Antinociceptive effect of intrathecal injection of miR-9-5p modified mouse bone marrow mesenchymal stem cells on a mouse model of bone cancer pain

Abstract

Background: A growing body of studies have indicated that bone marrow mesenchymal stem cells (BMSCs) have powerful analgesic effects in animal models of bone cancer pain. Here, we explored the molecular mechanisms underlying how BMSCs alleviate pain sensation in a mouse model of bone cancer pain.Methods: C3H/HeN adult male mice were used to generate a bone cancer pain model. BMSCs were isolated from mouse bone marrow, modified by transfection with microRNA-9-5p (miR-9-5p), and infused into the spinal cord. Spontaneous flinches, paw withdrawal latency, limb-use score, and weight-bearing score were used to assess painrelated behaviors. ELISA, RT-PCR, western blot, and luciferase assay were used to assess gene expressions. Results: Our results show that miR-9-5p regulated the expression of both repressor element silencing transcription factor (REST) and μ-opioid receptors (MOR) by targeting REST in primary mouse BMSCs. Overexpression of miR-9-5p reversed the activation of inflammatory pathway in TNF-α-and IL-6-treated BMSCs. In addition, miR-9-5p modified BMSCs alleviated cancer pain in the sarcoma-inoculated mouse model. MiR-9-5p modified BMSCs suppressed cytokine expression in the spinal cord of sarcoma-inoculated mice by suppressing REST gene expression. Conclusions:Our results indicate that miR-9-5p modified BMSCs can relieve bone cancer pain via modulating neuroinflammation in the central nervous system, suggesting genetically modified BMSCs could be a promising cell therapy in pain management.

Systematic analysis identifies REST as an oncogenic and immunological biomarker in glioma

“…Reports showed the inhibitory roles of miR-105-5p in the proliferation and migration of glioma cells, while the regulatory mechanism during the process is still undefined 36,37 . Previous studies have found that miR-9-5p could interact with REST and regulate its gene expression 38,39 . Taken together, miR-9-5p and miR-105-5p/REST axis were identified as potential regulatory pathways in glioma, representing a novel potential treatment strategy for glioma.…”

Regulation by noncoding RNAs of local translation, injury responses, and pain in the peripheral nervous system

“…Direct linkage of miR-9, in Schwann cells or otherwise, to pain phenotypes remains understudied. An anti-nociceptive effect from intrathecal administration of miR-9 overexpressing bone marrow mesenchymal stem cells, and consequent reduction in spinal cord neuroinflammatory readouts, has been reported in a mouse model of bone cancer pain (C. Zhu et al, 2020 ).…”

Schwann cells as a target cell for the treatment of cancer pain

“…Our previous study showed that transplantation of olfactory ensheathing cells (a type of glial cell similar to SCs) also had a pain‐relieving effect (Zhang et al, 2019; Zhang, Luo, Zhu, et al, 2020). Transplantation of other cells such as chromaffin cells and mesenchymal stem cells may relieve intractable cancer‐induced pain (Lazorthes et al, 1995; Zhu, Wang, et al, 2020). A recent clinical trial found that autologous SCs were injected into two patients with spinal cord injury; one patient's motor function improved by four points, sensory function improved by six points, and the level of nerve injury improved by one point.…”