STAT3-Mediated astrogliosis protects myelin development in neonatal brain injury
STAT3-Mediated astrogliosis protects myelin development in neonatal brain injury
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DOI：
10.1002/ana.23670
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发表时间：
2012-11-01
影响因子：
11.2
通讯作者：
Waschek, James A.
中科院分区：
文献类型：
--
作者：
Nobuta, Hiroko;Ghiani, Cristina A.;Waschek, James A.
目的：与早产相关的新生儿脑损伤的病理学表现包括局灶性和/或弥漫性白质损伤（WMI）。尽管这种情况具有异质性，但经常观察到反应性星形胶质细胞增生和小胶质细胞增生。因此，研究了神经胶质细胞激活促进 WMI 的分子机制。方法：对新生儿脑损伤的死后大脑进行研究，以确定反应性星形胶质细胞的分子特征。星形胶质细胞增生对 WMI 的影响在基因工程小鼠模型中得到了进一步测试。结果：发现反应性星形胶质细胞中激活的 STAT3 信号是新生儿脑损伤死后大脑的一个共同特征。在新生儿 WMI 小鼠模型中，星形胶质细胞中 STAT3 的条件性缺失导致 WMI 加剧，这与少突胶质细胞成熟延迟有关。从机制上讲，延迟的发生与小胶质细胞中转化生长因子（TGF）β-1的过度表达有关，在健康对照中，小胶质细胞中的转化生长因子（TGF）β-1以年龄依赖性方式随着髓磷脂成熟而减少。 TGF beta-1 直接且剂量依赖性地抑制纯化的少突胶质细胞祖细胞的成熟，体内 TGF beta-1 信号传导的药理学抑制可逆转髓磷脂发育的延迟。与野生型星形胶质细胞相比，STAT3缺陷型星形胶质细胞分泌的因子促进培养的小胶质细胞中TGFβ-1的产生升高。解释：这些结果表明髓磷脂的发育受到小胶质细胞和少突胶质细胞祖细胞之间串扰的机制的调节。反应性星形胶质细胞可能以 STAT3 依赖性方式修改这种信号传导，防止小胶质细胞中 TGF beta-1 的病理性表达和少突胶质细胞成熟的损害。安神经学 2012；72：750765
Objective: Pathological findings in neonatal brain injury associated with preterm birth include focal and/or diffuse white matter injury (WMI). Despite the heterogeneous nature of this condition, reactive astrogliosis and microgliosis are frequently observed. Thus, molecular mechanisms by which glia activation contribute to WMI were investigated. Methods: Postmortem brains of neonatal brain injury were investigated to identify molecular features of reactive astrocytes. The contribution of astrogliosis to WMI was further tested in a mouse model in genetically engineered mice. Results: Activated STAT3 signaling in reactive astrocytes was found to be a common feature in postmortem brains of neonatal brain injury. In a mouse model of neonatal WMI, conditional deletion of STAT3 in astrocytes resulted in exacerbated WMI, which was associated with delayed maturation of oligodendrocytes. Mechanistically, the delay occurred in association with overexpression of transforming growth factor (TGF)beta-1 in microglia, which in healthy controls decreased with myelin maturation in an age-dependent manner. TGF beta-1 directly and dose-dependently inhibited the maturation of purified oligodendrocyte progenitors, and pharmacological inhibition of TGF beta-1 signaling in vivo reversed the delay in myelin development. Factors secreted from STAT3-deficient astrocytes promoted elevated TGF beta-1 production in cultured microglia compared to wild-type astrocytes. Interpretation: These results suggest that myelin development is regulated by a mechanism involving crosstalk between microglia and oligodendrocyte progenitors. Reactive astrocytes may modify this signaling in a STAT3-dependent manner, preventing the pathological expression of TGF beta-1 in microglia and the impairment of oligodendrocyte maturation. ANN NEUROL 2012;72:750765