Unresolved excess accumulation of myelin-derived cholesterol contributes to scar formation after spinal cord injury

TL;DR

This study reveals that unresolved myelin-derived cholesterol accumulation in spinal cord injuries impairs healing and promotes scar formation, highlighting the importance of cholesterol clearance mechanisms in CNS repair.

Contribution

It uncovers the role of excess myelin-derived cholesterol in scar formation after spinal cord injury and demonstrates the importance of reverse cholesterol transport in healing.

Findings

Excess cholesterol accumulates in phagocytes in spinal cord lesions.

Impaired cholesterol efflux leads to scar formation and fibrosis.

Myelin transplantation disrupts healing by causing cholesterol buildup.

Abstract

Background: Spinal cord injury triggers complex pathological cascades, resulting in destructive tissue damage and incomplete tissue repair. Scar formation is generally considered as a barrier for regeneration in central nervous system (CNS), while the intrinsic mechanism of scar-forming after spinal cord injury has not been completed deciphered. Methods: We assessed cholesterol hemostasis in spinal cord lesions and injured peripheral nerves using confocal reflection microscopy and real-time PCR analyses. The involvement of the proteins, which were predicted to promote cholesterol efflux in spinal cord lesions, were assessed with Liver X receptor (LXR) agonist and Apolipoprotein E (APOE) deficiency. The role of reverse cholesterol transport (RCT) in cholesterol clearance was examined in APOE KO mice injured sciatic nerves and myelin-overloaded macrophages in vitro. Finally, we determined the consequence of excess cholesterol accumulation in CNS by transplantation of myelin into neonatal spinal cord lesions. Results: We found that excess cholesterol accumulates in phagocytes and is inefficiently removed in spinal cord lesions in young-adult mice. Interestingly, we observed that excessive cholesterol also accumulates in injured peripheral nerves, but is subsequently removed by RCT. Meanwhile, preventing RCT led to macrophage accumulation and fibrosis in injured peripheral nerves. Furthermore, the neonatal mouse spinal cord lesions are devoid of myelin-derived lipids, and able to 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, indicating myelin-derived cholesterol plays a critical role in impaired wound healing.