Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
Campus Institute for Dynamics of Biological Networks, University of Göttingen, Göttingen, Germany.
Acta Neuropathol Commun. 2020 Dec 24;8(1):224. doi: 10.1186/s40478-020-01105-2.
Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2 OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1 oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.
在血清渗透压变化后，在人类脑桥观察到脱髓鞘病变，被称为脑桥中央髓鞘溶解症（CPM）。星形胶质细胞损伤在神经炎症性疾病中很明显，如视神经脊髓炎（NMO）和多发性硬化症（MS），被认为是 CPM 病变形成过程中的主要事件。尽管关于星形胶质细胞衍生因子对少突胶质前体细胞（OPC）和髓鞘再生的影响有更多的数据，但对于原发性星形胶质细胞丢失病变的髓鞘再生仍知之甚少。在 CPM 患者的尸检组织和实验模型中，我们能够对 OPC 的激活和分化进行特征描述。BrdU 的胸腺嘧啶类似物注射可追踪在早期星形胶质细胞耗竭病变中激活的 OPC 的成熟。我们观察到在实验性星形胶质细胞耗竭性脱髓鞘病变中，实质 NG2 OPC 库迅速激活，导致广泛的 OPC 增殖。在病变起始后 1 周，大多数源自实质的 OPC 表达乳腺癌扩增序列-1（BCAS1），表明向预髓鞘形成状态的转变。源自该早期实质反应的细胞通常表现出功能失调的形态，细胞质浓缩，延伸过程较少，在产生髓磷脂的或成熟的少突胶质细胞中很少被检测到。相应地，人类 CPM 病变的早期阶段也显示出星形胶质细胞数量减少和非髓鞘形成的具有功能失调形态的 BCAS1 少突胶质细胞。在大鼠模型中，神经干细胞（NSC）在侧脑室下区（SVZ）中被激活，而病变已经部分被 OPC 再填充，产生巢蛋白祖细胞，在病变中产生少突胶质细胞谱系细胞，随后被星形胶质细胞再填充和髓鞘再生。在人类 CPM 病例中不存在这些巢蛋白干细胞衍生的祖细胞，这可能导致病变修复效率低下。本研究表明星形胶质细胞-少突胶质细胞相互作用对髓鞘再生的重要性，突出了在包括 MS 在内的脱髓鞘疾病中进一步确定星形胶质细胞功能障碍对髓鞘再生效率低下的影响的必要性。
