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
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, an...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2009-12-01
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| Series: | Cell Transplantation |
| Online Access: | https://doi.org/10.3727/096368909X12483162197321 |
| _version_ | 1818191614319788032 |
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| author | A. Bonora-Centelles R. Jover V. Mirabet A. Lahoz F. Carbonell J. V. Castell M. J. Gómez-Lechón |
| author_facet | A. Bonora-Centelles R. Jover V. Mirabet A. Lahoz F. Carbonell J. V. Castell M. J. Gómez-Lechón |
| author_sort | A. Bonora-Centelles |
| collection | DOAJ |
| description | 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 step-by-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. |
| first_indexed | 2024-12-12T00:17:24Z |
| format | Article |
| id | doaj.art-6c9aa10c5b9c4d599f51a6b2190e9656 |
| institution | Directory Open Access Journal |
| issn | 0963-6897 1555-3892 |
| language | English |
| last_indexed | 2024-12-12T00:17:24Z |
| publishDate | 2009-12-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cell Transplantation |
| spelling | doaj.art-6c9aa10c5b9c4d599f51a6b2190e96562022-12-22T00:44:50ZengSAGE PublishingCell Transplantation0963-68971555-38922009-12-011810.3727/096368909X12483162197321Sequential Hepatogenic Transdifferentiation of Adipose Tissue-Derived Stem Cells: Relevance of Different Extracellular Signaling Molecules, Transcription Factors Involved, and Expression of New Key Marker GenesA. Bonora-Centelles0R. Jover1V. Mirabet2A. Lahoz3F. Carbonell4J. V. Castell5M. J. Gómez-Lechón6CIBERehd, FIS, SpainDepartamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, SpainCentro de Transfusión de la Comunidad Valenciana, Generalidad Valenciana, Valencia, SpainCIBERehd, FIS, SpainCentro de Transfusión de la Comunidad Valenciana, Generalidad Valenciana, Valencia, SpainDepartamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Valencia, SpainCIBERehd, FIS, SpainAdipose 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 step-by-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.https://doi.org/10.3727/096368909X12483162197321 |
| spellingShingle | A. Bonora-Centelles R. Jover V. Mirabet A. Lahoz F. Carbonell J. V. Castell M. J. Gómez-Lechón 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 Cell Transplantation |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://doi.org/10.3727/096368909X12483162197321 |
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