Activation of valvular interstitial cells is mediated by transforming growth factor-β1 interactions with matrix molecules
Activation of valvular interstitial cells is mediated by transforming growth factor-β1 interactions with matrix molecules
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DOI：
10.1016/j.matbio.2005.06.007
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发表时间：
2005-09-01
期刊：
影响因子：
6.9
通讯作者：
Anseth, KS
中科院分区：
文献类型：
--
作者：
Cushing, MC;Liao, JT;Anseth, KS
用于构建活体心脏瓣膜替代物的组织工程策略受到合适支架材料缺乏的限制，这些材料既要保证细胞活力，又要对功能性组织的生长有积极作用。细胞外基质的成分能够定位和修饰生长因子信号，从而为细胞表型的定向提供指导性刺激。纤维连接蛋白、胶原蛋白1和肝素被作为亲和基质进行研究，用于隔离和呈递可溶性信号分子，以控制瓣膜间质细胞（VICs）向肌成纤维细胞分化。VIC分化通常以含有α -平滑肌肌动蛋白（α -SMA）的应力纤维表达为特征，转化生长因子 -β1（TGF -β1）是这种转变的核心介质。已知纤维连接蛋白和肝素都具有与TGF -β1结合的相互作用，发现它们都能增加VIC的α -SMA表达（分别是对照组表达量的120%和258%），而在胶原蛋白I修饰的基质上培养的VICs的α -SMA表达降低（为对照组的66%）。在所有测试浓度（50到400μg/ml）下，肝素处理都显著刺激了VIC产生TGF -β1。发现肝素修饰的基质通过增加血清蛋白（特别是TGF -β1）的吸附来改变细胞形态。总之，肝素通过从头产生TGF -β1以及将其定位在细胞周环境中，产生了α -SMA阳性的肌成纤维细胞。在纤维连接蛋白修饰的基质中添加肝素导致VIC的α -SMA表达协同增加，这是由纤维连接蛋白、肝素和细胞产生的TGF -β1相互结合产生的。对控制VIC活化的可溶性和不可溶性分子进行表征，对于为组织工程应用开发定制的3D培养环境将是重要的。（c）2005年由爱思唯尔B.V.出版社/国际基质生物学学会出版
Strategies for the tissue-engineering of living cardiac valve replacements are limited by a lack of appropriate scaffold materials that both permit cell viability and actively contribute to the growth of functional tissues. Components of the extracellular matrix can localize and modify growth factor signals, and by doing so impart instructional stimuli for direction of cell phenotype. Fibronectin, collagen 1, and heparin were explored as affinity matrices for sequestering and presenting soluble signaling molecules to control differentiation of valvular interstitial cells (VICs) to myofibroblasts. VIC differentiation is commonly characterized by expression of stress fibers containing alpha smooth muscle actin (alpha-SMA), and transforming growth factor-beta 1 (TGF-beta 1) is a central mediator of this transition. Both fibronectin and heparin, which are known to possess TGF-beta 1 binding interactions, were found to increase VIC a-SMA expression (120% and 258% of expression in controls), while VICs cultured on collagen I-modified substrates had diminished a-SMA expression (66% of control). Heparin treatment significantly stimulated VIC production of TGF-beta 1 at all concentrations tested (50 to 400 mu g/ml). Heparin-modified substrates were found to alter cell morphology through increased adsorption of serum proteins, specifically TGF-beta 1. In sum, heparin produced alpha-SMA-positive myofibroblasts through both the de novo production of TGF-beta 1, and its localization in the pericellular environment. The addition of heparin to fibronectin-modified substrates led to a synergistic increase in VIC alpha-SMA expression, produced by the reciprocal binding of fibronectin, heparin, cell-produced TGF-beta 1. The characterization of molecules, both soluble and insoluble, that control VIC activation will be important for the development of tailored 3D culture environments for tissue-engineering applications. (c) 2005 Published by Elsevier B.V./International Society of Matrix Biology.