Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.
Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.
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啮齿动物脑室下/室管膜下区（SVZ/SEZ）内的出生后/成年神经干细胞（NSC）产生双皮质素（DCX）+成神经细胞，其迁移并整合到嗅球回路中。成神经细胞的连续生产受SVZ微环境生态位控制。一般认为，增强内源性NSC的神经源性活性可以为疾病状态和脑损伤后提供所需的治疗选择。然而，SVZ NSC也可以分化为星形胶质细胞。目前尚不清楚是否有条件有利于SVZ龛中的星形细胞发生而不是神经发生，以及是否在那里产生的星形胶质细胞表现出与大脑中其他细胞不同的特性。我们已经发现，SVZ产生的星形胶质细胞表达高水平的血小板反应蛋白-4（Thbs 4），一种分泌的同型五聚体糖蛋白，与Thbs 4低的皮质星形胶质细胞相反。我们发现，局部光血栓/缺血性皮质损伤启动了显着增加Thbs 4 hi星形胶质细胞生产从出生后SVZ龛。他莫昔芬诱导的nestin-CreERtm 4谱系追踪表明，正是这些SVZ产生的Thbs 4 hi星形胶质细胞，而不是DCX+神经母细胞，归巢在受损的皮质上。这种强大的损伤后星形细胞反应需要SVZ Notch激活，由Thbs 4通过直接Notch 1受体结合和内吞作用调节以激活下游信号，包括增加对神经胶质细胞产生重要的Nfia转录因子表达。因此，Thbs 4KO/KO动物在皮质损伤诱导的SVZ星形细胞发生中表现出严重缺陷，而是从SVZ到损伤部位产生表达DCX的细胞。细胞反应的这些改变导致损伤后异常的胶质瘢痕形成，并显著增加Thbs 4 KO/KO动物脑实质中的微血管出血。总之，这些发现对内源性和移植的NSC在治疗环境中的损伤后应用以及Thbs家族成员发挥重要作用的疾病状态具有重要意义。
Postnatal/adult neural stem cells (NSCs) within the rodent subventricular/subependymal zone (SVZ/SEZ) generate Doublecortin (DCX)+ neuroblasts that migrate and integrate into olfactory bulb circuitry. Continuous production of neuroblasts is controlled by SVZ microenvironmental niche. It is generally believed that enhancing neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear if there are conditions that favor astrogenesis over neurogenesis in the SVZ niche, and if astrocytes produced there exhibit different properties from others in the brain. We have uncovered that SVZ-generated astrocytes express high levels of Thrombospondin-4 (Thbs4), a secreted homopentameric glycoprotein, in contrast to cortical astrocytes which are Thbs4low. We found that localized photothrombotic/ischemic cortical injury initiates a marked increase in Thbs4hi astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-CreERtm4 lineage-tracing demonstrated that it is these SVZ-generated Thbs4hi astrocytes, and not DCX+ neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation, modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production. Consequently, Thbs4KO/KO animals showed severe defects in cortical injury-induced SVZ astrogenesis, instead producing cells expressing DCX from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular hemorrhage into the brain parenchyma of Thbs4KO/KO animals. Taken together, these findings have significant implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members play important roles.
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