Focal adhesion kinase signaling regulates anti-inflammatory function of bone marrow mesenchymal stromal cells induced by biomechanical force.
Focal adhesion kinase signaling regulates anti-inflammatory function of bone marrow mesenchymal stromal cells induced by biomechanical force.
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DOI：
10.1016/j.cellsig.2017.06.012
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发表时间：
2017-10
影响因子：
4.8
通讯作者：
Wenzel PL
中科院分区：
文献类型：
--
作者：
Lee HJ;Diaz MF;Ewere A;Olson SD;Cox CS Jr;Wenzel PL
间充质基质细胞（MSC）由于其多能性和免疫细胞调节功能，在再生医学中具有巨大的应用潜力。在组织工程应用中，仿生物理力已被证明可以指导MSC的分化和成熟;然而，力对MSC的免疫调节活性的影响在很大程度上被忽视了。在这里，我们表明，在人骨髓来源的间充质干细胞的壁剪切应力（WSS）相当于流体摩擦力存在于成人动脉血管系统显着增强四个基因的表达，介导MSC免疫调节功能，PTGS 2，HMOX 1，IL 1 RN，和TNFAIP 6。WSS可刺激多种机械传导途径，包括钙离子（Ca 2+）流动和Akt、MAPK和粘着斑激酶（FAK）的激活。通过LY 294002或用螯合剂、离子通道抑制剂或无Ca 2+培养条件的Ca 2+信号传导抑制PI 3 K-Akt未能减弱WSS诱导的COX 2表达。相比之下，FAK抑制剂PF-562271阻断COX 2诱导，暗示局灶性粘连是这一关键免疫调节因子上游的关键感觉成分。在共培养试验中，WSS预处理刺激MSC抗炎活性以更有效地抑制活化免疫细胞产生TNF-α，并且这种提高的效力依赖于FAK刺激COX 2诱导的能力。总之，我们的数据表明，生物力学力通过FAK信号级联增强MSC的修复和再生特性，并强调了基于力的创新方法增强MSC治疗效果的潜力。
Mesenchymal stromal cells (MSCs) have tremendous potential for use in regenerative medicine due to their multipotency and immune cell regulatory functions. Biomimetic physical forces have been shown to direct differentiation and maturation of MSCs in tissue engineering applications; however, the effect of force on immunomodulatory activity of MSCs has been largely overlooked. Here we show in human bone marrow-derived MSCs that wall shear stress (WSS) equivalent to the fluid frictional force present in the adult arterial vasculature significantly enhances expression of four genes that mediate MSC immune regulatory function, PTGS2, HMOX1, IL1RN, and TNFAIP6. Several mechanotransduction pathways are stimulated by WSS, including calcium ion (Ca2+) flux and activation of Akt, MAPK, and focal adhesion kinase (FAK). Inhibition of PI3K-Akt by LY294002 or Ca2+ signaling with chelators, ion channel inhibitors, or Ca2+ free culture conditions failed to attenuate WSS-induced COX2 expression. In contrast, the FAK inhibitor PF-562271 blocked COX2 induction, implicating focal adhesions as critical sensory components upstream of this key immunomodulatory factor. In co-culture assays, WSS preconditioning stimulates MSC anti-inflammatory activity to more potently suppress TNF-α production by activated immune cells, and this improved potency depended upon the ability of FAK to stimulate COX2 induction. Taken together, our data demonstrate that biomechanical force potentiates the reparative and regenerative properties of MSCs through a FAK signaling cascade and highlights the potential for innovative force-based approaches for enhancement in MSC therapeutic efficacy.
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DOI：
10.1186/2047-1440-1-12
发表时间：
2012-09-28
期刊：
Transplantation research
影响因子：
--
作者：
Eggenhofer E;Hoogduijn MJ
通讯作者：
Hoogduijn MJ
DOI：
10.1084/jem.20142235
发表时间：
2015-05-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diaz MF;Li N;Lee HJ;Adamo L;Evans SM;Willey HE;Arora N;Torisawa YS;Vickers DA;Morris SA;Naveiras O;Murthy SK;Ingber DE;Daley GQ;García-Cardeña G;Wenzel PL
通讯作者：
Wenzel PL
影响因子：
8.1
作者：
Jiang, Ranhua;Han, Zhibo;Han, Zhong Chao
通讯作者：
Han, Zhong Chao
DOI：
10.1002/stem.2587
发表时间：
2017-05
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
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
通讯作者：
Wenzel PL
影响因子：
4
作者：
Dai, S.;Abu-Amer, W.;Abu-Amer, Y.
通讯作者：
Abu-Amer, Y.