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40 reviewsSpinal cord injury (SCI) remains a significant clinical challenge and poses a dramatic threat to the life quality of patients due tolimited neural regeneration and detrimental post-injury alternations in tissue microenvironment. We developed a therapeuticapproach by transplanting spinal neural progenitor cells (spNPGs), derived from human induced pluripotent stem cell (iPSC)-generated neuromesodermal progenitors, into a contusive SCI model in NOD-SCID mice. Single-cell RNA sequencing mapped the invitro differentiation of iPSC-spNPGs, confirming their specification into spinal neuronal lineages. Single-nucleus transcriptomics at1234567890();,:1 week post-transplantation showed that the grafted cells differentiated in vivo into motor neurons and two interneuron subtypes(V2 and dI4). Additionally, spNPGs integrated into host neural circuits, enhancing synaptic connectivity, while simultaneouslymodulating the injury microenvironment by shifting microglia and astrocyte polarization toward anti-inflammatory andneuroprotective phenotypes. This dual mechanism promoted axonal regrowth, remyelination, and significant sensorimotorrecovery, as evidenced by improved locomotor scores. Our findings highlight the therapeutic potential of human iPSC-spNPGs inreconstructing neural networks and mitigating secondary damage, providing compelling preclinical evidence for advancing stemcell-based SCI therapies.