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Fractalkine 通过 Jak2 信号通路和细胞骨架重排促进骨髓间充质干细胞向缺血性脑损伤部位趋化。

Fractalkine promotes chemotaxis of bone marrow-derived mesenchymal stem cells towards ischemic brain lesions through Jak2 signaling and cytoskeletal reorganization.

机构信息

Department of Orthopedics, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

出版信息

FEBS J. 2015 Mar;282(5):891-903. doi: 10.1111/febs.13187. Epub 2015 Jan 30.

Abstract

The fractalkine (FKN)-CX3CR1 (FKN receptor) axis reportedly plays an important role in the progression of many neural pathologies. However, its role in the recruitment of bone marrow-derived progenitor cells for neurogenesis remains elusive. The chemokine-based mechanism underlying the migration of bone marrow-derived mesenchymal stem cells (BMSCs) was investigated in a double-chamber transmigration model with recombinant FKN and endogenous FKN extract, and the results confirmed the involvement of FKN in migration. This chemotactic response was CX3CR1-dependent and FKN-sensitive. Western blotting, immunoprecipitation and transmigration assays revealed that the Janus kinase (Jak)2-signal transducer and activator of transcription (Stat)5α-extracellular signal-related kinase (ERK)1/2 pathway was activated by FKN. Confocal laser scanning microscopy was used to demonstrate cytoskeletal reorganization caused by remodeling of the surface receptor integrin α5β1, intracellular phosphorylation of Fak and Pax, and upregulation of intercellular adhesion molecule-1 during BMSC migration. Moreover, significant inhibition of signaling and migration was detected after treatment of cells with Jak2-interfering RNA or the antagonist AG490. In addition, the results of a fluorescence immunohistochemical analysis of an in vivo chemotactic model, developed via transplantation of BMSCs into transient middle cerebral artery-occluded rats, were consistent with the in vitro results. These findings suggest that FKN activates Jak2-Stat5α-ERK1/2 signaling through CX3CR1, thereby triggering integrin-dependent machinery reorganization to allow chemotactic migration of BMSCs towards an ischemic cerebral lesion.

摘要

趋化因子(FKN)-CX3CR1(FKN 受体)轴在许多神经病理的进展中据报道发挥着重要作用。然而,其在骨髓源性祖细胞募集用于神经发生中的作用仍不清楚。通过重组 FKN 和内源性 FKN 提取物的双层迁移模型研究了趋化因子为基础的骨髓源性间充质干细胞(BMSC)迁移机制,结果证实了 FKN 参与迁移。这种趋化反应依赖于 CX3CR1 和 FKN 敏感性。Western blot、免疫沉淀和迁移试验显示,FKN 激活了 Janus 激酶(Jak)2-信号转导和转录激活因子(Stat)5α-细胞外信号调节激酶(ERK)1/2 通路。共聚焦激光扫描显微镜用于证明细胞骨架的重排,由表面受体整合素 α5β1、 Fak 和 Pax 的细胞内磷酸化以及细胞间黏附分子-1 的上调引起,BMSC 迁移。此外,在用 Jak2 干扰 RNA 或拮抗剂 AG490 处理细胞后,检测到信号转导和迁移的显著抑制。此外,通过将 BMSC 移植到短暂性大脑中动脉闭塞大鼠中建立的体内趋化模型的荧光免疫组织化学分析结果与体外结果一致。这些发现表明,FKN 通过 CX3CR1 激活 Jak2-Stat5α-ERK1/2 信号通路,从而触发整合素依赖性机制的重排,允许 BMSC 向缺血性脑损伤进行趋化性迁移。

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