Biomechanical Forces Promote Immune Regulatory Function of Bone Marrow Mesenchymal Stromal Cells.
Biomechanical Forces Promote Immune Regulatory Function of Bone Marrow Mesenchymal Stromal Cells.
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DOI：
10.1002/stem.2587
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发表时间：
2017-05
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影响因子：
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通讯作者：
Wenzel PL
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文献类型：
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作者：
Diaz MF;Vaidya AB;Evans SM;Lee HJ;Aertker BM;Alexander AJ;Price KM;Ozuna JA;Liao GP;Aroom KR;Xue H;Gu L;Omichi R;Bedi S;Olson SD;Cox CS Jr;Wenzel PL
间充质基质细胞（MSC）被认为响应于炎症和损伤而从骨髓动员，但流出到脉管系统中对MSC功能的影响在很大程度上是未知的。在这里，我们表明，壁剪切应力（WSS）典型的流体摩擦力存在于血管腔刺激抗氧化剂和抗炎介质，以及能够免疫细胞募集的趋化因子。WSS通过NFκ B-COX 2-前列腺素E2（PGE 2）特异性促进信号传导，抑制活化免疫细胞产生肿瘤坏死因子-α（TNF-α）。WSS对MSC的体外调节改善了创伤性脑损伤大鼠模型的治疗效果，海马中凋亡和M1型激活的小胶质细胞减少证明了这一点。这些结果表明，力提供了关键线索，MSC驻留在血管界面，影响免疫调节和旁分泌活性，并建议潜在的治疗使用的MSC功能增强的力。血管腔上典型的流体摩擦力的剪切应力刺激MSC产生前列腺素E2（PGE 2）和其他抗炎因子，这些抗炎因子通过活化的免疫细胞抑制肿瘤坏死因子-α（TNF-α）的合成。在神经创伤的背景下，用剪切应力对治疗性MSC进行机械预处理也限制了损伤性反应性小胶质细胞在受损脑中的扩张。
Mesenchymal stromal cells (MSCs) are believed to mobilize from the bone marrow in response to inflammation and injury, yet the effects of egress into the vasculature on MSC function are largely unknown. Here we show that wall shear stress (WSS) typical of fluid frictional forces present on the vascular lumen stimulates antioxidant and anti-inflammatory mediators, as well as chemokines capable of immune cell recruitment. WSS specifically promotes signaling through NFκB-COX2-prostaglandin E2 (PGE2) to suppress tumor necrosis factor-α (TNF-α) production by activated immune cells. Ex vivo conditioning of MSCs by WSS improved therapeutic efficacy in a rat model of traumatic brain injury, as evidenced by decreased apoptotic and M1-type activated microglia in the hippocampus. These results demonstrate that force provides critical cues to MSCs residing at the vascular interface which influence immunomodulatory and paracrine activity, and suggest the potential therapeutic use of force for MSC functional enhancement. Shear stress typical of fluid frictional forces on the vascular lumen stimulates MSCs to produce prostaglandin E2 (PGE2) and other anti-inflammatory factors that suppress synthesis of tumor necrosis factor-α (TNF-α) by activated immune cells. In the context of neurotrauma, mechanical preconditioning of therapeutic MSCs with shear stress also limits expansion of damaging reactive microglia in the injured brain.