Characterization and hepatic differentiation of skin-derived precursors from adult foreskin by sequential exposure to hepatogenic cytokines and growth factors reflecting liver development
Characterization and hepatic differentiation of skin-derived precursors from adult foreskin by sequential exposure to hepatogenic cytokines and growth factors reflecting liver development
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DOI：
10.1016/j.tiv.2009.08.014
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发表时间：
2009-12-01
影响因子：
3.2
通讯作者：
Snykers, Sarah
中科院分区：
文献类型：
--
作者：
De Kock, Joery;Vanhaecke, Tamara;Snykers, Sarah
在本研究中，我们研究了从婴儿包皮真皮中分离的前体细胞在连续和逐渐暴露于肝源性因子[成纤维细胞生长因子(FGF)-4，肝细胞生长因子（HGF），胰岛素-转铁蛋白-亚硒酸盐（ITS），地塞米松和肿瘤抑制素M (OSM)]后，是否能够分化为肝细胞样细胞，模拟体内肝脏胚胎发生。未分化人皮肤源性前体（hSKP）具有成纤维细胞样形状。然而，它们已经表达了典型的肝脏蛋白，包括细胞角蛋白(CK)-18、肝细胞核因子(HNF)-4和HNF-1 α。芯片分析进一步揭示了(i)严重度标志物巢蛋白，POU5F1 (OCT-4)，端粒酶逆转录酶（TERT）和胸腺细胞分化抗原(THY)-1, （ii）胆道CK14和CK19， （iii）胆道/胎儿肝连接蛋白(Cx)-43, （iv）成人肝脏CK18， HNF-4和HNF-1 α的基因表达。在分化过程中，细胞经历形态和表型的改变。因此，hSKP采用更多的多边形到立方体的细胞形状。在蛋白水平上，Cx43的表达下调，而典型的肝脏标志物，包括甲胎蛋白（AFP）、前白蛋白（TTR）和白蛋白（ALB），则按照肝发生过程中观察到的体内模式表达。综上所述，这些数据首次表明hSKP能够通过在体外模拟肝细胞发育的体内微环境而“反”分化为肝细胞样细胞。2009爱思唯尔有限公司版权所有。
In the present study, we investigated whether precursor cells isolated from the dermis of infant human foreskin are capable to differentiate into hepatocyte-like cells upon sequential and gradual exposure to hepatogenic factors [fibroblast growth factor (FGF)-4, hepatocyte growth factor (HGF), insulin-transferrin-selenite (ITS), dexamethasone and oncostatin M (OSM)], mimicking the liver embryogenesis in vivo.Undifferentiated human skin-derived precursors (hSKP) are characterized by a fibroblast-like shape. Yet, they already express typical hepatic proteins, including cytokeratin (CK)-18, hepatocyte nuclear factor (HNF)-4 and HNF-1 alpha. Microarray analysis further reveals gene expression of (i) the sternness markers nestin, POU5F1 (OCT-4), telomerase reverse transcriptase (TERT) and thymocyte differentiation antigen (THY)-1, (ii) biliary CK14 and CK19, (iii) biliary/foetal hepatic connexin (Cx)-43, and (iv) adult hepatic CK18, HNF-4 and HNF-1 alpha. Upon differentiation, cells undergo morphological and phenotypic changes. As such, hSKP adopt a more polygonal-to-cuboidal cell shape. At the protein level, Cx43 expression is downregulated whereas typical hepatic markers, including alfa-foetoprotein (AFP), prealbumin (TTR) and albumin (ALB), become expressed in accordance to in vivo patterns observed during hepatogenesis. In conclusion, these data show for the first time that hSKP are capable to "trans" differentiate into hepatocyte-like cells upon mimicking the in vivo micro-environment of developing hepatocytes in vitro. (C) 2009 Elsevier Ltd. All rights reserved.