Experimental neurology · 2025
Bone marrow mesenchymal stem cell-derived exosomes alleviate neuropathic pain after spinal cord injury by inhibiting the TLR4/MyD88/NF-κB pathway.
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Xu Yuanzhi, Wang Shaoshuai, Li Zefu, Wang Junmin, Wang Menglu, Xue Qidi, Tao Jin, Huang Siyuan, Rastegar-Kashkooli Yousef, Xu Yusheng, Chen Xuemei
Аннотация
BACKGROUND: Spinal cord injury-induced neuropathic pain (SCI-NP), characterized by complex pathophysiological mechanisms, represents a significant therapeutic challenge. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have demonstrated potential efficacy in the management of NP, but the mechanism remains to be explored. Here, we aimed to further elucidate the potential analgesic mechanism of BMSC-Exos in SCI-NP.
METHODS: Bioinformatic analyses were conducted to identify target genes and associated pathways. We established a SCI-NP model in TLR4lps-del and wild-type (WT) C57BL/6 mice. Paw withdrawal tests were utilized to assess mechanical pain thresholds following SCI. Immunofluorescence staining and Western blotting analysis were employed to examine microglial activation and TLR4/MyD88/NF-κB pathway activity. We subsequently administered BMSC-Exos to the injury site. The analgesic effects and underlying mechanisms were evaluated via previously established methodologies.
RESULTS: A comprehensive literature review identified 287 articles on cell therapy for SCI-NP, and the abstracts of these articles were subjected to text mining, leading to the identification of 11 key SCI-NP-related genes and 23 associated pathways, including the TLR4, Toll-like receptor signaling and NF-κB signaling pathways. The SCI-NP model was successfully established. WT mice exhibited increased microglial activation and expression of TLR4/MyD88/NF-κB pathway members. Conversely, in TLR4lps-del mice, SCI-NP was suppressed, and the expression of TLR4/MyD88/NF-κB pathway members in microglia was decreased. Furthermore, exosome transplantation alleviated SCI-NP, reduced microglial activation, and attenuated TLR4/MyD88/NF-κB pathway expression.
CONCLUSION: BMSC-Exos mitigated SCI-NP by inhibiting microglial activation through the TLR4/MyD88/NF-κB pathway, which is a target for future treatment.
METHODS: Bioinformatic analyses were conducted to identify target genes and associated pathways. We established a SCI-NP model in TLR4lps-del and wild-type (WT) C57BL/6 mice. Paw withdrawal tests were utilized to assess mechanical pain thresholds following SCI. Immunofluorescence staining and Western blotting analysis were employed to examine microglial activation and TLR4/MyD88/NF-κB pathway activity. We subsequently administered BMSC-Exos to the injury site. The analgesic effects and underlying mechanisms were evaluated via previously established methodologies.
RESULTS: A comprehensive literature review identified 287 articles on cell therapy for SCI-NP, and the abstracts of these articles were subjected to text mining, leading to the identification of 11 key SCI-NP-related genes and 23 associated pathways, including the TLR4, Toll-like receptor signaling and NF-κB signaling pathways. The SCI-NP model was successfully established. WT mice exhibited increased microglial activation and expression of TLR4/MyD88/NF-κB pathway members. Conversely, in TLR4lps-del mice, SCI-NP was suppressed, and the expression of TLR4/MyD88/NF-κB pathway members in microglia was decreased. Furthermore, exosome transplantation alleviated SCI-NP, reduced microglial activation, and attenuated TLR4/MyD88/NF-κB pathway expression.
CONCLUSION: BMSC-Exos mitigated SCI-NP by inhibiting microglial activation through the TLR4/MyD88/NF-κB pathway, which is a target for future treatment.