The expression of mesenchymal, neural and haematopoietic stem cell markers in adult hepatocytes proliferating in vitro

Koenig, Sarah; Krause, Petra; Drabent, Birgit; Schaeffner, I.; Christ, Bruno; Schwartz, Peter J.; Unthan-Fechner, Kirsten; Probst, Irmelin

doi:10.1016/j.jhep.2005.09.016

Cited by 33 publications

(35 citation statements)

References 32 publications

(45 reference statements)

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“…They may also regain a spectrum of progenitor markers from different germ layers [21]. It is possible that, during proliferation, hepatocytes gain the characteristics of liver progenitor cells and then differentiate into insulin-expressing cells.…”

Section: Resultsmentioning

confidence: 99%

In Vitro Transdifferentiation of Mature Hepatocytes into Insulin-Producing Cells

et al. 2006

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Abstract. Adenovirus-mediated gene transfer of pancreatic duodenal homeobox transcription factor PDX-1, especially its super-active version (PDX-1/VP16), induces the expression of pancreatic hormones in murine liver and reverses streptozotocin-induced hyperglycemia. Histological analyses suggest that hepatocytes are the major source of insulinproducing cells by PDX-1 gene transfer, although the conversion of cultured hepatocytes into insulin-producing cells remains to be elucidated. The present study was conducted to address this issue. Hepatocytes were isolated from adult rats. Then, PDX-1 or PDX-1/VP16 gene was introduced by using adenovirus vector. Two days later, the expression of insulin was detected at mRNA and protein levels. Transfection of PDX-1/VP16 was more efficient in converting hepatocytes to insulin-producing cells. Immunoreactivity of albumin was downregulated in transdifferentiated cells and some of them almost completely lost albumin expression. During the course of transdifferentiation, upregulation of mRNA for CK19 and α-fetoprotein was observed. When cultured in collagen-1 gel sandwich configuration, hepatocytes maintained their mature phenotype and did not proliferate. In this condition, transfer of PDX-1/VP16 also induced the expression of insulin. These results clearly indicate that hepatocytes possess a potential to transdifferentiate into insulinproducing cells in vitro.

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Section: Resultsmentioning

confidence: 99%

In Vitro Transdifferentiation of Mature Hepatocytes into Insulin-Producing Cells

et al. 2006

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“…More precisely, nestin has been proposed as a transient marker for potential hepatic progenitor cells derived from embryonic stem cells ). The expression of nestin in adult hepatocytes proliferating in culture whilst adopting precursor characteristics was also demonstrated lately (Koenig et al 2006). In the present study, nestin expression could be demonstrated in non-ductular progenitor cells from adult rat liver.…”

Section: Discussionmentioning

confidence: 99%

Zonal hierarchy of differentiation markers and nestin expression during oval cell mediated rat liver regeneration

Koenig

Probst

Becker

et al. 2006

Histochem Cell Biol

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Oval cells constitute a heterogeneous population of proliferating progenitors found in rat livers following carcinogenic treatment (2-acetylaminofluorene and 70% hepatectomy). The aim of this study was to investigate the cellular pattern of various differentiation and cell type markers in this model of liver regeneration. Immunophenotypic characterisation revealed at least two subtypes emerging from the portal field. First, a population of oval cells formed duct-like structures and expressed bile duct (CD49f) as well as hepatocytic markers (alpha-foetoprotein, CD26). Second, a population of non-ductular oval cells was detected between and distally from the ductules expressing the neural marker nestin and the haematopoietic marker Thy1. Following oval cell isolation, a subset of the nestin-positive cells was shown to co-express hepatocytic and epithelial markers (albumin, CD26, pancytokeratin) and could be clearly distinguished from anti-desmin reactive hepatic stellate cells. The gene expression profiles (RT-PCR) of isolated oval cells and oval cell liver tissue were found to be similar to foetal liver (ED14). The present results suggest that the two oval cell populations are organised in a zonal hierarchy with a marker gradient from the inner (displaying hepatocytic and biliary markers) to the outer zone (showing hepatocytic and extrahepatic progenitor markers) of the proliferating progeny clusters.

