Intrathecal injection of bone marrow stromal cells attenuates neuropathic pain via inhibition of P2X4R in spinal cord microglia
Intrathecal injection of bone marrow stromal cells attenuates neuropathic pain via inhibition of P2X4R in spinal cord microglia
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DOI：
10.1186/s12974-019-1631-0
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发表时间：
2019-12-17
影响因子：
9.3
通讯作者：
Jia, Xiaofeng
中科院分区：
文献类型：
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作者：
Teng, Yongbo;Zhang, Yang;Jia, Xiaofeng
背景：神经病理性疼痛是所有慢性疼痛综合征中最易使人衰弱的一种。鞘内（i.t.）骨髓基质细胞（BMSC）注射具有良好的安全性;然而，结果一直不一致，并且对BMSC如何影响神经性疼痛的完全理解仍然难以捉摸。方法：我们在背根神经节（CCD）模型的慢性压迫中评价BMSC对神经性疼痛的镇痛作用。我们分析了BMSCs对小胶质细胞反应性和嘌呤受体P2 X（4）（P2 X（4）R）表达的影响。此外，我们还观察了BMSCs对背根神经节（DRG）神经元瞬时受体电位香草酸4（TRPV 4）表达的影响，TRPV 4是神经病理性疼痛发病机制中的关键分子。BMSC短暂但显著地改善神经性疼痛行为（2天减少37.6%）。我们没有发现骨髓间充质干细胞浸润到脊髓实质或背根神经节的证据，我们也证明了鞘内注射骨髓间充质干细胞裂解物提供了类似的缓解。这些结果表明，i.t.骨髓间充质干细胞主要是由于骨髓间充质干细胞衍生因子释放到鞘内空间。从机制上讲，我们发现，虽然i.t. BMSCs对DRG神经元TRPV 4表达无影响，但对脊髓小胶质细胞P2 X（4）R表达有明显抑制作用。BMSC裂解物还降低了体外活化小胶质细胞中P2 X（4）R的表达。同时给予靶向P2 X（4）R的其他药物干预证实，P2 X（4）R的调节可能是i.t.结论：总的来说，我们的结果表明，i.t. BMSC是神经性疼痛的有效和安全的治疗方法，并提供了新的证据表明BMSC的镇痛作用主要是由BMSC衍生因子的释放介导的，导致小胶质细胞P2 X（4）R下调。
Background: Neuropathic pain is one of the most debilitating of all chronic pain syndromes. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; however, results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive.Methods: We evaluated the analgesic effect of BMSCs on neuropathic pain in a chronic compression of the dorsal root ganglion (CCD) model. We analyzed the effect of BMSCs on microglia reactivity and expression of purinergic receptor P2X(4) (P2X(4)R). Furthermore, we assessed the effect of BMSCs on the expression of transient receptor potential vanilloid 4 (TRPV4), a key molecule in the pathogenesis of neuropathic pain, in dorsal root ganglion (DRG) neurons.Results: I.t. BMSC transiently but significantly ameliorated neuropathic pain behavior (37.6% reduction for 2 days). We found no evidence of BMSC infiltration into the spinal cord parenchyma or DRGs, and we also demonstrated that intrathecal injection of BMSC-lysates provides similar relief. These findings suggest that the analgesic effects of i.t. BMSC were largely due to the release of BMSC-derived factors into the intrathecal space. Mechanistically, we found that while i.t. BMSCs did not change TRPV4 expression in DRG neurons, there was a significant reduction of P2X(4)R expression in the spinal cord microglia. BMSC-lysate also reduced P2X(4)R expression in activated microglia in vitro. Coadministration of additional pharmacological interventions targeting P2X(4)R confirmed that modulation of P2X(4)R might be a key mechanism for the analgesic effects of i.t. BMSC.Conclusion: Altogether, our results suggest that i.t. BMSC is an effective and safe treatment of neuropathic pain and provides novel evidence that BMSC's analgesic effects are largely mediated by the release of BMSC-derived factors resulting in microglial P2X(4)R downregulation.