The mechanism by which miR-let-7b-modified BMSCs mediating Nogo/NgR signaling pathway in the repair of spinal cord injury.

Abstract

BACKGROUND: Spinal cord injury (SCI) leads to severe and often permanent neurological deficits. The inhibitory Nogo/NgR signaling pathway constitutes a major barrier to axonal regeneration. Transplantation of bone marrow mesenchymal stem cells (BMSCs) and modulation of microRNAs, such as miR-let-7b, represent promising therapeutic strategies for neural repair. OBJECTIVES: This study aimed to investigate the role and mechanism of miR-let-7b-modified BMSCs in repairing SCI, focusing on their interaction with the Nogo/NgR signaling pathway. METHODS: In vitro, an oxygen-glucose deprivation (OGD) neuronal model (VSC4.1 cells) was co-cultured with BMSCs or miR-let-7b-modified BMSCs. Neuronal marker expression (NSE, MAP-2, Tau) and targeting relationships were assessed via immunocytochemistry, RT-PCR, and dual-luciferase assays. In vivo, 40 SD rats with spinal cord hemisection were divided into control, BMSCs, miR-let-7b+BMSCs, and NgR antagonist groups. Hindlimb functional recovery was evaluated using the Tarlov score and Rivlin inclined plane test. RESULTS: miR-let-7b-modified BMSCs significantly increased neuronal marker expression in vitro (P<0.05). In vivo, this group showed sustained and optimal functional recovery from day 7 post-injury. The modified BMSCs directly targeted the Nogo gene, significantly reducing its protein expression, whereas the NgR antagonist did not affect Nogo levels. CONCLUSION: miR-let-7b-modified BMSCs promote functional recovery after SCI by targeting the Nogo gene and inhibiting the Nogo/NgR signaling pathway, likely via an exosome-mediated mechanism, thereby improving the inhibitory microenvironment for neural repair.