Zheng Bolin, He Yijing, Yin Shuai, Zhu Xu, Zhao Qing, Yang Huiyi, Wang Zhaojie, Zhu Rongrong, Cheng Liming
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education, Department of Orthopedics, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
Frontier Science Center for Stem Cell Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Research (Wash D C). 2023 May 4;6:0135. doi: 10.34133/research.0135. eCollection 2023.
Spinal cord injury triggers complex pathological cascades, resulting in destructive tissue damage and incomplete tissue repair. Scar formation is generally considered a barrier for regeneration in the central nervous system. However, the intrinsic mechanism of scar formation after spinal cord injury has not been fully elucidated. Here, we report that excess cholesterol accumulates in phagocytes and is inefficiently removed from spinal cord lesions in young adult mice. Interestingly, we observed that excessive cholesterol also accumulates in injured peripheral nerves but is subsequently removed by reverse cholesterol transport. Meanwhile, preventing reverse cholesterol transport leads to macrophage accumulation and fibrosis in injured peripheral nerves. Furthermore, the neonatal mouse spinal cord lesions are devoid of myelin-derived lipids and can heal without excess cholesterol accumulation. We found that transplantation of myelin into neonatal lesions disrupts healing with excessive cholesterol accumulation, persistent macrophage activation, and fibrosis. Myelin internalization suppresses macrophage apoptosis mediated by CD5L expression, indicating that myelin-derived cholesterol plays a critical role in impaired wound healing. Taken together, our data suggest that the central nervous system lacks an efficient approach for cholesterol clearance, resulting in excessive accumulation of myelin-derived cholesterol, thereby inducing scar formation after injury.
脊髓损伤引发复杂的病理级联反应，导致组织损伤严重且组织修复不完全。瘢痕形成通常被认为是中枢神经系统再生的障碍。然而，脊髓损伤后瘢痕形成的内在机制尚未完全阐明。在此，我们报告在年轻成年小鼠中，过量胆固醇在吞噬细胞中积累且从脊髓损伤部位清除效率低下。有趣的是，我们观察到过量胆固醇也在受伤的外周神经中积累，但随后通过逆向胆固醇转运被清除。同时，阻止逆向胆固醇转运会导致受伤外周神经中巨噬细胞积聚和纤维化。此外，新生小鼠的脊髓损伤部位缺乏髓磷脂衍生脂质，且能够在无过量胆固醇积累的情况下愈合。我们发现将髓磷脂移植到新生小鼠损伤部位会破坏愈合过程，出现过量胆固醇积累、巨噬细胞持续激活和纤维化。髓磷脂内化抑制由CD5L表达介导的巨噬细胞凋亡，表明髓磷脂衍生的胆固醇在伤口愈合受损中起关键作用。综上所述，我们的数据表明中枢神经系统缺乏有效的胆固醇清除途径，导致髓磷脂衍生胆固醇过度积累，从而在损伤后诱导瘢痕形成。
