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
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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DOI：
10.3727/096368909x12483162197321
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发表时间：
2009-01-01
影响因子：
3.3
通讯作者：
Gomez-Lechon, M. J.
中科院分区：
文献类型：
--
作者：
Bonora-Centelles, A.;Jover, R.;Gomez-Lechon, M. J.
脂肪组织中含有间充质干细胞（MSC），称为脂肪源性干细胞（ASC），能够分化为不同的细胞类型。我们的目的是诱导肝转分化的ASCs的细胞因子，生长因子和激素的几种组合顺序曝光。最有效的肝原性方案包括成纤维细胞生长因子（FGF）2和4和表皮生长因子（EGF）（步骤1），肝细胞生长因子（HGF）、FGF 2、FGF 4和烟酰胺（Nic）（步骤2），以及制瘤素M（OSM）、地塞米松（Dex）和胰岛素-转铁蛋白-硒（步骤3）。该方案激活转录因子[GATA 6、Hex、CCAAT/增强子结合蛋白α和β（CEBP α和β）、过氧化物酶体增殖物激活受体-γ、辅激活因子1 α（PGC 1 α）和肝细胞核因子4 α（HNF 4 α）]，其促进了特征性肝表型，如通过hMSC逐步肝转分化的新信息标记物所评估的[早期标记物：白蛋白（ALB）、α-2-巨球蛋白（α 2 M）、补体蛋白C3（C3）和硒蛋白PI（SEPPI）晚期标志物：细胞色素P450 3A 4（CYP 3A 4）、载脂蛋白E（APOE）、酰基辅酶A合成酶长链家族成员1（ACSL 1）和血管紧张素II受体1型（AGTR 1）]。通过Thy 1和DNA结合抑制因子3（Inhibitor of DNA binding 3，Id 3）表达的缺失检测脂肪成体干细胞表型的缺失。磷酸烯醇式丙酮酸羧激酶（PEPCK）、载脂蛋白C3（APOC III）、醛缩酶B（ALDO B）和细胞色素P450 1A 2（CYP 1A 2）的再表达通过HNF 4 α的重组腺病毒转导实现，最后还通过分析特异性生化标志物评估肝脏功能。我们的结论是，ASCs可以代表一种替代工具，在临床治疗肝功能障碍和再生医学。
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.