Mechanism of IFITM1 regulating epidural scar hyperplasia after laminectomy through SMAD3/CBR4 pathway

Haoran Wang¹Zekai Zhu²Kaiwei Wang¹Ruoyu Liuyang¹Jun Liu^2*Ning Xie^1*

• ¹Tongji Hospital Affiliated to Tongji University, Shanghai, China
• ²The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China

Epidural scar hyperplasia is a prevalent complication post-laminectomy, contributing significantly to persistent low back pain and other symptoms, ultimately undermining surgical outcomes. Previous studies have identified fibroblast proliferation and differentiation, as well as adipocyte fibrosis, as central to this process, though the precise mechanisms remain elusive. In a murine laminectomy model, fibroblast proliferation, activation, and adipocyte fibrosis were found to exacerbate epidural scar formation. IFITM1, a critical protein regulating cell proliferation, is expressed in fibroblasts. The proliferation and activation of fibroblasts, characterized by high IFITM1 expression, were inhibited by suppression of the SMAD3 signaling pathway. In vivo studies revealed a reduction in epidural fibrosis following laminectomy in the absence of IFITM1. Additionally, CBR4, a protein associated with IFITM1 and involved in fatty acid synthesis, showed reduced expression in adipocytes under inflammatory conditions, triggering their transformation into fibroblasts, a process regulated by IFITM1. Our animal experiments also confirmed the presence of adipose tissue within epidural scars, with IFITM1 deficiency correlating with reduced adipose tissue and increased CBR4 expression. In conclusion, these findings demonstrate that IFITM1 inhibits fibroblast proliferation and differentiation via SMAD3 signaling suppression and modulates adipocyte fibrosis by regulating CBR4 expression, thereby influencing epidural scar hyperplasia post-laminectomy.