Abstract
BackgroundOligovascular 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.MethodsIn 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.ResultsIn 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.ConclusionsEC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model.
Highlights
Perinatal white matter damage (WMI) is the most common type of brain damage in neonatal infants, which usually causes cerebral palsy and various neurobehavioral disorders
Fluorescence-activated cell sorting (FACS) and CCK-8 results showed that endothelial cells (ECs) apoptosis rate and viability of ECs was significantly decreased Oxygen-glucose deprivation (OGD) 6 h or 9 h compared to OGD 3 h, but there is no significant difference between OGD 6 h and 9 h (Supplemental Fig. 2)
Endothelial progenitor cells (EPCs) reduced oligodendrocyte precursor cells (OPCs) apoptosis induced by conditioned medium of OGD-ECs We compared the influence of Conditioned medium (CM) from OGD-ECs and OGD-ECs/EPCs co-culture on OPC apoptosis
Summary
Perinatal white matter damage (WMI) is the most common type of brain damage in neonatal infants, which usually causes cerebral palsy and various neurobehavioral disorders. It has been reported that EC injury caused brain-derived neurotrophic factor and fibroblast growth factor hyposecretion and matrix metalloproteinase-9 hypersecretion; “oligovascular niche” was disrupted and leads to OPC damage and WMI [6, 7]. Our recent study found there was a transient OPC proliferation and angiogenesis in the acute phase of the neonatal rat ischemia model, serious ECs and basement membrane damage may be a major deleterious effect on myelination in the recovery stage, prompting that oligovascular repair is a strategy for ischemia-induced WMI [9]. 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. We investigated the effects of EC-pEPCs on oligovascular remodeling in a neonatal rat model of WMI
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
