IGFBP2-Ceramides Pathway Mediates Divergent Myelin Breakdown in the PNS and CNS Following Injury

Following injury, the peripheral nervous system (PNS) exhibits remarkable regenerative capacity, whereas the central nervous system (CNS) has limited regenerative potential. This difference is partially attributed to distinct post-injury myelin breakdown. However, the underlying mechanisms driving this disparity remain unclear. By comparing the expression profiles of injured peripheral and central nerves in adult male and female C57BL/6J mice, we identified IGFBP2 as a key regulator that determines the differences in myelin breakdown between the injured PNS and CNS. Schwann cell-derived IGFBP2 in the injured PNS promotes myelin breakdown and facilitates axonal regeneration. Furthermore, through lipidomics, we identify ceramide, a sphingolipid regulated by ceramide synthase 6 in injured nerves, as playing a critical role in IGFBP2-mediated myelin breakdown. Conversely, minimal IGFBP2 expression is observed in the injured CNS, contributing to the limited myelin breakdown and axon regeneration in injured CNS. These findings provide insights into the divergent regenerative potential of the PNS and CNS and unveil IGFBP2 and ceramide as promising targets for promoting CNS regeneration after injury. Significance Statement Our research sheds light on the contrasting regenerative capacities of the peripheral nervous system (PNS) and central nervous system (CNS) after injury. Understanding why the PNS exhibits robust regeneration while the CNS does not could revolutionize treatments for neurological injuries and diseases. We discovered that Schwann cell-derived IGFBP2 plays a crucial role in promoting myelin breakdown and axon regeneration in the PNS. Moreover, our findings highlight the involvement of ceramide, a lipid molecule, in this process. Identifying these key players not only deepens our understanding of nerve regeneration but also unveils potential targets for therapeutic interventions aimed at enhancing CNS regeneration post-injury.