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首页> 外文期刊>American Journal of Physiology >Hepatocyte nuclear factor-4a promotes differentiation of intestinal epithelial cells in a coculture system
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Hepatocyte nuclear factor-4a promotes differentiation of intestinal epithelial cells in a coculture system

机译：肝细胞核因子4a促进共培养系统中肠上皮细胞的分化

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First published November 21, 2007; doi:10.1152/ajpgi.00418.2007.-Normal cellular models able to efficiently recapitulate intestinal epithelial cell differentiation in culture are not yet available. The aim of this work was to establish and genetically characterize a mesenchymal-epithelial coculture system to identify transcriptional regulators involved in this process. The deposition of rat intestinal epithelial cells on human intestinal mesenchymal cells led to the formation of clustered structures that expanded shortly after seeding. These structures were composed of polarized epithelial cells with brush borders and cell junction complexes. A rat GeneChip statistical analysis performed at different time points during this process identified hepatocyte nuclear factor-4a (HNF-4a) and hepatocyte nuclear factor-la (HNF-la) as being induced coincidently with the apparition of polarized epithelial structures. Stable introduction of HNF-4a in undifferentiated epithelial cells alone led to the rapid induction of HNF-la and several intestinal-specific markers and metabolism-related genes for which mRNA was identified to be upregulated during epithelial differentiation. HNF-4a was capable to transactivate the calbindin 3 gene promoter, a process that was synergistically increased in the presence of HNF-la. When HNF-4a-expressing cells were plated on mesenchymal cells, an epithelial monolayer formed rapidly with the apparition of dome structures that are characteristics of vectorial ion transport. Forced expression of HNF-la alone did not result in dome structures formation. In sum, this novel coculture system functionally identified for the first time HNF-4a as an important modulator of intestinal epithelial differentiation and offers an innovative opportunity to investigate molecular mechanisms involved in this process.
机译：首次发布于2007年11月21日; doi：10.1152 / ajpgi.00418.2007.-尚无能够在培养中有效概括肠道上皮细胞分化的正常细胞模型。这项工作的目的是建立一种间充质上皮共培养系统并对其进行遗传鉴定，以鉴定参与该过程的转录调节因子。大鼠肠上皮细胞在人肠间充质细胞上的沉积导致形成簇状结构，该结构在播种后不久即膨胀。这些结构由带有刷状边界和细胞连接复合物的极化上皮细胞组成。在此过程中的不同时间点进行的大鼠GeneChip统计分析确定，肝细胞核因子-4a（HNF-4a）和肝细胞核因子-1a（HNF-1a）与极化上皮结构的出现同时发生。单独在未分化的上皮细胞中稳定引入HNF-4a会导致HNF-1a的快速诱导，以及几个肠道特异性标记和代谢相关基因，其mRNA在上皮分化过程中被上调。 HNF-4a能够激活calbindin 3基因启动子，该过程在HNF-1α存在下协同增加。当将表达HNF-4a的细胞铺在间充质细胞上时，上皮单层迅速形成，其穹顶结构是矢量离子转运的特征。单独HNF-1α的强迫表达不会导致圆顶结构的形成。总之，这种新颖的共培养系统首次在功能上确定了HNF-4a是肠上皮分化的重要调节剂，并提供了一个创新的机会来研究参与这一过程的分子机制。

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