ZO-1-dependent fibrotic scar border formation impedes axon regeneration after spinal cord injury.

Fibrotic scarring acutely corrals inflammation but chronically impedes axon regeneration via dense border structures after spinal cord injury (SCI). Although the origin and heterogeneity of fibroblasts have been extensively studied, effective strategies to prevent fibrotic scarring, especially the formation of its border structure, remain elusive. Here, we identified a distinct fibroblast subpopulation with markedly upregulated tight junction protein 1 (ZO-1) expression, which contributes to the formation of fibrotic scar borders after SCI. While ZO-1 has been conventionally considered restricted to epithelial/endothelial cells, our data may indicate a novel role in the formation of fibrotic scar border by platelet-derived growth factor receptor beta (PDGFRβ)-positive fibroblasts. Genetic ablation of Tjp1 (encoding ZO-1) in fibroblasts disrupted the fibrotic scar border, allowing serotonergic and tyrosine hydroxylase axons to grow into the lesion core after SCI. Disruption of the fibrotic scar border induced by ZO-1 knockout did not exacerbate inflammatory spread or damage residual neurons after SCI. Furthermore, PDGFB/PDGFRβ pathway activation induced ZO-1 expression and scar border formation in the intact spinal cord, whereas its inhibition suppressed ZO-1 upregulation and disrupted the scar border after SCI. Remarkably, combined targeting of PDGFRβ (using SU16f) and ZO-1 function (via LAT-A) synergistically promoted axonal growth across the lesion. Our findings identify ZO-1 as a critical orchestrator of the fibrotic scar border and reveal a combined therapeutic approach for enhancing axon regeneration after SCI.