Endothelial progenitor cell-derived conditioned medium mitigates chronic cerebral ischemic injury through macrophage migration inhibitory factor-activated AKT pathway
Date Issued
2024-06-18
Author(s)
Ya-Wen Cheng
Ling-Yu Yang
Yi-Tzu Chen
Chuan-Rou Deng
I-Chin Chen
Wan-Ju Chou
Chen-Chih Chang
Yong-Ren Chen
Abstract
Background Chronic cerebral ischemia (CCI) is considered as a prelude to neurodegeneration. Endothelial progenitor cells (EPCs) have been implicated in revascularization and vascular repair in ischemic cerebrovascular diseases. However, due to the safety concern and the low survival rate of the transplanted EPCs, interest has shifted toward the paracrine effects of EPCs. In this study, we investigated the effects of EPC-derived conditioned medium (EPC-CM) on the vascular and neurological functional impairments in a rodent model of CCI and the mechanism involved. Methods Bilateral internal carotid artery ligation (BICAL) was performed in male Wistar rats to induce CCI. EPC-CM was intracisternally injected one week after BICAL. The cerebral microvasculature and neurobehavior of the rats were examined three weeks after BICAL. The EPC-CM was analyzed by cytokine array to identify factors involved in angiogenesis. The effects and mechanism of the candidate factor in the EPC-CM on CCI was validated in vitro with oxygen-glucose deprivation-injured endothelial cells and EPCs. Results EPC-CM significantly improved the vasculature, 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. In vitro study, recombinant MIF protein exhibited similar effects of EPC-CM on EPCs and ECs. These therapeutic effects were decreased by the co-treatment with EPC-CM and MIF-specific antibody both in vivo and in vitro. In addition, we found MIF promoted angiogenesis and anti-senescence via activating the AKT pathway. Inhibiting the AKT pathway diminished the protective effect of MIF in the CCI model in vitro. Conclusions We demonstrated that EPC-CM protected the brain from chronic ischemic injury and promoted functional recovery in rats with CCI through the MIF-mediated AKT pathway, which indicated that EPC-CM may serve as a potential agent in the therapy of CCI. © 2024, CC BY.
Subjects
AKT pathway
cerebral ischemia
Endothelial progenitor cell-derived conditioned medium
macrophage migration inhibitory factor
Publisher
Research Square
Type
other