一个连接蛋白 43/Yes 相关蛋白轴调节血红蛋白诱导的星形胶质细胞激活中的星形胶质细胞-间充质转化。
A connexin43/YAP axis regulates astroglial-mesenchymal transition in hemoglobin induced astrocyte activation.
机构信息
Department of Neurosurgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
Department of Neurosurgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
出版信息
Cell Death Differ. 2018 Oct;25(10):1870-1884. doi: 10.1038/s41418-018-0137-0. Epub 2018 Jun 7.
Reactive astrogliosis is a common response to insults to the central nervous system, but the mechanism remains unknown. In this study, we found the temporal and spatial differential expression of glial fibrillary acidic protein (GFAP) and Vimentin in the intracerebral hemorrhage (ICH) mouse brain, indicating that the de-differentiation and astroglial-mesenchymal transition (AMT) of astrocytes might be an early event in reactive astrogliosis. Further we verified the AMT finding in purified astrocyte cultures exposed to hemoglobin (Hb). Additionally, Connexin 43 (Cx43) downregulation and YAP nuclear translocation were observed in Hb-activated astrocytes. Knocking down Cx43 by siRNA triggered YAP nuclear translocation. Cx43 and YAP were physically associated as determined by immunofluorescence and co-immunoprecipitation. We propose that astrocytes undergo AMT during Hb-induced activation where Cx43 downregulation facilitates YAP nuclear translocation is a novel mechanism involved in this process. Cx43-YAP interaction may represent a potential therapeutic target for modulating astrocyte activation.
反应性星形胶质细胞增生是中枢神经系统损伤的常见反应，但机制尚不清楚。在这项研究中，我们发现脑内出血（ICH）小鼠脑内胶质纤维酸性蛋白（GFAP）和波形蛋白的时空差异表达，表明星形胶质细胞的去分化和星形胶质细胞-间充质转化（AMT）可能是反应性星形胶质细胞增生的早期事件。进一步我们在暴露于血红蛋白（Hb）的纯化星形胶质细胞培养物中验证了 AMT 发现。此外，在 Hb 激活的星形胶质细胞中观察到连接蛋白 43（Cx43）下调和 YAP 核易位。用 siRNA 敲低 Cx43 会触发 YAP 核易位。通过免疫荧光和共免疫沉淀确定 Cx43 和 YAP 物理相关。我们提出，星形胶质细胞在 Hb 诱导的激活过程中经历 AMT，其中 Cx43 下调促进 YAP 核易位是该过程中涉及的新机制。Cx43-YAP 相互作用可能代表调节星形胶质细胞激活的潜在治疗靶点。
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