Mechanism of BMSCs Inhibiting Microglia Activation and Neuroinflammatory Response to Alleviate BCP by Regulating TLR4/ NF-κB Signaling Pathway.

Introduction: Bone marrow mesenchymal stem cells (BMSCs) are effective in treating a variety of chronic pain conditions, including bone cancer pain (BCP); however, the underlying mechanism remains unclear. Microglia are the main cells involved in hyperalgesia and maintenance of BCP. Hence, their activation and polarization are key signs of neuroinflammation. The Toll-like receptor 4/ nuclear factor-kappa B (TLR4/ NF-κB) signaling pathway plays an essential role in microglial activation and neuroinflammation. Nonetheless, whether BMSCs can be used to treat BCP by regulating the TLR4/NF-κB signaling pathway and microglial activation requires further research. In this study, a series of experiments were conducted to explore the specific mechanisms underlying the beneficial effects of BMSCs on BCP.Methods: Initially, this study demonstrated the therapeutic effect of BMSCs on BCP through behavioral and pathological evaluations. Subsequently, the effects of BMSCs on microglia and related mechanisms were detected by Western blotting, immunofluorescence, ELISA, and RNA sequencing. Finally, based on the microglia BV2-BMSCs co-culture model, the mechanism of BMSCs regulation of microglia was further verified through in vitro experiments.Results: Intrathecal injection of BMSCs was found to alleviate BCP by inhibiting the activation of microglia in the spinal dorsal horn and the release of cytokines, which involves the regulation of the TLR4/NF-kB signaling pathway. In addition, BMSCs inhibited the nuclear transport of NF-κB in vitro.Discussion: These results revealed that the TLR4/NF-κB signaling pathway in microglia is one of the targets of BMSCs in BCP treatment.