Back Stephen A
Division of Pediatric Neuroscience, Departments of Pediatrics and Neurology, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, OR, 97239-3098, USA.
Acta Neuropathol. 2017 Sep;134(3):331-349. doi: 10.1007/s00401-017-1718-6. Epub 2017 May 22.
The human preterm brain is particularly susceptible to cerebral white matter injury (WMI) that disrupts the normal progression of developmental myelination. Advances in the care of preterm infants have resulted in a sustained reduction in the severity of WMI that has shifted from more severe focal necrotic lesions to milder diffuse WMI. Nevertheless, WMI remains a global health problem and the most common cause of chronic neurological morbidity from cerebral palsy and diverse neurobehavioral disabilities. Diffuse WMI involves maturation-dependent vulnerability of the oligodendrocyte (OL) lineage with selective degeneration of late oligodendrocyte progenitors (preOLs) triggered by oxidative stress and other insults. The magnitude and distribution of diffuse WMI are related to both the timing of appearance and regional distribution of susceptible preOLs. Diffuse WMI disrupts the normal progression of OL lineage maturation and myelination through aberrant mechanisms of regeneration and repair. PreOL degeneration is accompanied by early robust proliferation of OL progenitors that regenerate and augment the preOL pool available to generate myelinating OLs. However, newly generated preOLs fail to differentiate and initiate myelination along their normal developmental trajectory despite the presence of numerous intact-appearing axons. Disrupted preOL maturation is accompanied by diffuse gliosis and disturbances in the composition of the extracellular matrix and is mediated in part by inhibitory factors derived from reactive astrocytes. Signaling pathways implicated in disrupted myelination include those mediated by Notch, WNT-beta catenin, and hyaluronan. Hence, there exists a potentially broad but still poorly defined developmental window for interventions to promote white matter repair and myelination and potentially reverses the widespread disturbances in cerebral gray matter growth that accompanies WMI.
人类早产脑特别容易受到脑白质损伤（WMI）的影响，这种损伤会破坏发育性髓鞘形成的正常进程。早产儿护理的进步使得WMI的严重程度持续降低，其已从更严重的局灶性坏死性病变转变为较轻的弥漫性WMI。然而，WMI仍然是一个全球性的健康问题，并且是脑瘫和各种神经行为障碍导致慢性神经疾病的最常见原因。弥漫性WMI涉及少突胶质细胞（OL）谱系成熟依赖性的易损性，由氧化应激和其他损伤引发晚期少突胶质前体细胞（preOLs）的选择性退化。弥漫性WMI的程度和分布与易感preOLs的出现时间和区域分布均有关。弥漫性WMI通过异常的再生和修复机制破坏OL谱系成熟和髓鞘形成的正常进程。PreOL退化伴随着OL前体细胞的早期强烈增殖，这些细胞再生并增加了可用于生成髓鞘形成OL的preOL库。然而，尽管存在许多外观完整的轴突，但新生成的preOLs未能沿着其正常发育轨迹分化并启动髓鞘形成。PreOL成熟的破坏伴随着弥漫性胶质增生以及细胞外基质组成的紊乱，并且部分由反应性星形胶质细胞衍生的抑制因子介导。与髓鞘形成破坏有关的信号通路包括由Notch、WNT-β连环蛋白和透明质酸介导的信号通路。因此，存在一个潜在广泛但仍定义不明确的发育窗口，可用于干预以促进白质修复和髓鞘形成，并有可能逆转伴随WMI的广泛脑灰质生长紊乱。
