Miyamoto Nobukazu, Maki Takakuni, Shindo Akihiro, Liang Anna C, Maeda Mitsuyo, Egawa Naohiro, Itoh Kanako, Lo Evan K, Lok Josephine, Ihara Masafumi, Arai Ken
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
Multi-Modal Microstructure Analysis Unit, RIKEN CLST-JEOL Collaboration Center, RIKEN Center for Life Science Technologies, Kobe, Japan 650-0047, and.
J Neurosci. 2015 Oct 14;35(41):14002-8. doi: 10.1523/JNEUROSCI.1592-15.2015.
Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAP(cre)/BDNF(wt/fl)) in which BDNF expression is downregulated specifically in GFAP(+) astrocytes. Both wild-type (GFAP(wt)/BDNF(wt/fl) mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF.
The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However, the underlying mechanisms are still mostly unknown. Here, we use a combination of cell biology and an animal model to report a new pathway in which astrocyte-derived BDNF supports oligodendrogenesis and regeneration after white matter damage. These findings provide new mechanistic insight into white matter physiology and pathophysiology, which would be broadly and clinically applicable to CNS disease.
成体脑中的少突胶质前体细胞（OPC）有助于维持白质稳态。白质损伤后，OPC通过分化为成熟少突胶质细胞来补偿少突胶质细胞的损失。然而，其潜在机制仍有待充分阐明。在此，我们检验了这样一个假设，即在白质缺血性损伤的内源性恢复过程中，星形胶质细胞通过分泌脑源性神经营养因子（BDNF）来支持OPC的成熟。对于体外实验，从出生后第2天的大鼠皮质制备原代培养的OPC和星形胶质细胞。当通过将OPC暴露于亚致死剂量的CoCl₂ 7天使其受到化学性缺氧应激时，体外OPC向少突胶质细胞的分化显著受到抑制。即使在应激条件下，星形胶质细胞的条件培养基（星形胶质细胞培养基）也能恢复OPC的成熟过程。当用TrkB-Fc过滤星形胶质细胞培养基以去除BDNF时，缺乏BDNF的星形胶质细胞培养基不再支持OPC的成熟。对于体内实验，我们分析了一种转基因小鼠品系（GFAP(cre)/BDNF(wt/fl)），其中BDNF的表达在GFAP(+)星形胶质细胞中特异性下调。野生型（GFAP(wt)/BDNF(wt/fl)小鼠）和转基因小鼠均通过双侧颈总动脉狭窄进行长时间的脑灌注不足处理。正如预期的那样，与野生型小鼠相比，转基因小鼠新生少突胶质细胞数量更少，白质损伤更大。总之，这些发现表明，在白质损伤的内源性恢复过程中，星形胶质细胞可能通过分泌BDNF促进少突胶质细胞生成。
脑损伤和神经退行性变后白质修复仍然是广泛的中枢神经系统疾病的巨大障碍。一个潜在的重要机会可能在于残余少突胶质前体细胞（OPC）的反应。OPC可能作为损伤白质中生成成熟少突胶质细胞的后备细胞。然而，其潜在机制大多仍不清楚。在此，我们结合细胞生物学和动物模型报告了一条新途径，即星形胶质细胞衍生的BDNF在白质损伤后支持少突胶质细胞生成和再生。这些发现为白质生理学和病理生理学提供了新的机制性见解，在临床上广泛适用于中枢神经系统疾病。
