Piezo1 drives fibroblast activation in epidural fibrotic remodelling via the ET-1/HIF-1α pathway.

Aims: Epidural fibrosis is a major cause of failed back surgery syndrome following laminectomy. While previous studies have focused primarily on the early phases of scar formation, fibrotic remodelling remains poorly understood. This study aimed to investigate the interaction between collagen accumulation and fibroblasts during the remodelling phase of epidural fibrosis. Methods: In this study, a 3D collagen encapsulation model was used to simulate mechanical stress. Fibrotic and mechanosensitive pathway-related molecules were analyzed to assess fibroblast activation, and specific pharmacological inhibitors were applied to verify the proposed mechanism. Additionally, a mouse laminectomy model was used to evaluate the therapeutic effect of Piezo1 blockade on epidural fibrosis. Results: We found that collagen fibres encapsulate fibroblasts during the stage of scar remodelling. In vitro, collagen may activate the transforming growth factor beta-1 (TGF-β1)/Smad3 pathway in fibroblasts, which is mediated by the Piezo1 and hypoxia-inducible factor 1-alpha (HIF-1α) signalling pathways. This process establishes a positive feedback loop between collagen accumulation and fibroblast activation. Furthermore, we demonstrated that Piezo1-mediated activation of HIF-1α occurs through calcium ion influx and stabilization of endothelin-1 (ET-1). More importantly, blocking the activation of Piezo1 attenuated fibrosis progression in a mouse model of laminectomy. Conclusion: These results highlight the critical role of the Piezo1/ET-1/HIF-1α pathway in epidural fibrotic remodelling. Targeting Piezo1 may offer a promising therapeutic strategy for alleviating epidural fibrosis and improving outcomes after spinal surgery.