Early Transplantation of Mesenchymal Stem Cells After Spinal Cord Injury Relieves Pain Hypersensitivity Through Suppression of Pain-Related Signaling Cascades and Reduced Inflammatory Cell Recruitment
Early Transplantation of Mesenchymal Stem Cells After Spinal Cord Injury Relieves Pain Hypersensitivity Through Suppression of Pain-Related Signaling Cascades and Reduced Inflammatory Cell Recruitment
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DOI：
10.1002/stem.2006
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发表时间：
2015-06-01
期刊：
影响因子：
5.2
通讯作者：
Baba, Hisatoshi
中科院分区：
文献类型：
--
作者：
Watanabe, Shuji;Uchida, Kenzo;Baba, Hisatoshi
骨髓间充质干细胞（BMSC）可调节脊髓损伤（SCI）后的炎症/免疫反应并促进运动功能恢复。然而，骨髓间充质干细胞移植对脊髓损伤后中枢神经病理性疼痛和神经元过度兴奋的影响仍不清楚。这是重要的，因为基于BMSC的疗法已被提出用于临床治疗。我们研究了骨髓间充质干细胞移植对绿色荧光蛋白（GFP）阳性骨髓嵌合体小鼠脊髓损伤后疼痛超敏反应的影响及其机制。脊髓损伤后第3天移植骨髓间充质干细胞可改善运动功能，减轻脊髓损伤引起的对机械和热刺激的超敏反应。疼痛的改善是通过抑制背角神经元中蛋白激酶C和磷酸环AMP反应元件结合蛋白的表达来介导的。BMSC移植显著降低了造血巨噬细胞和常驻小胶质细胞中p-p38丝裂原活化蛋白激酶和细胞外信号调节激酶（p-ERK 1/2）的水平，并显著减少了CD 11b和GFP双阳性造血巨噬细胞的浸润，而不减少CD 11b阳性和GFP阴性活化的脊髓小胶质细胞群。BMSC移植通过恢复血脊髓屏障（BSCB）阻止了造血巨噬细胞的募集，这与（a）炎性细胞因子水平的降低有关（肿瘤坏死因子-，白细胞介素-6）;（B）早期继发性血管发病机制的介质（基质金属肽酶9）;（c）巨噬细胞募集因子（CCL 2，CCL 5和CXCL 10），但增加了小胶质细胞刺激因子（粒细胞-巨噬细胞集落刺激因子）的水平。这些发现支持使用骨髓间充质干细胞移植治疗脊髓损伤。此外，他们认为BMSC通过多种相关机制减少神经性疼痛，包括通过调节脊髓驻留小胶质细胞的活性和造血巨噬细胞的活性和募集介导的神经元保留和恢复受干扰的BSCB。干细胞2015;33：1902-1914
Bone marrow-derived mesenchymal stem cells (BMSC) modulate inflammatory/immune responses and promote motor functional recovery after spinal cord injury (SCI). However, the effects of BMSC transplantation on central neuropathic pain and neuronal hyperexcitability after SCI remain elusive. This is of importance because BMSC-based therapies have been proposed for clinical treatment. We investigated the effects of BMSC transplantation on pain hypersensitivity in green fluorescent protein (GFP)-positive bone marrow-chimeric mice subjected to a contusion SCI, and the mechanisms of such effects. BMSC transplantation at day 3 post-SCI improved motor function and relieved SCI-induced hypersensitivities to mechanical and thermal stimulation. The pain improvements were mediated by suppression of protein kinase C- and phosphocyclic AMP response element binding protein expression in dorsal horn neurons. BMSC transplants significantly reduced levels of p-p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (p-ERK1/2) in both hematogenous macrophages and resident microglia and significantly reduced the infiltration of CD11b and GFP double-positive hematogenous macrophages without decreasing the CD11b-positive and GFP-negative activated spinal-microglia population. BMSC transplants prevented hematogenous macrophages recruitment by restoration of the blood-spinal cord barrier (BSCB), which was associated with decreased levels of (a) inflammatory cytokines (tumor necrosis factor-, interleukin-6); (b) mediators of early secondary vascular pathogenesis (matrix metallopeptidase 9); (c) macrophage recruiting factors (CCL2, CCL5, and CXCL10), but increased levels of a microglial stimulating factor (granulocyte-macrophage colony-stimulating factor). These findings support the use of BMSC transplants for SCI treatment. Furthermore, they suggest that BMSC reduce neuropathic pain through a variety of related mechanisms that include neuronal sparing and restoration of the disturbed BSCB, mediated through modulation of the activity of spinal-resident microglia and the activity and recruitment of hematogenous macrophages. Stem Cells2015;33:1902-1914