Abstract
AbstractBackgroundChronic cerebral ischemia (CCI) is considered as a prelude to neurodegeneration. Endothelial progenitor cells (EPCs) have been implicated in revascularization and vascular repair in cerebral ischemic diseases. Due to the safety concern and the low survival rate of the transplanted cells, interest has shifted toward the paracrine effect of EPCs. Here, we investigate the effects of EPC-derived conditioned medium (EPC-CM) on the vascular and functional impairments in a rodent model of CCI and the mechanism via which the EPC-CM involves.MethodsBilateral internal carotid artery ligation (BICAL) was performed in rats to induce cerebral ischemia. EPC-CM was intracisternally injected 1 week after BICAL. The changes of the microvasculature and behavior were examined 3 weeks after BICAL. The EPC-CM was analyzed by cytokine array for the factors that involved in angiogenesis. The therapeutic effects and mechanism of the candidate factor was validated with oxygen-glucose deprivation-injured endothelial cells and EPCsin vitro.ResultsEPC-CM significantly improved the vascular, motor and cognitive impairments of the BICAL rats. Macrophage migration inhibitory factor (MIF) was identified as a key factor in EPC-CM involved in angiogenesis and anti-senescence. Furthermore, recombinant MIF protein mirrored the effects of EPC-CM on EPCs and ECs. These therapeutic effects were decreased by the co-treatment with EPC-CM and MIF-specific antibody bothin vivoandin vitro. MIF operates through multiple pathways, including the AKT pathway, which plays a crucial role in cellular homeostasis. Inhibiting the AKT pathway diminished the protective effect of MIF in the CCI model.ConclusionsWe demonstrated that EPC-CM protected the chronic ischemic rat brain from ischemic injury and promoted functional recovery in rats through MIF-mediated AKT pathway, which indicated that EPC-CM may serve as an alternative potential therapy in chronic cerebral ischemia.
Publisher
Cold Spring Harbor Laboratory