Formation of normal desmin intermediate filaments in mouse hepatic stellate cells requires vimentin
Formation of normal desmin intermediate filaments in mouse hepatic stellate cells requires vimentin
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DOI：
10.1053/jhep.2001.21045
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发表时间：
2001-01-01
期刊：
影响因子：
13.5
通讯作者：
Pekny, M
中科院分区：
文献类型：
--
作者：
Geerts, A;Eliasson, C;Pekny, M
肝星状细胞转分化为肌纤维母细胞样细胞的标志之一是结蛋白合成增加和含结蛋白的中间丝（IF）的形成。这些结蛋白富集的肌成纤维细胞样细胞是慢性疾病肝脏纤维化细胞外基质的主要来源。肌成纤维细胞样细胞也参与血窦的收缩，这导致肝内压升高和门静脉高压。为了解决在静止和转分化的星状细胞中形成含结蛋白的IF的要求，我们使用了胶质细胞酸性蛋白（GFAP）和/或波形蛋白缺陷的小鼠，这是星状细胞中存在的额外IF蛋白。在这项研究中，我们表明，结蛋白不能形成全长束的IF在没有GFAP和波形蛋白。静止和转分化的GFAP（-/-）Vim（-/-）星状细胞缺乏正常的IFs束。相反，他们只表现出残留的IF束限制皮质下的细胞质，虽然这些细胞含有相同的结蛋白mRNA和蛋白质水平的野生型细胞。单独的波形蛋白的缺乏限制了含结蛋白的IF束的形成到核周区域，而静止星状细胞的远端突起和肌成纤维细胞样细胞的皮质下区仍然没有含结蛋白的IF束。单独缺乏GFAP不会干扰含结蛋白的IF的形成。因此，为了在星状细胞中形成正常的IF，结蛋白需要与波形蛋白伴侣化。此外，这些小鼠模型将被证明是有助于解决的作用，IFs在星状细胞转分化的过程中。
Increased desmin synthesis and formation of desmin-containing intermediate filaments (IFs) is one of the hallmarks of transdifferentiation of hepatic stellate cells into myofibroblast-like cells. These desmin-enriched myofibroblast-like cells are the major sources of fibrotic extracellular matrix in chronically diseased liver. Myofibroblast-like cells are also involved in the contraction of sinusoids, which leads to increased intrahepatic pressure and portal hypertension. To address the requirements for the formation of desmin-containing IFs both in quiescent and in transdifferentiated stellate cells, we used mice deficient for glial fibrillary acidic protein (GFAP) and/or vimentin, which are additional IF proteins present in stellate cells. In this study, we show that desmin cannot form full-length bundles of IFs in the absence of both GFAP and vimentin. Quiescent and transdifferentiated GFAP(-/-)vim(-/-) stellate cells are devoid of normal bundles of IFs. Instead, they exhibit only residual IF bundles restricted to subcortical cytoplasm, although these cells contain equal desmin mRNA and protein levels as wild-type cells. The absence of vimentin alone restricts formation of desmin-containing IF bundles to the perinuclear region, while both the distal processes in quiescent stellate cells and the subcortical zone in myofibroblast-like cells remain free of desmin-containing IF bundles. The absence of GFAP alone does not interfere with the formation of desmin-containing IFs. Thus, to form normal IFs in stellate cells, desmin is required to partnerize with vimentin. In addition, these mouse models will prove to be instrumental in addressing the role of IFs in the process of stellate cell transdifferentiation.