Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital, 20132 Milan, Italy,
Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Hospital, 20132 Milan, Italy.
J Neurosci. 2019 Jul 10;39(28):5481-5492. doi: 10.1523/JNEUROSCI.0227-18.2019. Epub 2019 May 28.
Myelin loss occurring in demyelinating diseases, including multiple sclerosis, is the leading cause of long-lasting neurological disability in adults. While endogenous remyelination, driven by resident oligodendrocyte precursor cells (OPCs), might partially compensate myelin loss in the early phases of demyelinating disorders, this spontaneous reparative potential fails at later stages. To investigate the cellular mechanisms sustaining endogenous remyelination in demyelinating disorders, we focused our attention on endogenous neural precursor cells (eNPCs) located within the subventricular zone (SVZ) since this latter area is considered one of the primary sources of new OPCs in the adult forebrain. First, we fate mapped SVZ-eNPCs in cuprizone-induced demyelination and found that SVZ endogenous neural stem/precursor cells are recruited during the remyelination phase to the corpus callosum (CC) and are capable of forming new oligodendrocytes. When we ablated SVZ-derived eNPCs during cuprizone-induced demyelination in female mice, the animals displayed reduced numbers of oligodendrocytes within the lesioned CC. Although this reduction in oligodendrocytes did not impact the ensuing remyelination, eNPC-ablated mice experienced increased axonal loss. Our results indicate that, in toxic models of demyelination, SVZ-derived eNPCs contribute to support axonal survival. One of the significant challenges in MS research is to understand the detrimental mechanisms leading to the failure of CNS tissue regeneration during disease progression. One possible explanation is the inability of recruited oligodendrocyte precursor cells (OPCs) to complete remyelination and to sustain axonal survival. The contribution of endogenous neural precursor cells (eNPCs) located in the subventricular zone (SVZ) to generate new OPCs in the lesion site has been debated. Using transgenic mice to fate map and to selectively kill SVZ-derived eNPCs in the cuprizone demyelination model, we observed migration of SVZ-eNPCs after injury and their contribution to oligodendrogenesis and axonal survival. We found that eNPCs are dispensable for remyelination but protect partially from increased axonal loss.
髓鞘脱失发生在脱髓鞘疾病中，包括多发性硬化症，是成年人长期神经功能障碍的主要原因。虽然由少突胶质前体细胞（OPC）驱动的内源性髓鞘再生可能在脱髓鞘疾病的早期阶段部分补偿髓鞘丢失，但这种自发的修复潜能在后期阶段会失效。为了研究维持脱髓鞘疾病中内源性髓鞘再生的细胞机制，我们将注意力集中在脑室下区（SVZ）内的内源性神经前体细胞（eNPCs）上，因为后者被认为是成年大脑中新 OPC 的主要来源之一。首先，我们在铜诱导的脱髓鞘模型中对 SVZ-eNPC 进行了命运图谱分析，发现 SVZ 内源性神经干细胞/前体细胞在髓鞘再生阶段被募集到胼胝体（CC），并能够形成新的少突胶质细胞。当我们在雌性小鼠的铜诱导脱髓鞘模型中清除 SVZ 衍生的 eNPC 时，损伤的 CC 内少突胶质细胞数量减少。尽管这种少突胶质细胞的减少并没有影响随后的髓鞘再生，但 eNPC 缺失的小鼠经历了更多的轴突丢失。我们的结果表明，在脱髓鞘的毒性模型中，SVZ 衍生的 eNPC 有助于支持轴突存活。MS 研究的一个重要挑战是理解导致中枢神经系统组织在疾病进展过程中再生失败的有害机制。一种可能的解释是，募集的少突胶质前体细胞（OPC）无法完成髓鞘再生并维持轴突存活。位于脑室下区（SVZ）的内源性神经前体细胞（eNPC）在病变部位产生新的 OPC 的贡献一直存在争议。我们使用转基因小鼠对 SVZ 衍生的 eNPC 进行命运图谱分析，并在铜诱导的脱髓鞘模型中选择性地杀死它们，观察到损伤后 SVZ-eNPC 的迁移及其对少突胶质生成和轴突存活的贡献。我们发现 eNPC 对于髓鞘再生是可有可无的，但可以部分保护免受轴突丢失的增加。
