Activation of Endogenous Spinal Cord Stem Cell Mediates Recovery Induced by Olfactory Ensheathing Cell Transplantation Following Spinal Cord Injury

Abstract

Spinal cord injury (SCI) leads to irreversible motor and sensory deficits and currently has no curative treatment. Among the various therapeutic strategies explored, cell transplantation-- using either stem or differentiated cells--has been extensively studied. One of the most promising approaches involves the use of olfactory ensheathing cells (OECs), which have demonstrated unique potential to promote functional recovery and tissue repair following SCI. However, the mechanisms underlying these effects remain poorly understood. In this study, we investigated how OEC transplantation modulates endogenous spinal stem cells, with a particular focus on ependymal cells. Using inducible transgenic mouse lines and fate-mapping approaches, we show that OEC transplantation significantly enhances ependymal cell proliferation and self-renewal both in vivo and in vitro. Moreover, OECs promote astrocytic differentiation of ependymal progeny, which express low levels of inhibitory molecules-- suggesting a supportive role in creating a permissive scar microenvironment. Transcriptomic analyses further revealed that OEC transplantation downregulates genes associated with axonal growth inhibition, thereby contributing to improved neuronal survival. Finally, by using a unique transgenic mouse model in which ependymal cell proliferation is genetically blocked, we demonstrate that the beneficial effects of OEC transplantation depend on ependymal cell activation. Together, these findings establish ependymal cells as essential mediators of the regenerative response induced by OECs. They also highlight a therapeutic strategy based on activating and modulating endogenous stem cells via the transient presence of non-integrating transplanted glial cells. This work contributes to our understanding of SCI repair and supports the clinical potential of OEC-based cell therapies.