  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.
