The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts
The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts
复制标题
DOI：
10.1074/jbc.m107666200
复制
发表时间：
2001-12-14
影响因子：
4.8
通讯作者：
Lau, LF
中科院分区：
文献类型：
--
作者：
Chen, CC;Mo, FE;Lau, LF
Cyr 61是CCN家族的肝素结合、细胞外基质相关蛋白，其还包括结缔组织生长因子、Nov、WISP-1、WISP-2和WISP-3。Cyr 61具有多种功能，包括诱导体内血管生成。纯化的Cyr 61介导细胞粘附并诱导粘附信号传导，刺激细胞迁移，增强细胞增殖，并促进成纤维细胞和内皮细胞中的细胞存活。在这项研究中，我们已经使用cDNA阵列杂交，以确定基因调控Cyr 61在原代人皮肤成纤维细胞。Cyr 61调节的基因分为几组，已知参与皮肤伤口愈合的重要过程，包括：1）血管生成和淋巴细胞生成（VEGF-A和VEGF-C）; 2）炎症（白细胞介素-1 β）; 3）细胞外基质重塑（MMP 1、MMP 3、TIMP 1、uPA和派-1）;和4）细胞-基质相互作用（Col 1 α 1、Col 1 α 2和整合素α（3）和α（5））。Cyr 61介导的基因表达需要Cyr 61的肝素结合活性、细胞从头转录和蛋白质合成，并且在很大程度上依赖于p42/p44 MAPK的激活。Cyr 61不仅在无血清培养基中调节基因表达，而且在各种基质蛋白或存在10%血清的情况下培养的成纤维细胞中也调节基因表达。Cyr 61的这些作用可以持续至少5天，与体内伤口愈合的时间过程一致。有趣的是，Cyr 61可以与转化生长因子-β 1相互作用，以拮抗、相加或协同的方式调节特定基因的表达。此外，我们发现Cyr 61基因在皮肤伤口修复过程中肉芽组织的真皮成纤维细胞中高度诱导。总之，这些结果表明Cyr 61在创伤后肉芽组织中诱导表达，并且Cyr 61激活皮肤成纤维细胞中伤口修复的遗传程序。我们提出了一种模型，其中Cyr 61整合其对内皮细胞，成纤维细胞和巨噬细胞的活性，以调节皮肤伤口愈合背景下的血管生成，炎症和基质重塑的过程。
Cyr61 is a heparin-binding, extracellular matrix-associated protein of the CCN family, which also includes connective tissue growth factor, Nov, WISP-1, WISP-2, and WISP-3. Cyr61 is capable of multiple functions, including induction of angiogenesis in vivo. Purified Cyr61 mediates cell adhesion and induces adhesive signaling, stimulates cell migration, enhances cell proliferation, and promotes cell survival in both fibroblasts and endothelial cells. In this study, we have used cDNA array hybridization to identify genes regulated by Cyr61 in primary human skin fibroblasts. The Cyr61-regulated genes fall into several groups known to participate in processes important for cutaneous wound healing, including: 1) angiogenesis and lymphogenesis (VEGF-A and VEGF-C); 2) inflammation (interleukin-1 beta); 3) extracellular matrix remodeling (MMP1, MMP3, TIMP1, uPA, and PAI-1); and 4) cell-matrix interactions (Col1 alpha1, Col1 alpha2, and integrins alpha (3) and alpha (5)). Cyr61-mediated gene expression requires heparin binding activity of Cyr61, cellular de novo transcription, and protein synthesis and is largely dependent on the activation of p42/p44 MAPKs. Cyr61 regulates gene expression not only in serum-free medium but also in fibroblasts cultured on various matrix proteins or in the presence of 10% serum. These effects of Cyr61 can be sustained for at least 5 days, consistent with the time course of wound healing in vivo. Interestingly, Cyr61 can interact with transforming growth factor-beta1 to regulate expression of specific genes in an antagonistic, additive, or synergistic manner. Furthermore, we show that the Cyr61 gene is highly induced in dermal fibroblasts of granulation tissue during cutaneous wound repair. Together, these results show that Cyr61 is inducibly expressed in granulation tissues after wounding and that Cyr61 activates a genetic program for wound repair in skin fibroblasts. We propose a model in which Cyr61 integrates its activities on endothelial cells, fibroblasts, and macrophages to regulate the processes of angiogenesis, inflammation, and matrix remodeling in the context of cutaneous wound healing.