Abstract：
Ischaemic stroke causes neuron loss and long-term functional deficits. Unfortunately, effective approaches to preserving neurons and promoting functional recovery remain unavailable. Oligodendrocytes, the myelinating cells in the CNS, are susceptible to oxygen and nutrition deprivation and undergo degeneration after ischaemic stroke. Technically, new oligodendrocytes and myelin can be generated by the differentiation of oligodendrocyte precursor cells (OPCs). However, myelin dynamics and their functional significance after ischaemic stroke remain poorly understood. Here, we report numerous denuded axons accompanied by decreased neuron density in sections from ischaemic stroke lesions in human brain, suggesting that neuron loss correlates with myelin deficits in these lesions. To investigate the longitudinal changes in myelin dynamics after stroke, we labelled and traced pre-existing and newly-formed myelin, respectively, using cell-specific genetic approaches. Our results indicated massive oligodendrocyte death and myelin loss 2 weeks after stroke in the transient middle cerebral artery occlusion (tMCAO) mouse model. In contrast, myelin regeneration remained insufficient 4 and 8 weeks post-stroke. Notably, neuronal loss and functional impairments worsened in aged brains, and new myelin generation was diminished. To analyse the causal relationship between remyelination and neuron survival, we manipulated myelinogenesis by conditional deletion of Olig2 (a positive regulator) or muscarinic receptor 1 (M1R, a negative regulator) in OPCs. Deleting Olig2 inhibited remyelination, reducing neuron survival and functional recovery after tMCAO. Conversely, enhancing remyelination by M1R conditional knockout or treatment with the pro-myelination drug clemastine after tMCAO preserved white matter integrity and neuronal survival, accelerating functional recovery. Together, our findings demonstrate that enhancing myelinogenesis is a promising strategy to preserve neurons and promote functional recovery after ischaemic stroke.
摘要：
缺血性中风导致神经元丢失和长期功能缺陷。不幸的是,保护神经元和促进功能恢复的有效方法仍然不可用。少突胶质细胞(OLs),中枢神经系统中的髓鞘细胞，易受氧气和营养剥夺的影响，缺血性中风后发生变性。从技术上讲,从少突胶质前体细胞(OPCs)的分化可以产生新的OLs和髓鞘。然而,缺血性卒中后髓磷脂动力学及其功能意义仍知之甚少。这里,我们报道了在缺血性卒中的人脑切片的病变中大量的脱氮轴突，伴随着神经元密度的降低，提示神经元丢失与卒中病变的髓磷脂缺陷相关。了解卒中后髓鞘动力学的纵向变化,我们标记并追踪预先存在或新形成的髓鞘，分别,通过使用细胞特异性遗传方法。我们的结果表明，在短暂性大脑中动脉阻塞（tMCAO）小鼠模型中，中风后2周出现大量的OLs死亡和髓磷脂丢失。相比之下,卒中后4周和8周髓鞘再生仍然不足。值得注意的是,神经元损失和功能损伤进一步恶化，在老年大脑，伴随着正在消失的新一代髓鞘。了解髓鞘再生和神经元存活之间的因果关系，我们通过条件缺失Olig2（正调节因子）或毒蕈碱受体1（M1R，OPCs中的负调节器)。删除Olig2会抑制髓鞘再生,抑制tMCAO后神经元存活和功能恢复。相反，tMCAO后通过M1RcKO增强髓鞘再生或治疗前髓鞘形成药物clemastine保持白质完整性和神经元存活，加速功能恢复。一起,我们的研究结果表明,增强髓鞘形成是缺血性卒中后保护神经元和促进功能恢复的有前景的策略.
