Unidad de Hepatología Experimental, Centro de Investigación, Hospital La Fe, Valencia, Spain.
Cell Transplant. 2009;18(12):1319-40. doi: 10.3727/096368909X12483162197321. Epub 2009 Aug 5.
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 alpha and beta (CEBPalpha and beta), peroxisome proliferator-activated receptor-gamma, coactivator 1 alpha (PGC1alpha), and hepatocyte nuclear factor 4 alpha (HNF4alpha)], 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 (alpha2M), 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 HNF4alpha 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.
脂肪组织中含有一种间充质干细胞（MSC）群体，称为脂肪来源的干细胞（ASCs），能够分化为不同的细胞类型。我们的目的是通过连续暴露于几种细胞因子、生长因子和激素的组合来诱导 ASC 的肝转分化。最有效的肝生成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）（第 1 步）、肝细胞生长因子（HGF）、FGF2、FGF4 和烟酰胺（Nic）（第 2 步）和 Oncostatin M（OSM）、地塞米松（Dex）和胰岛素转铁蛋白硒（第 3 步）。该方案激活了转录因子[GATA6、Hex、CCAAT/增强子结合蛋白α和β（CEBPα和β）、过氧化物酶体增殖物激活受体-γ、共激活因子 1α（PGC1α）和肝细胞核因子 4α（HNF4α）]，这促进了特征性的肝表型，如通过 hMSC 逐步肝转分化的新信息性标记物评估[早期标记物：白蛋白（ALB）、α-2-巨球蛋白（α2M）、补体蛋白 C3（C3）和硒蛋白 P1（SEPP1）；晚期标记物：细胞色素 P450 3A4（CYP3A4）、载脂蛋白 E（APOE）、长链酰基辅酶 A 合成酶家族成员 1（ACSL1）和血管紧张素 II 受体，1 型（AGTR1）]。通过表达抑制物 3（Id3）的丧失检测到脂肪成体干细胞表型的丧失。通过转导重组腺病毒进行 HNF4alpha 重新表达磷酸烯醇丙酮酸羧激酶（PEPCK）、载脂蛋白 C3（APOCIII）、醛缩酶 B（ALDOB）和细胞色素 P450 1A2（CYP1A2），最终通过分析特定的生化标记物评估肝功能。我们得出结论，ASCs 可能成为肝功能障碍和再生医学临床治疗的替代工具。
