Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, School of Basic Medical Science, Capital Medical University, Beijing, China.
The Neurological Department, Fu Wai Hospital, National Center for Cardiovascular Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Glia. 2022 Oct;70(10):1971-1991. doi: 10.1002/glia.24232. Epub 2022 Jun 28.
Ischemic stroke, which accounts for nearly 80% of all strokes, leads to white matter injury and neurobehavioral dysfunction, but relevant therapies to inhibit demyelination or promote remyelination after white matter injury are still unavailable. In this study, the middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro were used to establish the ischemic models. We found that Eph receptor A4 (EphA4) had no effect on the apoptosis of oligodendrocytes using TUNEL staining. In contrast, EphA4 promoted proliferation of oligodendrocyte precursor cells (OPCs), but reduced the numbers of mature oligodendrocytes and the levels of myelin-associated proteins (MAG, MOG, and MBP) in the process of remyelination in ischemic models in vivo and in vitro as determined using PDGFRα-EphA4-shRNA and LV-EphA4 treatments. Notably, conditional knockout of EphA4 in OPCs (EphA4 + AAV-PDGFRα-Cre) improved the levels of myelin-associated proteins and functional recovery following ischemic stroke. In addition, regulation of remyelination by EphA4 was mediated by the Ephexin-1/RhoA/ROCK signaling pathway. Therefore, EphA4 did not affect oligodendrocyte (OL) apoptosis but regulated white matter remyelination after ischemic stroke through the Ephexin-1/RhoA/ROCK signaling pathway. EphA4 may provide a novel and effective therapeutic target in clinical practice of ischemic stroke.
缺血性中风占所有中风的近 80%，导致白质损伤和神经行为功能障碍，但目前仍缺乏抑制脱髓鞘或促进白质损伤后髓鞘再生的相关治疗方法。在本研究中，采用体内大脑中动脉闭塞/再灌注（MCAO/R）和体外氧葡萄糖剥夺/再氧合（OGD/R）建立缺血模型。我们发现，Eph 受体 A4（EphA4）通过 TUNEL 染色对少突胶质细胞凋亡没有影响。相比之下，EphA4 促进少突胶质前体细胞（OPC）的增殖，但在体内和体外缺血模型的髓鞘再生过程中减少了成熟少突胶质细胞的数量和髓鞘相关蛋白（MAG、MOG 和 MBP）的水平，这是通过 PDGFRα-EphA4-shRNA 和 LV-EphA4 处理确定的。值得注意的是，EphA4 在 OPC 中的条件敲除（EphA4+AAV-PDGFRα-Cre）改善了缺血性中风后的髓鞘相关蛋白水平和功能恢复。此外，EphA4 对髓鞘再生的调节是通过 Ephexin-1/RhoA/ROCK 信号通路介导的。因此，EphA4 不影响少突胶质细胞（OL）凋亡，但通过 Ephexin-1/RhoA/ROCK 信号通路调节缺血性中风后的白质髓鞘再生。EphA4 可能为缺血性中风的临床实践提供一个新的有效的治疗靶点。
