Abstract
Spinal cord injury (SCI) leads to irreversible loss of motor, sensory, and autonomic functions and currently has no cure. While cell therapies in animal models have shown benefits such as scar reduction and neuroprotection, their translation to humans remains limited, partly because clinical applications rely on autologous rather than healthy donor cells. This prompted us to investigate how the lesion context alters the neuro-reparative potential of olfactory ensheathing cells (OECs). OECs were cultured from healthy animals or from animals 1 week after SCI, and both populations were transplanted into recipient mice after SCI.Our results demonstrate for the first time that SCI-derived OECs display impaired therapeutic properties compared with healthy-donor OECs. Transplantation of post-injury cells failed to reduce fibrotic scar, demyelination, or astrocytic defects at the lesion epicenter, and did not promote sensory-motor recovery. In addition, SCI-derived OECs showed a markedly reduced ability to limit neuronal death, support axonal survival, and preserve synaptic integrity, whereas transplantation of healthy-donor OECs significantly improved all these outcomes. At the molecular level, SCI-derived OECs secreted pro-inflammatory mediators that polarized microglia toward a pro-inflammatory phenotype, thereby exacerbating the hostile lesion environment. Altogether, these combined in vivo and in vitro findings reveal that the lesion-induced context profoundly compromises OEC reparative functions. They highlight a previously unrecognized limitation of autologous OEC transplantation and underscore the importance of considering the lesion context when designing cell-based strategies for SCI.