Fibroblast migration is mediated by CD44-dependent TGFβ activation
Fibroblast migration is mediated by CD44-dependent TGFβ activation
复制标题
DOI：
10.1242/jcs.021683
复制
发表时间：
2008-05-01
影响因子：
4
通讯作者：
Pure, Ellen
中科院分区：
文献类型：
--
作者：
Acharya, Pinak S.;Majumdar, Sonali;Pure, Ellen
CD44有助于炎症和纤维化对损伤的反应。由于成纤维细胞募集对伤口愈合至关重要，我们比较了野生型（CD44WT）和CD44缺陷型（CD44KO）成纤维细胞的细胞骨架结构和迁移。与CD44WT成纤维细胞相比，CD44KO成纤维细胞表现出较少的应力纤维和粘着斑复合物，其迁移的特征在于速度增加但方向性丧失。从机制上讲，我们证明了CD44WT细胞比CD44KO细胞产生更活跃的TGF β，并且CD44通过MMP依赖性机制促进TGF β的活化。CD44表达的重建完全挽救了CD44 KO细胞的表型，而CD44 KO细胞暴露于外源性活性TGF β挽救了应力纤维和迁移速度的缺陷，但不足以恢复迁移的方向性。这些结果解决了CD44对成纤维细胞迁移的TGF β介导和TGF β非依赖性作用，并表明CD44可能对成纤维细胞向损伤部位的募集以及成纤维细胞在组织重塑和纤维化中的功能至关重要。
CD44 contributes to inflammation and fibrosis in response to injury. As fibroblast recruitment is critical to wound healing, we compared cytoskeletal architecture and migration of wildtype (CD44WT) and CD44-deficient (CD44KO) fibroblasts. CD44KO fibroblasts exhibited fewer stress fibers and focal adhesion complexes, and their migration was characterized by increased velocity but loss of directionality, compared with CD44WT fibroblasts. Mechanistically, we demonstrate that CD44WT cells generated more active TGF beta than CD44KO cells and that CD44 promotes the activation of TGF beta via an MMP-dependent mechanism. Reconstitution of CD44 expression completely rescued the phenotype of CD44KO cells whereas exposure of CD44KO cells to exogenous active TGF beta rescued the defect in stress fibers and migrational velocity, but was not sufficient to restore directionality of migration. These results resolve the TGF beta-mediated and TGF beta-independent effects of CD44 on fibroblast migration and suggest that CD44 may be critical for the recruitment of fibroblasts to sites of injury and the function of fibroblasts in tissue remodeling and fibrosis.