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“…Induction of hepatogenic transdifferentiation in vitro tional hepatocyte-like cells. A first approach was the use of a cocktail of exogenous factors (39,76), while other of ASC is a process that likely differs from embryonic liver development. Consequently, in vitro differentiation reports (3-5,80), including ours (87), used multistep transdifferentiation protocols by sequential exposure of protocols attempting to experimentally reproduce the embryonic development of the liver may not adequately ASC to growth factors, cytokines, and hormones, re- Transcriptional activation of liver genes by the forced expression of HNF4α ASCs was transduced with an adenoviral vector encoding the transcription factor HNF4α (Ad-HNF4α on day 7 of the hepatogenic protocol B and were collected on day 9.…”

Section: Gfp or Ad-pac (Insertless Adenoviral Vector) Neithermentioning

confidence: 99%

Sequential Hepatogenic Transdifferentiation of Adipose Tissue-Derived Stem Cells: Relevance of Different Extracellular Signaling Molecules, Transcription Factors Involved, and Expression of New Key Marker Genes

et al. 2009

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Adipose tissue contains a mesenchymal stem cell (MSC) population known as adipose-derived stem cells (ASCs) capable of differentiating into different cell types. Our aim was to induce hepatic transdifferentiation of ASCs by sequential exposure to several combinations of cytokines, growth factors, and hormones. The most efficient hepatogenic protocol includes fibroblastic growth factors (FGF) 2 and 4 and epidermal growth factor (EGF) (step 1), hepatocyte growth factor (HGF), FGF2, FGF4, and nicotinamide (Nic) (step 2), and oncostatin M (OSM), dexamethasone (Dex), and insulin-tranferrin-selenium (step 3). This protocol activated transcription factors [GATA6, Hex, CCAAT/enhancer binding protein α and β (CEBPα and β), peroxisome proliferator-activated receptor-γ, coactivator 1 α (PGC1α), and hepatocyte nuclear factor 4 α (HNF4α)], which promoted a characteristic hepatic phenotype, as assessed by new informative markers for the stepby-step hepatic transdifferentiation of hMSC [early markers: albumin (ALB), α-2-macroglobuline (α2M), complement protein C3 (C3), and selenoprotein P1 (SEPP1); late markers: cytochrome P450 3A4 (CYP3A4), apolipoprotein E (APOE), acyl-CoA synthetase long-chain family member 1 (ACSL1), and angiotensin II receptor, type 1 (AGTR1)]. The loss of adipose adult stem cell phenotype was detected by losing expression of Thy1 and inhibitor of DNA binding 3 (Id3). The reexpression of phosphoenolpyruvate corboxykinase (PEPCK), apolipoprotein C3 (APOCIII), aldolase B (ALDOB), and cytochrome P450 1A2 (CYP1A2) was achieved by transduction with a recombinant adenovirus for HNF4α and finally hepatic functionality was also assessed by analyzing specific biochemical markers. We conclude that ASCs could represent an alternative tool in clinical therapy for liver dysfunction and regenerative medicine.

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The expression of mesenchymal, neural and haematopoietic stem cell markers in adult hepatocytes proliferating in vitro

Cited by 33 publications

References 32 publications

In Vitro Transdifferentiation of Mature Hepatocytes into Insulin-Producing Cells

In Vitro Transdifferentiation of Mature Hepatocytes into Insulin-Producing Cells

Zonal hierarchy of differentiation markers and nestin expression during oval cell mediated rat liver regeneration

Sequential Hepatogenic Transdifferentiation of Adipose Tissue-Derived Stem Cells: Relevance of Different Extracellular Signaling Molecules, Transcription Factors Involved, and Expression of New Key Marker Genes

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