Recombinant human platelet-derived growth factor and transforming growth factor-β mediated contraction of human dermal fibroblast populated lattices is inhibited by Rho/GTPase inhibitor but does not require phosphatidylinositol-3′ kinase
Recombinant human platelet-derived growth factor and transforming growth factor-β mediated contraction of human dermal fibroblast populated lattices is inhibited by Rho/GTPase inhibitor but does not require phosphatidylinositol-3′ kinase
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DOI：
10.1046/j.1524-475x.2002.10801.x
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发表时间：
2002-05-01
影响因子：
2.9
通讯作者：
Garner, WL
中科院分区：
文献类型：
--
作者：
Han, YP;Nien, YD;Garner, WL
基质重组和组织收缩是伤口愈合所必需的。然而，调节这些过程的细胞内信号在很大程度上是未知的。我们研究了细胞因子诱导的信号及其在成人真皮成纤维细胞填充的胶原网收缩中的潜在作用。结果表明，重组人血小板衍生生长因子-BB和转化生长因子-β单独刺激成纤维细胞填充的胶原网的收缩，而两种细胞因子的组合导致收缩增加。重组人血小板衍生生长因子-BB虽能促进胶原收缩，但不能刺激人真皮成纤维细胞中的磷脂醇-3‘-激酶。磷脂酰肌醇3‘激酶抑制剂Wortmannin对细胞因子介导的胶原收缩无影响。此外，这种磷脂酰肌醇3‘激酶的失败激活与细胞在胶原基质中时血小板衍生生长因子受体没有酪氨酸磷酸化是一致的。相反，在单层的真皮成纤维细胞中很容易检测到血小板衍生生长因子受体的酪氨酸磷酸化。我们还探讨了Rho/GTPase在细胞因子介导的成纤维细胞胶原网收缩中的潜在作用。艰难梭菌毒素B在皮摩尔浓度下可阻断重组人血小板衍生生长因子和转化生长因子-β诱导的收缩。此外，这种抑制与细胞在胶原中铺展的抑制有关，这表明细胞内肌动蛋白纤维的形成对于成纤维细胞填充的胶原晶格的细胞因子介导的收缩是必不可少的。综上所述，这些结果表明，Rho/GTPase信号而不是磷酸肌醇-3‘激酶参与了细胞因子介导的胶原蛋白晶格中成纤维细胞的收缩。这些发现提示了这些信号成分在人体伤口收缩过程中的潜在机制。
Matrix reorganization and tissue contraction are essential for wound healing. However, the intracellular signals that mediate these processes are largely unknown. We investigated cytokine-induced signaling and its potential role in contraction of adult human dermal fibroblast populated collagen lattices. The results document that recombinant human platelet-derived growth factor-BB and transforming growth factor-beta individually stimulate contraction of fibroblast populated collagen lattices, while a combination of the two cytokines leads to increased contraction. Although recombinant human platelet-derived growth factor-BB promoted collagen contraction, it failed to stimulate phosphaticylinositol-3' kinase in the human dermal fibroblasts. An inhibitor for phosphatidylinositol 3' kinase, wortmannin, had no effect on the cytokine-mediated collagen contraction. In addition, this failed activation of phosphatidylinositol 3' kinase is consistent with absence of tyrosine phosphorylation of the platelet-derived growth factor receptor when the cells are in a collagen matrix. In contrast, tyrosine phosphorylation of the platelet-derived growth factor receptor was readily detected in the dermal fibroblasts in monolayers. We also probed the potential role of Rho/GTPase in the cytokine-mediated contraction of fibroblast populated collagen lattices. Toxin B from Clostridium difficile at picomolar concentrations blocked both recombinant human platelet-derived growth factor and transforming growth factor-beta induced contraction. Further, this inhibition was correlated with the inhibition of cell spreading in collagen, which suggests the formation of actin fibers inside the cells is essential for cytokine-mediated contraction of fibroblast populated collagen lattices. Taken together, these results imply that Rho/GTPase signaling but not phosphoinositol-3' kinase is involved in the cytokine-mediated contraction of fibroblasts populated collagen lattice. These findings suggest a potential mechanism for these signaling components during human wound contraction.