Reactive oligodendrocyte progenitor cells (re-)myelinate the regenerating zebrafish spinal cord [Single cell]

Spinal cord injury (SCI) results in loss of neurons, oligodendrocytes and myelin sheaths, all of which are not efficiently restored. The scarcity of oligodendrocytes in the lesion site impairs remyelination of spared fibres, which leaves axons denuded, impedes signal transduction and contributes to permanent functional deficits. In contrast to mammals, zebrafish can functionally regenerate the spinal cord. Yet, little is known about oligodendroglial lineage biology and remyelination capacity after SCI in a regeneration-permissive context. Here, we report that in adult zebrafish, SCI results in axonal, oligodendrocyte and myelin sheath loss. We find that OPCs, the oligodendorocyte progenitor cells, survive the injury, enter a reactive state, proliferate and differentiate into oligodendrocytes. Concomitantly, the oligodendrocyte population is re-established to pre-injury levels within two weeks.Transcriptional profiling revealed that reactive OPCs upregulate the expression of several myelination-related genes. Interestingly, global reduction of axonal tracts and partial re-myelination, relative to pre-injury levels, persist at later stages of regeneration, yet suffices for functional recovery. Taken together, these findings imply that in the zebrafish spinal cord, OPCs replace lost oligodendrocytes and, thus, re-establish myelination during regeneration.

脊髓损伤（Spinal cord injury, SCI）会造成神经元、少突胶质细胞（oligodendrocytes）与髓鞘（myelin sheaths）的丢失，且这类损伤无法得到有效修复。损伤部位内少突胶质细胞的稀缺会损害残存神经纤维的髓鞘再生过程，导致轴突裸露、阻碍信号转导，并最终引发永久性的功能缺损。与哺乳动物不同，斑马鱼（zebrafish）可实现脊髓的功能性再生。然而在脊髓再生许可的微环境中，脊髓损伤后少突胶质细胞谱系的生物学特性与髓鞘再生能力仍鲜为人知。本研究显示，在成年斑马鱼体内，脊髓损伤同样会引发轴突、少突胶质细胞与髓鞘的丢失。我们观察到，少突胶质细胞前体细胞（oligodendrocyte progenitor cells, OPCs）可在损伤后存活，进入激活状态，随后增殖并分化为少突胶质细胞。与此同时，少突胶质细胞群体可在损伤后两周内恢复至损伤前水平。转录组分析（transcriptional profiling）结果显示，激活的少突胶质细胞前体细胞会上调多种髓鞘相关基因的表达。值得注意的是，相较于损伤前水平，再生后期仍存在轴突束整体减少与部分髓鞘再生不完全的情况，但这已足够支持斑马鱼实现功能恢复。综上，本研究结果表明，在斑马鱼脊髓的再生过程中，少突胶质细胞前体细胞可替代丢失的少突胶质细胞，从而重建髓鞘结构。