Conditioned medium-preconditioned EPCs enhanced the ability in oligovascular repair in cerebral ischemia neonatal rats

Abstract

Background Oligovascular niche mediates interactions between cerebral endothelial cells and oligodendrocyte precursor cells (OPCs). Disruption of OPC-endothelium trophic coupling may aggravate the progress of cerebral white matter injury (WMI) because endothelial cells could not provide sufficient support under diseased conditions. Endothelial progenitor cells (EPCs) have been reported to ameliorate WMI in the adult brain by boosting oligovascular remodeling. It is necessary to clarify the role of the conditioned medium from hypoxic endothelial cells preconditioned EPCs (EC-pEPCs) in WMI since EPCs usually were recruited and play important roles under blood-brain barrier disruption. Here, we investigated the effects of EC-pEPCs on oligovascular remodeling in a neonatal rat model of WMI. Methods In vitro, OPC apoptosis induced by the conditioned medium from oxygen-glucose deprivation-injured brain microvascular endothelial cells (OGD-EC-CM) was analyzed by TUNEL and FACS. The effects of EPCs on EC damage and the expression of cytomokine C-X-C motif ligand 12 (CXCL12) were examined by western blot and FACS. The effect of the CM from EC-pEPCs against OPC apoptosis was also verified by western blot and silencing RNA. In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia and treated with EPCs or EC-pEPCs at P7, and then angiogenesis and myelination together with cognitive outcome were evaluated at the 6th week. Results In vitro, EPCs enhanced endothelial function and decreased OPC apoptosis. Meanwhile, it was confirmed that OGD-EC-CM induced an increase of CXCL12 in EPCs, and CXCL12-CXCR4 axis is a key signaling since CXCR4 knockdown alleviated the anti-apoptosis effect of EPCs on OPCs. In vivo, the number of EPCs and CXCL12 protein level markedly increased in the WMI rats. Compared to the EPCs, EC-pEPCs significantly decreased OPC apoptosis, increased vascular density and myelination in the corpus callosum, and improved learning and memory deficits in the neonatal rat WMI model. Conclusions EC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model.

Outgrowth Endothelial Cell Conditioned Medium Negates TNF-α-Evoked Cerebral Barrier Damage: A Reverse Translational Research to Explore Mechanisms

“…Co-treatment of HBMEC and OECs with OEC-CM in the current study attenuated the apoptotic effects of TNF-α, markedly increased cell viability and invariably helped maintain appropriate BBB function. Treatment of oligodendrocyte precursor cells subjected to oxygen–glucose deprivation with EPC-CM has previously been shown to inhibit apoptosis [ 62 ]. Activation of canonical NF-κB pathway that regulates expression of various genes related to cell survival, proliferation, differentiation and inflammatory responses may also be instrumental in TNF-α-evoked barrier disruption.…”

Hydrogen Repairs LPS-Induced Endothelial Progenitor Cells Injury via PI3K/AKT/eNOS Pathway

“…EPCs were first initially discovered in 1997 by Asahara et al EPCs are defined as a cell population capable of differentiating into mature ECs and have vasculogenic potential, which contributes to vasculogenic, wound healing ( Asahara et al, 1997 ) and repair of ischemic tissue damage ( Fan et al, 2014 ). As a potential therapeutic agent, EPCs have attracted attention for a variety of diseases including cerebral ischemia ( Zhou et al, 2021 ), diabetes ( Wang K. et al, 2020 ), ALI etc. ( Asahara et al, 1997 ).…”

The NG2-glia is a potential target to maintain the integrity of neurovascular unit after acute ischemic stroke

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