (MSCs) transplantation is an ideal therapeutic strategy for ischemic heart diseases. However, the poor homing and low retention rate of MSCs following their transplantation has compromised the benefits of cell therapy. The migration ability of stem cell could be an important target as it is reasonable to assume that enhanced MSCs migration would significantly improve the retention rate of MSCs and hence the therapeutic effects. Our previous study showed that hypoxia preconditioning (HP) enhanced migration contributed to enhanced therapeutic effects of MSCs transplantation. Our preliminary data showed that HP can up-regulate miR-211expression levels. Many other studies have demonstrated that miR-211has a crucial role in cell migration, while the role of miR-211on MSCs has not been fully understood. In the present study we aimed to investigate whether and how miR-211was responsible for the improved MSCs migration, especially whether manipulation of miR-211can offer beneficial therapeutic efficacy of MSCs transplantation.METHODS AND RESULTS:In vitro transwell assays showed that miR-211 knock-down in MSCs significantly impaired migration whereas over-expression of miR-211enhanced the biological capability. MiR-211over-expressing MSCs also exhibited significantly increased cell engraftment in peri-infarct area of female rat heart two days after intravenous transplantation of male MSCs, using GFP tracking and SYR gene quantification, which was associated with an improved cardiac performance. With Dual luciferase reporter gene system, PCR and western blot, we demonstrated that STAT5A is a target of miR-211. We further showed that the beneficial effects offered by miR-211over-expression can be abolished when MSCs simultaneously over-expressed STAT5A, consistent with the role of miR-211/STAT5A signaling. The absence of favorable effects of MSCs with silenced miR-211can be rescued when STAT5A was simultaneously down-regulated. Using ChIP-PCR and luciferase assay, we provided novel evidence that STAT3can directly bind to the promoter region and up-regulate miR-211expression.CONCLUSION:STAT3/miR-211/STAT5A signaling pathway plays a key role in MSCs migration. Intravenous delivery of genetically modified miR-211over-expressing MSCs provides beneficial effects against adverse post-MI remodeling.