TGFβ induced myofibroblast differentiation of rabbit keratocytes requires synergistic TGFβ, PDGF and integrin signaling
TGFβ induced myofibroblast differentiation of rabbit keratocytes requires synergistic TGFβ, PDGF and integrin signaling
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DOI：
10.1006/exer.2002.2066
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发表时间：
2002-12-01
影响因子：
3.4
通讯作者：
Cavanagh, HD
中科院分区：
文献类型：
--
作者：
Jester, JV;Huang, JY;Cavanagh, HD
越来越多的人认为，角膜肌成纤维细胞来源于相邻的基质角质细胞，这些细胞经历了从静止的角质细胞到活化的成纤维细胞再到肌成纤维细胞的有序表型转变。体内和体外研究都表明，这种转变部分依赖于转化生长因子β (tgfβ)。在许多成纤维细胞中，血小板衍生生长因子（PDGF）的自分泌可介导TGFP对其生长的上调。在本研究中，PDGF阻断抗体显著降低了80% (P < 0.025) TGFβ1刺激无血清培养兔角膜角质细胞的细胞周期进入。抗pdgf处理还显著降低tgf β1诱导的细胞内肌动蛋白丝重组、纤维连接蛋白纤维组装和局灶接触形成，并使肌成纤维细胞分化特征的α-平滑肌（α-SM）特异性肌动蛋白亚型的表达降低80%。尽管PDGF处理的静止角化细胞产生了活化的成纤维细胞类型，但PDGF刺激的角化细胞对TGFβ1表现出与静止角化细胞相同的时间肌成纤维细胞分化反应。此外，用含Arg-Gly-Asp的肽GRGDdSP阻断tgf - β1诱导的肌成纤维细胞分化3天，然后通过去除GRGDdSP允许肌成纤维细胞分化进展，这不会改变导致肌成纤维细胞分化的时间反应或酪氨酸磷酸化级联反应（2-72小时）。PDGF处理的角化细胞也不能逆转RGD阻断TGFβ1诱导的肌成纤维细胞分化。总的来说，这些累积的发现表明，兔角膜角质细胞的肌成纤维细胞分化需要包括TGFβ、PDGF和纤维连接蛋白受体在内的协同生长因子/整合素信号传导。此外，与原始角质细胞相比，pdgf刺激下的tgf - β1时间反应相似，这表明肌成纤维细胞分化不需要通过成纤维细胞表型过渡。(C) 2002 Elsevier Science Ltd.
There is a growing consensus that corneal myofibroblasts are derived from adjacent stromal keratocytes which undergo an orderly phenotypic transition from quiescent keratocyte to activated fibroblast to myofibroblast. Both in vivo and in vitro studies have shown this transition to be dependent, in part, on transforming growth factor beta (TGFbeta). In many fibroblastic cells autocrine production of platelet derived growth factor (PDGF) is known to mediate the growth up-regulation by TGFP. In this study, blocking antibodies to PDGF significantly reduced by 80 % (P < 0.025) the TGFβ1 stimulated cell cycle entry of serum-free cultured rabbit corneal keratocytes. AntiPDGF treatment also markedly reduced the TGFβ1-induced intracellular actin filament re-organization, fibronectin fibril assembly, and focal contact formation as well as reducing by 80 % the expression of α-smooth muscle (α-SM) specific isoform of actin characteristic of myofibroblast differentiation. Although PDGF treatment of quiescent keratocytes produced an activated, fibroblastic cell type, PDGF stimulated keratocytes exhibited the same temporal, myofibroblastic differentiation response to TGFβ1 as did quiescent keratocytes. Furthermore, blocking TGFβ1 induction of myofibroblast differentiation with the Arg-Gly-Asp containing peptide, GRGDdSP, for 3 days followed by allowing progression of myofibroblast differentiation by removing GRGDdSP did not change the temporal response or tyrosine phosphorylation cascade (2-72 hr) leading to myofibroblast differentiation. Nor did PDGF treatment of keratocytes reverse the RGD blockade of TGFβ1 induced myofibroblast differentiation. Overall these cumulative findings indicate that myofibroblast differentiation in the rabbit corneal keratocyte requires synergistic growth factor/integrin signaling involving TGFβ, PDGF, and the fibronectin receptor. Additionally, the similar TGFβ1 temporal response of PDGF-stimulated compared to naive keratocytes suggests that myofibroblast differentiation does not require transition through a fibroblast phenotype. (C) 2002 Elsevier Science Ltd.