The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis
The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis
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DOI：
10.1097/01.lab.0000054178.01162.e4
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发表时间：
2003-02-01
影响因子：
5
通讯作者：
Housset, C
中科院分区：
文献类型：
--
作者：
Kinnman, N;Francoz, C;Housset, C
肌成纤维细胞的起源以及肝纤维化过程中促进其分化的因素仍不清楚。在胆道型纤维形成过程中，血小板源性生长因子（PDGF）介导肝星状细胞（HSC）向胆管的增殖和化学吸引，同时也发生与HSC不同的胆周细胞的肌成纤维细胞转化。我们在此检查了这些胆管周围肌成纤维细胞与肌成纤维细胞 HSC 的表型，并测试了它们的分化是否受到 PDGF 的影响。通过大鼠胆总管结扎诱导胆道型肝纤维化。 48小时后，门管中的导管周围纤维化与平滑肌α-肌动蛋白免疫反应性肌成纤维细胞共存，其中大多数结蛋白阴性。同时，在血窦中，在大量平滑肌α-肌动蛋白阴性的HSC中诱导结蛋白免疫反应性。从分离的胆管段扩增胆管周围肌成纤维细胞培养物，并与肌成纤维细胞 HSC 进行比较。从胆管段长出的胆管周围肌成纤维细胞表达平滑肌 α-肌动蛋白、α1 (1) 胶原 mRNA 和 PDGF 受体 β 亚基。在培养的胆周肌成纤维细胞中结蛋白免疫反应性逐渐降低，与所有肌成纤维细胞 HSC 的持续标记形成对比。此外，胆管周围肌成纤维细胞中的IL-6表达比肌成纤维细胞HSC低100倍，而两种细胞类型中补体激活蛋白酶13100的表达几乎没有差异，并且细胞外基质成分fibulin 2的表达相似。培养的胆管周围肌成纤维细胞中平滑肌α-肌动蛋白的表达受到PDGF-BB的刺激，并被PDGF受体酪氨酸激酶抑制剂STI571抑制，而在胆管结扎的大鼠中，给予STI571导致胆管周围平滑肌α-肌动蛋白免疫反应性显着降低，并在较小程度上减少胆管周围纤维化。这些结果表明，不同于HSC的胆周细胞经历PDGF介导的转化为肌成纤维细胞，其表达IL-6的水平低于肌成纤维细胞HSC，并有助于胆管型肝纤维化的最初形成。
The origin of myofibroblasts and the factors promoting their differentiation during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the proliferation and chemoattraction of hepatic stellate cells (HSC) toward bile ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic conversion of peribiliary cells distinct from HSC also occurs. We herein examined the phenotype of these peribiliary myofibroblasts as compared with myofibroblastic HSC and tested whether their differentiation was affected by PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in rats. After 48 hours, periductular fibrosis in portal tracts colocalized with smooth muscle alpha-actin-immunoreactive myofibroblasts, the majority of which were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was induced in a large number of HSC, which were smooth muscle alpha-actin negative. Cultures of peribiliary myofibroblasts were expanded from isolated bile duct segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts outgrowing from bile duct segments expressed smooth muscle alpha-actin, alpha1 (1) collagen mRNA, and PDGF receptor-beta subunit. Desmin immunoreactivity gradually decreased in cultured peribiliary myofibroblasts, contrasting with constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC, whereas the expression of the complement-activating protease 13100 in both cell types showed little difference and that of the extracellular matrix component fibulin 2 was similar. The expression of smooth muscle a-actin protein in cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct-ligated rats, the administration of STI571 caused a significant decrease in peribiliary smooth muscle a-actin immunoreactivity, and to a lesser extent, a decrease in peribiliary fibrosis. These results indicate that peribiliary cells distinct from HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at lower levels than myofibroblastic HSC and contribute to the initial formation of biliary-type liver fibrosis.