Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706;
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706.
Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11807-E11816. doi: 10.1073/pnas.1808064115. Epub 2018 Nov 28.
Endogenous remyelination of the CNS can be robust and restore function, yet in multiple sclerosis it becomes less complete with time. Promoting remyelination is a major therapeutic goal, both to restore function and to protect axons from degeneration. Remyelination is thought to depend on oligodendrocyte progenitor cells, giving rise to nascent remyelinating oligodendrocytes. Surviving, mature oligodendrocytes are largely regarded as being uninvolved. We have examined this question using two large animal models. In the first model, there is extensive demyelination and remyelination of the CNS, yet oligodendrocytes survive, and in recovered animals there is a mix of remyelinated axons interspersed between mature, thick myelin sheaths. Using 2D and 3D light and electron microscopy, we show that many oligodendrocytes are connected to mature and remyelinated myelin sheaths, which we conclude are cells that have reextended processes to contact demyelinated axons while maintaining mature myelin internodes. In the second model in vitamin B-deficient nonhuman primates, we demonstrate that surviving mature oligodendrocytes extend processes and ensheath demyelinated axons. These data indicate that mature oligodendrocytes can participate in remyelination.
中枢神经系统内源性髓鞘再生能力很强,可以恢复功能,但多发性硬化症患者随着时间的推移,其髓鞘再生能力会逐渐减弱。促进髓鞘再生是一个主要的治疗目标,既能恢复功能,又能保护轴突免受退化。髓鞘再生被认为依赖于少突胶质前体细胞,这些细胞会产生新生的髓鞘形成少突胶质细胞。存活的成熟少突胶质细胞在很大程度上被认为不参与其中。我们使用两种大型动物模型研究了这个问题。在第一个模型中,中枢神经系统有广泛的脱髓鞘和髓鞘再生,但少突胶质细胞存活,在恢复的动物中,新生的髓鞘形成少突胶质细胞与成熟的、厚的髓鞘鞘混合在一起。通过二维和三维的光镜和电子显微镜,我们发现许多少突胶质细胞与成熟和髓鞘再生的髓鞘鞘相连,我们推断这些细胞是在维持成熟髓鞘节段的同时,重新伸出突起以接触脱髓鞘轴突的细胞。在维生素 B 缺乏的非人灵长类动物的第二个模型中,我们证明了存活的成熟少突胶质细胞可以延伸突起并包裹脱髓鞘的轴突。这些数据表明成熟的少突胶质细胞可以参与髓鞘再生。