Characterization and Functional Analyses of Hepatic Mesothelial Cells in Mouse Liver Development
Characterization and Functional Analyses of Hepatic Mesothelial Cells in Mouse Liver Development
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DOI：
10.1053/j.gastro.2009.12.059
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发表时间：
2010-04-01
期刊：
影响因子：
29.4
通讯作者：
Miyajima, Atsushi
中科院分区：
文献类型：
--
作者：
Onitsuka, Izumi;Tanaka, Minoru;Miyajima, Atsushi
背景与目的：在肝脏发育开始时，心脏中胚层、横隔间充质和内皮细胞参与成肝细胞的特化和/或增殖。然而，在此初始阶段之后，尚不清楚哪些细胞支持肝细胞的增殖和分化。在这里，我们的特点是小鼠肝间皮细胞（MC）的性质，并调查其在器官发生中的作用。方法：使用抗足糖萼蛋白样蛋白1（PCLP 1）和抗间皮素抗体，我们通过免疫组织化学，流式细胞术和基因表达分析表征了肝脏发育过程中的MCs。通过体外培养和分析Wilms' tumor 1 homologue（WT 1）基因敲除小鼠，研究MC在肝发生中的可能作用。结果：PCLP 1在未成熟的MC中高度表达，覆盖在脑叶表面。MCs中PCLP 1的表达沿着发育而下调，而间皮素的表达上调，表明这些分子区分MCs的发育阶段。MCs的增殖能力在胎儿期较高，出生后下降。胎MCs表达多种生长因子，并强烈增强体外胎肝细胞的扩增，而分化的MCs表现出较少的生长因子表达，分化的MCs未能增强体外肝细胞增殖。在WT 1缺陷的胚胎中，由于MC缺陷，肝细胞增殖受损。结论：间皮细胞不仅是覆盖在薄壁组织上的惰性保护膜，而且在发育过程中动态地改变其特性，通过促进薄壁组织细胞的扩张在器官发生中起着积极的作用。
BACKGROUND & AIMS: At the onset of liver development, cardiac mesoderm, septum transversum mesenchyme, and endothelial cells are involved in the specification and/or proliferation of hepatoblasts. After this initial stage, however, it is unclear which cells support the proliferation and differentiation of hepatocytes. Here we characterized the nature of mouse hepatic mesothelial cells (MCs) and investigated their role in organogenesis. METHODS: Using anti-podocalyxin-like protein 1 (PCLP1) and anti-mesothelin antibodies, we characterized MCs during liver development by immunohistochemistry, flow cytometry, and gene expression analysis. The possible role of MCs in hepatogenesis was investigated by in vitro culture and analysis of Wilms' tumor 1 homologue (WT1) knockout mice. RESULTS: PCLP1 was highly expressed in immature MCs, covering the surface of lobes. PCLP1 expression in MCs was down-regulated along with development, whereas mesothelin expression was up-regulated, indicating that these molecules distinguished developmental stages of MCs. The proliferation potential of MCs was high in the fetus and declined after birth. Fetal MCs expressed various growth factors and strongly enhanced the expansion of fetal hepatocytes in vitro, whereas differentiated MCs exhibited less growth factor expression, and differentiated MCs failed to enhance hepatocyte proliferation in vitro. In WT1-deficient embryos, hepatocyte proliferation was impaired due to defective MCs. CONCLUSIONS: The mesothelium is not only an inert protective sheet covering the parenchyma but also changes its characteristics dynamically during development and plays an active role in organogenesis by promoting expansion of parenchymal cells.