Genetically engineered senescence-resistant human mesenchymal progenitor cells promote spinal cord injury repair.

Spinal cord injury (SCI) is a devastating condition affecting the central nervous system, often leading to persistent neurological dysfunction. While mesenchymal progenitor cells (MPCs) hold considerable promise for treating various disorders, their application in SCI repair remains hampered by challenges such as poor efficacy and safety concerns. In this study, we developed genetically engineered human MPCs with enhanced resistance to senescence and stress-termed senescence- and stress-resistant cells (SRCs)-and systematically evaluated their therapeutic potential and mechanisms in SCI repair. Intramedullary implantation of SRCs improved functional recovery after SCI. Mechanistically, SRCs exerted therapeutic effects through a dual approach: by mitigating neuronal and axonal loss while stimulating endogenous neuroregeneration, and by suppressing neuroinflammation while modulating astrocyte distribution to restrict lesion expansion. Importantly, we identified exosomes derived from SRCs as key mediators of these reparative effects. Our findings provide comprehensive insights into the therapeutic role of engineered SRCs in SCI repair, delineating both direct cellular and exosome-mediated mechanisms, thus providing experimental support for future clinical translation.