EPCs-derived conditioned medium mitigates chronic cerebral ischemic injury through the MIF-activated AKT pathway
Journal
medRxiv
Date Issued
2023-11-20
Author(s)
Cheng, Ya-Wen
Yang, Ling-Yu
Chen, Yi-Tzu
Chou, Sheng-Che
Chen, Yi-Hsing
Deng, Chuan-Rou
Chen, I. Chin
Chou, Wan-Ju
Chang, Chen-Chih
Chen, Yong-Ren
Hwa, Hsiao-Lin
Wang, Kuo-Chuan
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 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. Methods Bilateral 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 EPCs in vitro. Results EPC-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 both in vivo and in 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. Conclusions We 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. The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Subjects
AKT pathway; cerebral ischemia; Endothelial progenitor cell-derived conditioned medium; macrophage migration inhibitory factor
SDGs
Type
other