星形-少突胶质细胞缝隙连接受损在缺血性白质损伤后少突胶质细胞生成中的作用

White matter injury characterized by oligodendrocytes death, demyelination and axonal damage is a critical component of ischemic stroke as well as a major pathology associated with vascular dementia. Oligodendrocytes are the main myelinating cells in the central nervous system, forming myelin to wrap around nearby axons, and thereby facilitating neuronal signal transduction. Although endogenous oligodendrogenesis occurs after cerebral ischemia, limited myelin formation often leads to failure of white matter repair and decline of neurologic functions. Astrocytes are coupled with oligodendrocytes via heterotypic gap junctions. Astrocytes expressing connexin (Cx) 30 and Cx43 forms gap junctions with oligodendrocytes expressing Cx32 and Cx47, respectively. Gap junctions are the molecular basis for the panglial syncytium and are vital for oligodendrocyte survival as well as white matter integrity. Disruption of astrocyte-oligodendrocyte (A/O) gap junctions has been shown in several demyelinating central nervous system disorders. However, their involvement in cerebral ischemia remains largely unknown. Our preliminary findings suggest that disruption of A/O gap junctions, demonstrated as mismatch expression of Cx43 and Cx47 in white matter lesions, is associated with ischemic white matter injury in mice induced by long-term bilateral carotid artery sclerosis (BCAS). Therefore, we are here aiming to further examine the role of A/O gap junctions disruption in ischemic white matter injury, with an emphasis on its effect on oligodendrogenesis after cerebral ischemia. We hope our findings will shed new lights on potential therapeutic strategies for promoting oligodendrogensis and white matter integrity after ischemic white matter injury.

白质损伤是缺血性脑损伤的重要组成部分, 主要表现为少突胶质细胞死亡、髓鞘脱失及轴突损伤等，也是血管性痴呆的主要病理改变之一。缺血性白质损伤可诱发内源性少突胶质细胞生成，但其生成有限，不足以维持白质结构及功能的完整性。星形胶质细胞-少突胶质细胞间的（A/O）缝隙连接Cx30/Cx32及Cx43/Cx47是两细胞间进行信息及营养物质传递的分子基础。A/O缝隙连接受损与多种脱髓鞘病变相关，但其在缺血性白质损伤中的作用尚不明确。我们的前期研究结果发现，慢性双侧颈动脉狭窄诱导可诱导小鼠发生缺血性脑白质损伤，在白质损伤区存在A/O缝隙连接损，Cx43、Cx47表达失衡，提示其可能与白质损伤相关。因此，在本课题中，我们将进一步探讨A/O缝隙连接受损在缺血性白质损伤中的作用，特别是在缺血性白质损伤后少突胶质细胞生成中的作用及机制，试图为促进少突胶质细胞生成及白质损伤修复提供潜在的治疗靶标。

白质损伤是缺血性脑损伤的重要组成部分, 主要表现为少突胶质细胞死亡、髓鞘脱失及轴突损伤等，也是血管性痴呆的主要病理改变之一。本研究利用双侧颈内动脉狭窄（bilateral carotid artery stenosis, BCAS）这一被广泛认同的血管性认知功能障碍模型，证实了在慢性双侧颈动脉狭窄模型中可诱导小鼠发生缺血性脑白质损伤，在白质损伤区存在A/O缝隙连接损，Cx43、Cx47表达失衡，提示其可能与白质损伤相关。此外，星形胶质细胞激活和血脑屏障破坏在介导白质损伤中具有重要作用。在本研究中，我们通过使用激光多普勒血流仪检测脑血流量（CBF），几种行为学实验评估认知功能、伊文斯蓝外渗试验、蛋白免疫印迹、CBA和免疫荧光等方法在BCAS小鼠脑组织和培养的星形胶质细胞中，证实了抑制星形胶质细胞活性及保护血脑屏障，能够在一定程度上减少BCAS小鼠白质损伤，改善小鼠认知功能障碍。具体机制与减轻BBB破坏和内皮细胞损伤、内皮紧密连接损伤以及抑制活化的星形胶质细胞、促炎因子释放和MMPs的活性相关。因此，我们的研究结果表明有效抑制星形胶质细胞激活，减轻血脑屏障损伤及A/O缝隙连接能够减轻慢性缺血诱导的白质损伤，是治疗慢性脑灌注不足引起的认知障碍的有效方法。