EphA4/EphrinB2 信号介导血脑屏障周细胞诱导的短暂胶质界膜形成，作为蛛网膜下腔出血后小鼠的二级保护屏障。
EphA4/EphrinB2 signaling mediates pericyte-induced transient glia limitans formation as a secondary protective barrier after subarachnoid hemorrhage in mice.
机构信息
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Chongqing Clinical Research Center for Neurosurgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.
出版信息
Exp Neurol. 2023 Feb;360:114293. doi: 10.1016/j.expneurol.2022.114293. Epub 2022 Dec 6.
BACKGROUND
Most patients with subarachnoid hemorrhage (SAH) do not exhibit brain parenchymal injury upon imaging but present significant blood-brain barrier (BBB) disruption and secondary neurological deficits. The aim of this study was to investigate whether stressed astrocytes act as a secondary barrier to exert a protective effect after SAH and to investigate the mechanism of glial limitan formation.
METHODS
A total of 204 adult male C57BL/6 mice and an endovascular perforation SAH model were employed. The spatiotemporal characteristics of glial limitan formation after SAH were determined by immunofluorescence staining and transmission electron microscopy. The molecular mechanisms by which pericytes regulate glia limitans formation were analyzed using polymerase chain reaction, Western blotting, immunofluorescence staining and ELISA in a pericyte-astrocyte contact coculture system. The findings were validated ex vivo and in vivo using lentiviruses and inhibitors. Finally, pericytes were targeted to regulate glial limitan formation, and the effect of the glia limitans on secondary brain injury after SAH was evaluated by flow cytometry and analysis of neurological function.
RESULTS
Stress-induced glial limitan formation occurred 1 day after SAH and markedly subsided 3 days after ictus. Pericytes regulated astrocyte glia limitan formation via EphA4/EphrinB2 signaling, inhibited inflammatory cell infiltration and altered neurological function.
CONCLUSIONS
Astrocyte-derived glia limitans serve as a secondary protective barrier following BBB disruption after SAH in mice, and pericytes can regulate glial limitan formation and alter neurological function via EphA4/EphrinB2 signaling. Strategies for maintaining this secondary protective barrier may be novel treatment approaches for alleviating early brain injury after SAH.
背景
大多数蛛网膜下腔出血（SAH）患者的影像学检查未见脑实质损伤，但存在明显的血脑屏障（BBB）破坏和继发性神经功能缺损。本研究旨在探讨应激星形胶质细胞是否作为次级屏障在 SAH 后发挥保护作用，并研究胶质界膜形成的机制。
方法
共使用 204 只成年雄性 C57BL/6 小鼠和血管内穿孔 SAH 模型。通过免疫荧光染色和透射电镜观察 SAH 后胶质界膜形成的时空特征。在周细胞-星形胶质细胞接触共培养系统中，通过聚合酶链反应、Western blot、免疫荧光染色和 ELISA 分析周细胞调节胶质界膜形成的分子机制。使用慢病毒和抑制剂在体外和体内验证这些发现。最后，通过靶向周细胞调节胶质界膜形成，并通过流式细胞术和神经功能分析评估胶质界膜对 SAH 后继发性脑损伤的影响。
结果
SAH 后 1 天出现应激诱导的胶质界膜形成，发病后 3 天明显消退。周细胞通过 EphA4/EphrinB2 信号调节星形胶质细胞的胶质界膜形成，抑制炎症细胞浸润并改变神经功能。
结论
在小鼠的 SAH 后，星形胶质细胞衍生的胶质界膜作为 BBB 破坏后的次级保护屏障，周细胞可以通过 EphA4/EphrinB2 信号调节胶质界膜形成并改变神经功能。维持这种次级保护屏障的策略可能是减轻 SAH 后早期脑损伤的新治疗方法。
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