Department of Anesthesiology, Central People's Hospital of Zhanjiang, Zhanjiang, Guangdong, People's Republic of China.
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
J Neuroinflammation. 2022 Sep 7;19(1):221. doi: 10.1186/s12974-022-02578-9.
Mesenchymal stem cell (MSCs)-derived small Extracellular Vesicles (sEVs) are considered as a new cell-free therapy for pain caused by nerve injury, but whether human placental mesenchymal stem cell-derived sEVs relieve pain in sciatic nerve injury and its possible mechanism are still unclear. In this study, we investigated the roles of hPMSCs-derived sEVs and related mechanisms in neuropathic pain.
The spared nerve injury (SNI) mouse model was employed. Intrathecal injection of sEVs or miR-26a-5p agomir was performed on the seventh day of modeling, to study its anti-nociceptive effect. sEVs' miRNA sequencing (miRNA-Seq) and bioinformatics analysis were performed to study the downstream mechanisms of miRNAs. RT-qPCR, protein assay and immunofluorescence were used for further validation.
A single intrathecal injection of sEVs durably reversed mechanical hypersensitivity in the left hind paw of mice with partial sciatic nerve ligation. Immunofluorescence studies found that PKH26-labeled sEVs were visible in neurons and microglia in the dorsal horn of the ipsilateral L4/5 spinal cord and more enriched in the ipsilateral. According to miRNA-seq results, we found that intrathecal injection of miR-26a-5p agomir, the second high counts microRNA in hPMSCs derived sEVs, significantly suppressed neuropathic pain and neuroinflammation in SNI mice. Bioinformatics analysis and dual-luciferase reporter gene analysis identified Wnt5a as a direct downstream target gene of miR-26a-5p. The results showed that overexpression of miR-26a-5p in vivo could significantly reduce the expression level of Wnt5a. In addition, Foxy5, a mimetic peptide of Wnt5a, can significantly reverse the inhibitory effect of miR-26a-5p on neuroinflammation and neuropathic pain, and at the same time, miR-26a-5p can rescue the effect of Foxy5 by overexpression.
We reported that hPMSCs derived sEVs as a promising therapy for nerve injury induced neuropathic pain. In addition, we showed that the miR-26a-5p in the sEVs regulated Wnt5a/Ryk/CaMKII/NFAT partly take part in the analgesia through anti-neuroinflammation, which suggests an alleviating pain effect through non-canonical Wnt signaling pathway in neuropathic pain model in vivo.
间充质干细胞（MSCs）衍生的小细胞外囊泡（sEVs）被认为是一种治疗神经损伤引起疼痛的新型无细胞治疗方法，但人胎盘间充质干细胞衍生的 sEVs 是否能缓解坐骨神经损伤引起的疼痛及其可能的机制仍不清楚。在这项研究中，我们研究了 hPMSCs 衍生的 sEVs 在神经病理性疼痛中的作用及其相关机制。
采用 spared nerve injury（SNI）小鼠模型。在造模第 7 天，鞘内注射 sEVs 或 miR-26a-5p agomir，以研究其抗伤害作用。对 sEVs 的 miRNA 测序（miRNA-Seq）和生物信息学分析进行研究，以研究 miRNA 的下游机制。采用 RT-qPCR、蛋白测定和免疫荧光进一步验证。
单次鞘内注射 sEVs 可持久逆转部分坐骨神经结扎小鼠左后爪的机械性痛敏。免疫荧光研究发现，PKH26 标记的 sEVs 在同侧 L4/5 脊髓背角的神经元和小胶质细胞中可见，且在同侧更丰富。根据 miRNA-seq 结果，我们发现鞘内注射 miR-26a-5p agomir，即 hPMSCs 衍生 sEVs 中第二高计数的 microRNA，可显著抑制 SNI 小鼠的神经病理性疼痛和神经炎症。生物信息学分析和双荧光素酶报告基因分析表明，Wnt5a 是 miR-26a-5p 的直接下游靶基因。结果表明，体内过表达 miR-26a-5p 可显著降低 Wnt5a 的表达水平。此外，Wnt5a 的模拟肽 Foxy5 可显著逆转 miR-26a-5p 对神经炎症和神经病理性疼痛的抑制作用，同时，miR-26a-5p 可通过过表达来挽救 Foxy5 的作用。
我们报道了 hPMSCs 衍生的 sEVs 作为一种有前途的治疗神经损伤引起的神经病理性疼痛的方法。此外，我们表明 sEVs 中的 miR-26a-5p 通过调节 Wnt5a/Ryk/CaMKII/NFAT 部分参与了镇痛作用，通过非经典 Wnt 信号通路缓解了神经病理性疼痛模型中的疼痛，提示了一种非经典 Wnt 信号通路缓解神经病理性疼痛模型中疼痛的作用。
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