Regulation of Hepatic Genes and Liver Transcription Factors in Rat Hepatocytes by Extracellular Matrix

Nagaki, Masahito; Shidoji, Yoshihiro; Yamada, Yoko; Sugiyama, Akiko; Tanaka, Masatsugu; Akaike, Toshihiro; Ohnishi, Hiroe; Moriwaki, Hisataka; Muto, Yoshihiro

doi:10.1006/bbrc.1995.1624

Cited by 70 publications

(56 citation statements)

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“…29 The correlated expression of these two liver-specific transcription factors has been observed in the well-differentiated status of primary rat hepatocytes cultured on Matrigel. 32 In our three-dimensional culture model, hepatocytic spheroids transformed into ductular structures composed of small cuboidal cells, which were morphologically similar to bile ductules. However, after redifferentiation on Matrigel in the presence of IL-6+Dex or OSM+Dex, they recovered the original morphology of mature hepatocytes with accumulated glycogen in their cytoplasm.…”

Section: Discussionmentioning

confidence: 88%

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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We previously demonstrated that mature rat hepatocytes transdifferentiate to bile ductular cells when cultured in a three-dimensional collagen-rich matrix. Here, we show that the phenotype of transdifferentiated hepatocytes can be reversed by modulating culture conditions. Spheroidal aggregates of hepatocytes were cultured within a collagen gel matrix in the presence of serum and tumor necrosis factor-α. Spheroids transformed into ductular structures composed of small cuboidal cells, lost the expression of hepatocytic markers, while aberrantly expressed bile ductular markers. The transdifferentiated cells were then retrieved from the gels, plated on Matrigel-coated surfaces, and cultured in serum-free media. Cells spontaneously formed spheroidal aggregates and recovered hepatocytic phenotype. While Dexamethasone (Dex), which suppressed the phosphorylation of ERK and Jun N-terminal kinase, facilitated the recovery, the combination with interleukin-6 or oncostatin M resulted in the recovery of HNF-4α protein expression and the typical hepatocytic morphology and a decrease in the expression of bile ductular markers. A cDNA microarray analysis revealed that the hepatocyte-specific mRNA expression profile was recovered in these cells. Our results demonstrate that hepatocytes are able to recover their phenotypes following bile ductular transdifferentiation, suggesting that hepatocytic and bile ductular phenotypes may be mutually reversible.4

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Section: Discussionmentioning

confidence: 88%

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Sone

Nishikawa

Nagahama

et al. 2012

The American Journal of Pathology

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“…Dedifferentiated hepatoma variants (7) and intertypic rat hepatoma-human fibroblast hybrids that show extinction of liver-specific gene expression (8) are deficient for the expression only of HNF-4 and HNF-1, and re-expression of liverspecific genes in revertants correlates with the re-expression of both liver-enriched transcriptional factors. We have demonstrated that when hepatocytes are plated onto a model basement membrane, such as that derived from the EngelbrethHolm-Swarm (EHS) gel, they retain their normal cell polarity and liver-specific gene expression by up-regulation of hepatic transcription factors, namely by HNF-1 and HNF-4 expression (9). These results strongly imply that among the liver-enriched transcription factors, HNF-1 and HNF-4, play a crucial role in the determination and maintenance of hepatocyte-specific differentiation status.…”

mentioning

confidence: 99%

Analysis of Gene Expression Profile Induced by Hepatocyte Nuclear Factor 4α in Hepatoma Cells Using an Oligonucleotide Microarray

