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首页> 外文期刊>Molecular biology of the cell >Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation
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Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation

机译：尿激酶受体裂解：成纤维细胞向成肌纤维细胞分化的关键一步。

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Fibroblasts migrate into and repopulate connective tissue wounds. At the wound edge, fibroblasts differentiate into myofibroblasts, and they promote wound closure. Regulated fibroblast-to-myofibroblast differentiation is critical for regenerative healing. Previous studies have focused on the role in fibroblasts of urokinase plasmingen activator/urokinase plasmingen activator receptor (uPA/uPAR), an extracellular protease system that promotes matrix remodeling, growth factor activation, and cell migration. Whereas fibroblasts have substantial uPA activity and uPAR expression, we discovered that cultured myofibroblasts eventually lost cell surface uPA/uPAR. This led us to investigate the relevance of uPA/uPAR activity to myofibroblast differentiation. We found that fibroblasts expressed increased amounts of full-length cell surface uPAR (D1D2D3) compared with myofibroblasts, which had reduced expression of D1D2D3 but increased expression of the truncated form of uPAR (D2D3) on their cell surface. Retaining full-length uPAR was found to be essential for regulating myofibroblast differentiation, because 1) protease inhibitors that prevented uPAR cleavage also prevented myofibroblast differentiation, and 2) overexpression of cDNA for a noncleavable form of uPAR inhibited myofibroblast differentiation. These data support a novel hypothesis that maintaining full-length uPAR on the cell surface regulates the fibroblast to myofibroblast transition and that down-regulation of uPAR is necessary for myofibroblast differentiation.
机译：成纤维细胞迁移进入结缔组织伤口并在其中繁殖。在伤口边缘，成纤维细胞分化为成肌纤维细胞，它们促进伤口闭合。调节的成纤维细胞向成肌纤维细胞分化对于再生愈合至关重要。先前的研究集中在尿激酶纤溶酶激活剂/尿激酶纤溶酶激活剂受体（uPA / uPAR）在成纤维细胞中的作用，这是一种促进基质重构，生长因子活化和细胞迁移的细胞外蛋白酶系统。鉴于成纤维细胞具有实质性的uPA活性和uPAR表达，我们发现培养的成纤维细胞最终失去了细胞表面uPA / uPAR。这促使我们研究uPA / uPAR活性与成肌纤维细胞分化的相关性。我们发现，与成肌纤维细胞相比，成纤维细胞表达的全长细胞表面uPAR（D1D2D3）数量增加，肌成纤维细胞表达的D1D2D3减少，但截短形式的uPAR（D2D3）的表达增加。发现保留全长uPAR对于调节成肌纤维细胞分化是必不可少的，因为1）阻止uPAR裂解的蛋白酶抑制剂也阻止了肌纤维母细胞分化，以及2）不可裂解形式的uPAR的cDNA过表达抑制了肌纤维母细胞分化。这些数据支持了一种新颖的假设，即在细胞表面上维持全长uPAR会调节成纤维细胞向成肌纤维细胞的转化，而uPAR的下调对于成肌纤维细胞的分化是必需的。

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