Revisiting the unobtrusive role of exogenous stem cells beyond neural circuits replacement in spinal cord injury repair

<b>Rationale:</b> Stem cell transplantation is a promising strategy to establish neural relays in situ for spinal cord injury (SCI) repair. Recent research has reported short-term survival of exogenous cells, irrespective of immunosuppressive drugs (ISD), results in similar function recovery, though the mechanisms remain unclear. This study aims to validate this short-term repair effect and the potential mechanisms in large animals. <b>Methods:</b> In this study, human spinal cord neural progenitor cells (hscNPCs) and human umbilical cord mesenchymal stem cells (hUMSCs) were transplanted into two different SCI model without ISD, respectively; Immunofluorescence was utilized to visualize neuronal regeneration and angiogenesis in the lesion site. Motor evoked potentials (MEPs) were detected to assess the integrity of motor pathways. And RNA sequencing was used to observe transcriptomic changes at the edge of the lesion. <b>Results:</b> The findings revealed hscNPCs failed to survive long-term, but the dogs exhibited better motor function recovery. Moreover, hscNPCs remodeled the injury microenvironment shortly after transplantation by reducing inflammation and enhancing angiogenesis, leading to increased endogenous neuronal regeneration. Similarly, hUMSCs neither survive long-term nor directly reconstruct neural circuits. However, basal functional recovery and endogenous neuronal regeneration were also detected in monkeys with hUMSCs. <b>Conclusions:</b> Exogenous short-term transplantation of stem cells in large animal SCI models does not restore basal function by directly replacing neural circuits throughout the lesion site. Rather, it does so by remodeling the lesion microenvironment in the early stages of transplantation to promote endogenous neural regeneration.