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Transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into spinal cord injury (SCI) may alleviate neuropathic pain and promote functional recovery. The underlying mechanism likely involves activation of glial cells and regulation of inflammatory factors but requires further validation. SCI was induced in 16 ICR mice using an SCI compression model, followed by injection of lentiviral vector-mediated green fluorescent protein- (GFP-) labeled hUC-MSCs 1 week later. Behavioral tests, histological evaluation, and inflammatory factor detection were performed in the treatment (SCI+hUC-MSCs) and model (SCI) groups. Histological evaluation revealed GFP expression in the spinal cord tissue of the treatment group, implying that the injected MSCs successfully migrated to the SCI. The Basso, Beattie, and Bresnahan (BBB) scores showed that motor function gradually recovered over time in both groups, but recovery speed was significantly higher in the treatment group than in the model group. The pain threshold in mice decreased after SCI but gradually increased over time owing to the self-repair function of the body. The corresponding pain threshold of the treatment group was significantly higher than that of the model group, indicating the therapeutic and analgesic effects of hUC-MSCs. Expression of IL-6 and TNF- α in the spinal cord tissue of the treated group decreased, whereas glial cell line-derived neurotrophic factor (GDNF) expression along with ED1 expression increased compared with those in the model group, suggesting that SCI activated ED1 inflammatory macrophages/microglia, which were subsequently reduced by hUC-MSC transplantation. hUC-MSCs are speculated to enhance the repair of the injured spinal cord tissue and exert an analgesic effect by reducing the secretion of inflammatory factors IL-6 and TNF- α and upregulating the expression of GDNF., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2020 Ling-ling Wu et al.)