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

被引:31
作者
Bonora-Centelles, A. [1 ,2 ,3 ]
Jover, R. [1 ,3 ,4 ]
Mirabet, V. [5 ]
Lahoz, A. [1 ,3 ]
Carbonell, F. [5 ]
Castell, J. V. [1 ,3 ,4 ]
Gomez-Lechon, M. J. [1 ,2 ,3 ]
机构
[1] Hosp La Fe, Ctr Invest, Unidad Hepatol Expt, E-46009 Valencia, Spain
[2] Hosp La Fe, Unidad Terapia Celular Hepat, E-46009 Valencia, Spain
[3] CIBERehd, Fis, Spain
[4] Univ Valencia, Fac Med, Dept Bioquim & Biol Mol, Valencia, Spain
[5] Ctr Transfus Comunidad Valenciana, Valencia, Spain
关键词
Adipose tissue; Mesenchymal stem cell; Hepatocyte differentiation; Transcription factors; MESENCHYMAL PROGENITOR CELLS; ENHANCER BINDING-PROTEIN; HUMAN BONE-MARROW; IN-VITRO; LIVER DEVELOPMENT; GROWTH-FACTORS; ONCOSTATIN-M; HUMAN HEPATOCYTES; STROMAL CELLS; HEPATIC DIFFERENTIATION;
D O I
10.3727/096368909X12483162197321
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Adipose tissue contains a mesenchymal stein cell (MSC) population Known as adipose-derived stein 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 alpha and beta (CEBP alpha and beta), peroxisome proliferator-activated receptor-gamma, coactivator 1 alpha (PGC1 alpha), and hepatocyte nuclear factor 4 alpha (HNF4 alpha)], 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), alpha-2-macroglobuline (alpha 2M), complement protein C3 (C3), and selenoprotein PI (SEPPI) 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 stein 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 HNF4 alpha 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.
引用
收藏
页码:1319 / 1340
页数:22
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