Cell-therapy using microglia to prompt functional recovery after ischemic stroke

Abstract

It is necessary to establish therapeutic strategies to promote functional recovery in stroke patients in the subacute and chronic phases. We hypothesized that microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2-like microglia. We confirmed marked secretion of remodeling factors using primary microglia under 18 h OGD conditions. In particular, expression of the anti-inflammatory cytokine, transforming growth factor-β (TGF-β), was 25 times higher after OGD compared with a normoxic condition (P=0.002), and the ratio of TGF-β per tumor necrosis factor-α, which shows the polarization of M1-like and M2-like microglia, was six times higher after OGD, compared with a normoxic condition (P=0.009). Finally, we found that intraarterial administration of OGD microglia caused increased expression of vascular endothelial growth factor, matrix metalloproteinase-9, and TGF-β in various cells around the injured brain parenchyma using suture technique in ischemic Sprague-Dawley rats. The treatment promoted functional recovery via angiogenesis in the border area within the ischemic core as well as axonal outgrowth in the ischemic penumbra by remodeling factors at 28 days after ischemia. In conclusion, intravascular administration of M2-like microglia preconditioned by optimal OGD might be a novel therapeutic strategy against ischemic stroke.