Systematic review of neural progenitor cell transplantation for spinal cord injury

BackgroundSpinal cord injury (SCI) causes irreversible neurological deficits and represents a major global health and socioeconomic burden. Although neural progenitor cell (NPC) transplantation is strongly supported by preclinical evidence through cell replacement, intrinsic neuroregeneration, and broad neurotrophic and immunomodulatory effects, its clinical translation has progressed more slowly than anticipated. In parallel, rapid advances in gene editing, biomaterial engineering, and organoid technologies are reshaping the therapeutic landscape. Therefore, it is timely to systematically re-evaluate the current evidence on NPC-based therapies for SCI and to refine future translational strategies.Main bodyThis review provides an updated and comprehensive overview of NPC therapy for SCI across the full translational continuum. First, we summarize the biological properties, advantages, and limitations of NPCs derived from adult or embryonic neural tissues, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), highlighting issues such as tumorigenicity, immune responses, and manufacturing standardization. We then focus on efficacy-oriented genetic modifications and engineered delivery systems, including NPCs overexpressing neurotrophic, synaptogenic, or pro-survival factors, as well as combination strategies integrating NPCs with biomaterials, small molecules, or immunomodulatory agents to enhance graft survival, circuit reconstruction, and motor and sensory recovery. Subsequently, we systematically analyze 19 clinical trials of NPC/NSC-based products conducted in 10 countries, covering HuCNS-SC, LCTOPC1, NSI-566, hESC-OPC, and the emerging iPSC-derived product XS228. Trial designs, dosing regimens, routes of administration, safety profiles, and preliminary functional outcomes are compared, and key design principles for next-generation clinical trials and patient selection are proposed. Finally, we discuss organoid-based approaches and artificial intelligence (AI)–assisted decision tools as emerging platforms for disease modeling, protocol optimization, and precision indication refinement.ConclusionNPC-based therapy for SCI remains at an early but promising translational stage. No NPC product has yet achieved regulatory approval, reflecting persistent challenges in cell source optimization, safety control, graft survival, in vivo tracking, and trial design. Nevertheless, by integrating rigorous cell source selection, rational gene modification, advanced delivery systems, and well-designed clinical trials targeting carefully defined patient populations, NPCs are expected to achieve meaningful—and potentially transformative—clinical benefits for individuals with SCI in the future.