BM-MSC Transplantation Alleviates Intracerebral Hemorrhage-Induced Brain Injury, Promotes Astrocytes Vimentin Expression, and Enhances Astrocytes Antioxidation via the Cx43/Nrf2/HO-1 Axis
BM-MSC Transplantation Alleviates Intracerebral Hemorrhage-Induced Brain Injury, Promotes Astrocytes Vimentin Expression, and Enhances Astrocytes Antioxidation via the Cx43/Nrf2/HO-1 Axis
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BM-MSC 移植可减轻脑出血引起的脑损伤，促进星形胶质细胞波形蛋白表达，并通过 Cx43/Nrf2/HO-1 轴增强星形胶质细胞抗氧化作用。
DOI：
10.3389/fcell.2020.00302
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发表时间：
2020-05-08
影响因子：
5.5
通讯作者：
Bian, Liuguan
中科院分区：
文献类型：
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作者：
Chen, Xiao;Liang, Huaibin;Bian, Liuguan
脑出血（ICH）是一种特别严重的中风形式，反应性星形胶质细胞增生是中枢神经系统（CNS）损伤后的常见反应。据报道，间充质干细胞（MSC）可以促进神经发生并减轻受损脑区的晚期副作用。间隙连接（Gjs）在脑中是丰富的，其中最丰富的连接蛋白（Cx）是Cx 43，其在星形胶质细胞中最显著地表达。核因子红细胞2相关因子2（Nrf 2）是一种重要的转录因子，调节抗氧化反应。本研究旨在探讨骨髓间充质干细胞（BM-MSCs）能否通过调节Cx43和Nrf 2来减轻脑损伤和保护星形胶质细胞免于凋亡。我们验证了BM-MSC移植在体内和体外ICH模型中的作用，并使用免疫荧光检测了其变化，以及胶质细胞酸性蛋白（GFAP），波形蛋白（Vim），Cx43，Nrf 2和血红素加氧酶-1（HO-1）的蛋白和mRNA表达。我们的研究结果表明，骨髓间充质干细胞移植减轻脑出血后的脑损伤和上调Vim表达在体内和体外。此外，在与BM-MSC共培养的星形胶质细胞中观察到Cx43上调和Nrf 2核转位。通过siRNA敲低Cx43抑制Nrf 2核转位。免疫荧光和免疫共沉淀法证实Cx43和Nrf 2之间存在连接。我们证明了星形胶质细胞经历星形胶质细胞-间充质细胞表型转换，并在BM-MSC移植后具有抗凋亡能力，其中Cx43上调触发Nrf 2核转位并促进其II相酶表达。BM-MSC移植后星形胶质细胞Cx43/Nrf 2相互作用可能为ICH的治疗提供一个重要的靶点。
Intracerebral hemorrhage (ICH) is a particularly severe form of stroke, and reactive astrogliosis is a common response following injury to the central nervous system (CNS). Mesenchymal stem cells (MSCs) are reported to promote neurogenesis and alleviate the late side effects in injured brain regions. Gap junctions (Gjs) are abundant in the brain, where the richest connexin (Cx) is Cx43, most prominently expressed in astrocytes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor regulating antioxidant reactions. Here, we aimed to explore whether bone marrow MSCs (BM-MSCs) could alleviate brain injury and protect astrocytes from apoptosis, by regulating Cx43 and Nrf2. We validated the effect of BM-MSC transplantation in an ICH model in vivo and in vitro and detected changes using immunofluorescence, as well as protein and mRNA expression of glial fibrillary acidic protein (GFAP), vimentin (VIM), Cx43, Nrf2, and heme oxygenase-1 (HO-1). Our results showed that BM-MSC transplantation attenuated brain injury after ICH and upregulated VIM expression in vivo and in vitro. Additionally, Cx43 upregulation and Nrf2 nuclear translocation were observed in astrocytes cocultured with BM-MSC. Knockdown of Cx43 by siRNA restrained Nrf2 nuclear translocation. Cx43 and Nrf2 had a connection as determined by immunofluorescence and coimmunoprecipitation. We demonstrated that astrocytes undergo astroglial-mesenchymal phenotype switching and have anti-apoptotic abilities after BM-MSC transplantation, where Cx43 upregulation triggers Nrf2 nuclear translocation and promotes its phase II enzyme expression. The Cx43/Nrf2 interaction of astrocytes after BM-MSC transplantation may provide an important therapeutic target in the management of ICH.