Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2.
Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2.
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四氢大麻酚预处理涉及大麻素受体 CB2 上调小鼠骨髓间充质干细胞的免疫调节作用
DOI：
10.18632/oncotarget.7042
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
Yu L
中科院分区：
文献类型：
--
作者：
Xie J;Xiao D;Xu Y;Zhao J;Jiang L;Hu X;Zhang Y;Yu L
慢性疼痛通常与炎症密切相关。大麻素信号传导和间充质干细胞（MSCs）已被证明可以减轻炎症性疼痛。虽然大麻素信号对间充质干细胞的存活和分化至关重要，但其在间充质干细胞对炎症和疼痛敏感性的调节作用中所起的作用尚不清楚。在这里，我们发现小鼠骨髓来源的间充质干细胞（BM-MSCs）表达大麻素受体1型和2型（CB1和CB2）。CB2在脑间充质干细胞中的表达水平随其成熟而升高。此外，我们发现四氢大麻酚（THC）激活CB2受体和ERK信号，从而增强MSCs对脂多糖刺激的小胶质细胞释放炎症相关细胞因子的调节。与体外实验结果一致，四氢大麻酚预处理通过减少促炎细胞因子的释放，增强了BM-MSC对慢性收缩性损伤模型热痛觉过敏和机械异常痛的免疫调节作用。我们的研究揭示了四氢大麻酚在促进间充质干细胞免疫调节作用中的重要作用，并提出了一种基于干细胞治疗的疼痛缓解新策略。
Chronic pain is commonly and closely correlated with inflammation. Both cannabinoid signaling and mesenchymal stem cells (MSCs) have been demonstrated to reduce inflammatory pain. Although cannabinoid signaling is essential for mesenchymal stem cell survival and differentiation, little is known about its role in modulatory effect of MSCs on inflammation and pain sensitivity. Here we showed that mouse bone-marrow derived MSCs (BM-MSCs) expressed both cannabinoid receptor type 1 and 2 (CB1 and CB2). CB2 expression level in BM-MSCs increased with their maturation. In addition, we found that tetrahydrocannabinol (THC) activated CB2 receptor and ERK signaling, consequently enhancing the modulation of MSCs on inflammation-associated cytokine release from lipopolysaccharides-stimulated microglia. Consistent with in vitro data, THC pretreatment enhanced the immunomodulatory effects of BM-MSC on thermal hyperalgesia and mechanical allodynia in chronic constriction injury model, by decreasing the release of pro-inflammation cytokines. Our study revealed the crucial role of THC in promoting the immunomodulatory effects of MSCs and proposed a new strategy to alleviate pain based on stem cells therapy.