Neuroscience Graduate Program, Ohio State University, Columbus, Ohio, USA.
Belford Center for Spinal Cord Injury, Ohio State University, Columbus, Ohio, USA.
Glia. 2023 Sep;71(9):2096-2116. doi: 10.1002/glia.24382. Epub 2023 May 20.
Our prior work examining endogenous repair after spinal cord injury (SCI) in mice revealed that large numbers of new oligodendrocytes (OLs) are generated in the injured spinal cord, with peak oligodendrogenesis between 4 and 7 weeks post-injury (wpi). We also detected new myelin formation over 2 months post-injury (mpi). Our current work significantly extends these results, including quantification of new myelin through 6 mpi and concomitant examination of indices of demyelination. We also examined electrophysiological changes during peak oligogenesis and a potential mechanism driving OL progenitor cell (OPC) contact with axons. Results reveal peak in remyelination occurs during the 3rd mpi, and that myelin generation continues for at least 6 mpi. Further, motor evoked potentials significantly increased during peak remyelination, suggesting enhanced axon potential conduction. Interestingly, two indices of demyelination, nodal protein spreading and Nav1.2 upregulation, were also present chronically after SCI. Nav1.2 was expressed through 10 wpi and nodal protein disorganization was detectable throughout 6 mpi suggesting chronic demyelination, which was confirmed with EM. Thus, demyelination may continue chronically, which could trigger the long-term remyelination response. To examine a potential mechanism that may initiate post-injury myelination, we show that OPC processes contact glutamatergic axons in the injured spinal cord in an activity-dependent manner. Notably, these OPC/axon contacts were increased 2-fold when axons were activated chemogenetically, revealing a potential therapeutic target to enhance post-SCI myelin repair. Collectively, results show the surprisingly dynamic nature of the injured spinal cord over time and that the tissue may be amenable to treatments targeting chronic demyelination.
我们之前的研究发现，在脊髓损伤（SCI）后，大量的少突胶质细胞（OLs）在损伤的脊髓中产生，在损伤后 4 至 7 周时达到少突胶质生成的高峰。我们还在损伤后 2 个月检测到新的髓鞘形成。我们目前的工作显著扩展了这些结果，包括通过 6 个月时的髓鞘定量以及同时检查脱髓鞘指数。我们还研究了在 OL 祖细胞（OPC）与轴突接触的高峰期的电生理变化和潜在的驱动机制。结果显示，髓鞘再生的高峰发生在第 3 个月时，髓鞘生成至少持续到第 6 个月时。此外，在髓鞘生成高峰期，运动诱发电位显著增加，表明轴突潜在的传导能力增强。有趣的是，SCI 后慢性期还存在两个脱髓鞘指数，即节点蛋白扩散和 Nav1.2 上调。Nav1.2 表达持续到损伤后 10 周，节点蛋白结构紊乱在整个 6 个月时均可检测到，这表明存在慢性脱髓鞘，电镜检查也证实了这一点。因此，脱髓鞘可能持续慢性存在，这可能引发长期的髓鞘修复反应。为了研究一种可能启动损伤后髓鞘形成的潜在机制，我们发现 OPC 过程以活性依赖的方式与损伤脊髓中的谷氨酸能轴突接触。值得注意的是，当轴突被化学激活时，这些 OPC/轴突接触增加了两倍，这揭示了一个潜在的治疗靶点，以增强 SCI 后的髓鞘修复。总之，结果显示了损伤的脊髓随时间推移具有惊人的动态特性，并且组织可能适合针对慢性脱髓鞘的治疗。
