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. 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. 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. EC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model.

中文翻译：

---

条件中预处理的EPC增强了脑缺血新生大鼠的微血管修复能力

少血管的利基介导大脑内皮细胞和少突胶质细胞前体细胞（OPC）之间的相互作用。OPC-内皮营养耦合的破坏可能会加重脑白质损伤（WMI）的进程，因为在疾病条件下内皮细胞无法提供足够的支持。据报道，内皮祖细胞（EPC）可通过促进少血管重构来改善成人大脑中的WMI。由于WPC通常是募集的并且在血脑屏障破坏下起重要作用，因此有必要弄清WMI中低氧内皮细胞预处理的EPC（EC-pEPC）产生的条件培养基的作用。在这里，我们调查了EC-pEPCs对WMI新生大鼠模型中的微血管重构的影响。体外，通过TUNEL和FACS分析条件培养基诱导的氧葡萄糖剥夺损伤的脑微血管内皮细胞（OGD-EC-CM）诱导的OPC凋亡。免疫印迹和流式细胞仪检测了EPCs对EC损伤和细胞因子CXC基序配体12（CXCL12）表达的影响。Western blot和沉默RNA也证实了EC-pEPCs的CM对OPC凋亡的作用。在体内，对P3大鼠幼崽进行右颈总动脉结扎和缺氧，并在P7用EPCs或EC-pEPCs处理，然后在第6周评估血管生成和髓鞘形成以及认知结果。在体外，EPC可增强内皮功能并减少OPC凋亡。同时，已确认OGD-EC-CM诱导了EPC中CXCL12的增加，CXCL4敲除减轻了EPC对OPC的抗凋亡作用，而CXCL12-CXCR4轴是关键信号。在体内，WMI大鼠体内的EPC和CXCL12蛋白水平明显增加。与EPC相比，EC-pEPC显着降低了OPC凋亡，增加了call体中的血管密度和髓鞘形成，并改善了新生大鼠WMI模型中的学习和记忆障碍。EC-pEPC在新生大鼠WMI模型中通过CXCL12-CXCR4轴更有效地促进了少血管重构和髓鞘形成。并改善了新生大鼠WMI模型中的学习和记忆障碍。EC-pEPC在新生大鼠WMI模型中通过CXCL12-CXCR4轴更有效地促进了少血管重构和髓鞘形成。并改善了新生大鼠WMI模型中的学习和记忆障碍。EC-pEPC在新生大鼠WMI模型中通过CXCL12-CXCR4轴更有效地促进了少血管重构和髓鞘形成。