Naiki¹,

Nagaki²,

Shidoji³

et al. 2002

Journal of Biological Chemistry

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Hepatocyte nuclear factor 4␣ (HNF-4␣), a liver-specific transcription factor, plays a significant role in many liver-specific functions, including lipid, glucose, drug, and ammonia metabolism, and also in embryonal liver development. However, its functions and regulation are not yet clearly understood. In this study, we constructed an adenovirus vector carrying rat HNF-4␣ cDNA and transfected the adenovirus to human hepatoma cells, HuH-7, to enforce expression of the exogenous HNF-4␣ gene. We analyzed HNF-4␣-induced genes using cDNA microarray technology, which included over 9000 genes. As a result, 62 genes showed a greater than 2.0-fold change in expression level after the viral transfection. Fifty-six genes were consistently induced by HNF-4␣ overexpression, and six genes were repressed. To assess HNF-4␣ function, we attempted to classify the genes, which had been classified by their encoding protein functions in a previous report. We could classify 45 genes. The rest of the HNF-4␣-sensitive genes were unclassified (4 genes) or not identified (13 genes). Among the classified genes, almost half of the induced genes (26 of 40) were related to metabolism genes and particularly to lipid metabolism-related genes. This cDNA microarray analysis showed that HNF-4␣ is one of the central liver metabolism regulators.Differentiation of mammalian cells is associated with changes in gene expression that are primarily controlled at the level of transcription. Tissue-specific gene transcription is regulated based on the recognition of cis-elements of the target genes, accomplished by transcription factors that have restricted tissue distributions. Transcription factors that control embryonic cell differentiation are often required to maintain and regulate gene expression in the adult cell. Liver-specific gene expression is governed by the combinatorial action of a small set of liver-enriched transcription factors as follows: hepatocyte nuclear factor-1 (HNF-1), 1 a member of the POU homeobox gene family (1); the leucine zipper dimerization family, including CCAAT/enhancer-binding protein (C/EBP) ␣ (2); Dsite-binding protein (3); and C/EBP␤/liver activator protein (4); HNF-4, a member of the steroid hormone receptor superfamily (5); and HNF-3, the DNA binding domain, which is very similar to that of the Drosophila homeotic forkhead gene (6). Although many of these factors have been shown to be important components of the differentiation process that culminates in the fully functional liver, the manner in which different members of these families participate in the determination of cell phenotypes is poorly understood. Dedifferentiated hepatoma variants (7) and intertypic rat hepatoma-human fibroblast hybrids that show extinction of liver-specific gene expression (8) are deficient for the expression only of HNF-4 and HNF-1, and re-expression of liverspecific genes in revertants correlates with the re-expression of both liver-enriched transcriptional factors. We have demonstrated that when hepatocytes are plated onto a model ba...

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“…24,25 The receptors may seize the galactose ends on the side chains of the glycopolymer and may tend to ingest them through cellular endocytosis. However, the hydrophobic interaction between the polymer backbone and PS can attach PVLA to the surface of nontreated cell culture dishes.…”

Section: Discussionmentioning

confidence: 99%

A hybrid substratum for primary hepatocyte culture that enhances hepatic functionality with low serum dependency

Meng¹,

Tao²,

Qiu³

et al. 2015

IJN

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Cell culture systems have proven to be crucial for the in vitro maintenance of primary hepatocytes and the preservation of hepatic functional expression at a high level. A poly-(N-p-vinylbenzyl-4-O-β-D-galactopyranosyl-D-gluconamide) matrix can recognize cells and promote liver function in a spheroid structure because of a specific galactose–asialoglycoprotein receptor interaction. Meanwhile, a fusion protein, E-cadherin-Fc, when incubated with various cells, has shown an enhancing effect on cellular viability and metabolism. Therefore, a hybrid substratum was developed for biomedical applications by using both of these materials to combine their advantages for primary hepatocyte cultures. The isolated cells showed a monolayer aggregate morphology on the coimmobilized surface and displayed higher functional expression than cells on traditional matrices. Furthermore, the hybrid system, in which the highest levels of cell adhesion and hepatocellular metabolism were achieved with the addition of 1% fetal bovine serum, showed a lower serum dependency than the collagen/gelatin-coated surface. Accordingly, this substrate may attenuate the negative effects of serum and further contribute to establishing a defined culture system for primary hepatocytes.

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Regulation of Hepatic Genes and Liver Transcription Factors in Rat Hepatocytes by Extracellular Matrix

Cited by 70 publications

References 0 publications

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Analysis of Gene Expression Profile Induced by Hepatocyte Nuclear Factor 4α in Hepatoma Cells Using an Oligonucleotide Microarray

A hybrid substratum for primary hepatocyte culture that enhances hepatic functionality with low serum dependency

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Regulation of Hepatic Genes and Liver Transcription Factors in Rat Hepatocytes by Extracellular Matrix

Cited by 70 publications

References 0 publications

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Recovery of Mature Hepatocytic Phenotype following Bile Ductular Transdifferentiation of Rat Hepatocytes in Vitro

Analysis of Gene Expression Profile Induced by Hepatocyte Nuclear Factor 4α in Hepatoma Cells Using an Oligonucleotide Microarray

A hybrid substratum for primary hepatocyte culture that enhances hepatic functionality with&nbsp;low serum dependency

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A hybrid substratum for primary hepatocyte culture that enhances hepatic functionality with low serum dependency