TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration
TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration
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DOI：
10.1038/sj.emboj.7601441
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发表时间：
2006-12-13
期刊：
影响因子：
11.4
通讯作者：
Zheng, Timothy S.
中科院分区：
文献类型：
--
作者：
Girgenrath, Mahasweta;Weng, Shawn;Zheng, Timothy S.
炎症通过多种机制参与组织修复，包括直接调节对成功再生至关重要的常驻祖细胞的细胞命运。通过研究TNF配体TWEAK的靶细胞类型，我们观察到TWEAK与间充质干细胞的所有祖细胞结合，诱导NF-kappa B活化，并在间充质干细胞中表达促生存、促增殖和归巢受体基因，这表明这种促炎症细胞因子可能在控制祖细胞生物学中发挥重要作用。我们利用已建立的C2C12细胞系和原代小鼠肌成肌细胞探索了这种潜力，并证明了TWEAK促进了它们的增殖并抑制了它们的终端分化。通过培养缺乏TWEAK受体Fn14的小鼠，我们进一步发现，缺乏Fn14的原代成肌细胞增殖能力显著降低，肌管形成发生改变。注射心脏毒素（卫星细胞驱动骨骼肌再生的已知触发因素）后，与野生型小鼠相比，fn14缺陷小鼠表现出炎症反应降低和肌纤维再生延迟。这些结果表明，TWEAK/Fn14通路是骨骼肌前体细胞的一种新的调节因子，并阐明了炎症细胞因子影响组织再生和修复的重要机制。再加上我们最近的研究表明，TWEAK增强了肝祖细胞的增殖，Fn14在所有间充质谱系祖细胞上的表达支持了这一途径在其他组织损伤和疾病环境中的广泛参与。
Inflammation participates in tissue repair through multiple mechanisms including directly regulating the cell fate of resident progenitor cells critical for successful regeneration. Upon surveying target cell types of the TNF ligand TWEAK, we observed that TWEAK binds to all progenitor cells of the mesenchymal lineage and induces NF-kappa B activation and the expression of pro-survival, pro-proliferative and homing receptor genes in the mesenchymal stem cells, suggesting that this pro- inflammatory cytokine may play an important role in controlling progenitor cell biology. We explored this potential using both the established C2C12 cell line and primary mouse muscle myoblasts, and demonstrated that TWEAK promoted their proliferation and inhibited their terminal differentiation. By generating mice deficient in the TWEAK receptor Fn14, we further showed that Fn14-deficient primary myoblasts displayed significantly reduced proliferative capacity and altered myotube formation. Following cardiotoxin injection, a known trigger for satellite cell-driven skeletal muscle regeneration, Fn14-deficient mice exhibited reduced inflammatory response and delayed muscle fiber regeneration compared with wild-type mice. These results indicate that the TWEAK/Fn14 pathway is a novel regulator of skeletal muscle precursor cells and illustrate an important mechanism by which inflammatory cytokines influence tissue regeneration and repair. Coupled with our recent demonstration that TWEAK potentiates liver progenitor cell proliferation, the expression of Fn14 on all mesenchymal lineage progenitor cells supports a broad involvement of this pathway in other tissue injury and disease settings.