Liver fibrosis: Insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors
Liver fibrosis: Insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors
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DOI：
10.1053/gast.2003.50012
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发表时间：
2003-01-01
期刊：
影响因子：
29.4
通讯作者：
Kalluri, R
中科院分区：
文献类型：
--
作者：
Yang, CQ;Zeisberg, M;Kalluri, R
背景和目标：在肝纤维化中，Disse微环境空间内发生改变，并促进慢性肝病的进一步进展。在纤维化过程中，存在于Disse间隙内的正常基底膜样基质转化为富含纤维形成胶原的基质。研究方法：为了进一步了解肝纤维化的发病机制，我们修改了体外Boyden室系统，以部分模拟健康和疾病期间肝星状细胞（HSC）的体内条件。结果如下：用血小板衍生生长因子（PDGF）-BB、转化生长因子（TGF）-β 1和/或上皮生长因子（EGF）刺激HSC导致其迁移能力增加和基质金属蛋白酶（MMP）-2活性上调。PDGF-BB诱导的迁移与增殖增加相关，而TGF-β 1/EGF诱导的迁移与增殖无关。COL-3是一种MMP-2和MMP-9抑制剂，可抑制PDGF-BB或TGF-β 1直接激活诱导的HSC迁移，但对无直接接触的趋化刺激诱导的HSC迁移无影响，表明PDGF-BB或TGF-β 1诱导的迁移有两种不同的MMP依赖性和MMP非依赖性机制。此外，我们表明，I型胶原蛋白本身诱导的HSC的迁移。由PDGF-BB、TGF-β 1和胶原I诱导的迁移可被α（1）-和/或α（2）-整联蛋白阻断抗体抑制，共同表明HSC的整联蛋白依赖性MMP-2介导的迁移。结论：基底膜基质的完整性、组成和细胞-基质相互作用在锚定HSC和防止它们在Disse空间内以及潜在地在肝脏中的其他地方扩散中起重要作用。此外，我们的数据提供了强有力的证据，MMPs在调控HSC迁移。
Background & Aims: In liver fibrosis, alterations within the space of Disse microenvironment occur and facilitate further progression of chronic liver disease. The normal basement membrane-like matrix present within the space of Disse converts to a matrix rich in fibril-forming collagens during fibrosis. Methods: To further understand the pathogenesis of liver fibrosis, we modified an in vitro Boyden chamber system to partially mimic in vivo conditions of hepatic stellate cells (HSCs) during health and disease. Results: Stimulation of HSCs with platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta1, and/or epithelial growth factor (EGF) resulted in an increase in their migratory capacity and up-regulated matrix metalloproteinase (MMP)-2 activity. Migration induced by PDGF-BB was associated with increased proliferation, whereas TGF-beta1/EGF-induced migration was proliferation independent. COL-3, an inhibitor of MMP-2 and MMP-9, inhibited migration of HSCs induced by direct activation of PDGF-BB or TGF-beta1 but had no effect on migration induced by chemotactic stimuli without direct contact, suggesting 2 distinct MMP-dependent and MMP-independent mechanisms of PDGF-BB- or TGF-beta1-induced migration. Additionally, we show that type I collagen by itself induced migration of HSCs. Migration induced by PDGF-BB, TGF-beta1, and collagen I could be inhibited by alpha(1)- and/or alpha(2)-integrin blocking antibodies, collectively suggesting an integrin-dependent, MMP-2-mediated migration of HSCs. Conclusions: Basement membrane matrix integrity, composition, and cell-matrix interactions play an important role in anchoring HSCs and preventing them from spreading within the space of Disse and potentially elsewhere in the liver. Additionally, our data provide strong evidence for MMPs in regulation of HSCs migration.