Perlecan Improves Blood Spinal Cord Barrier Repair Through the Integrin β1/ROCK/MLC Pathway After Spinal Cord Injury.

Spinal cord injury (SCI) can lead to the destruction of the blood-spinal cord barrier (BSCB), causing various inflammatory cytokines, neutrophils, and macrophages to infiltrate the lesion area, resulting in secondary injury. Basement membranes (BMs) are maintained by all types of cells in the BSCB and contribute to BSCB maintenance. Perlecan is an important constituent of vascular BMs, maintaining vascular integrity and neuroprotection. However, it is not clear whether Perlecan is involved in BSCB repair after SCI. In this study, we found that Perlecan was specifically expressed in the BMs in the spinal cord and underwent degradation/remodeling after SCI. Subsequently, a CRISPR/Cas9-based SAM system was used to overexpress Perlecan in the injured spinal cord, resulting in significantly enhanced locomotor recovery and neural regeneration. Overexpression of Perlecan reduced BSCB permeability along with the neuroinflammatory response. Interestingly, Perlecan inhibited stress fiber formation by interacting with integrin β1 and inhibiting downstream ROCK/MLC signaling, resulting in reduced tight junctions (TJs) disassembly and improved BSCB integrity. Furthermore, the integrin receptor antagonist GRGDSP abolished the effects of Perlecan overexpression on BSCB permeability and TJs integrity. Overall, our findings suggest that Perlecan reduces BSCB permeability and the neuroinflammatory response by interacting with integrin β1 and inhibiting the downstream ROCK/MLC pathway to promote neurological recovery after SCI.