Phenotype reversion in fetal human liver epithelial cells identifies the role of an intermediate meso-endodermal stage before hepatic maturation
Phenotype reversion in fetal human liver epithelial cells identifies the role of an intermediate meso-endodermal stage before hepatic maturation
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DOI：
10.1242/jcs.019315
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发表时间：
2008-04-01
影响因子：
4
通讯作者：
Gupta, Sanjeev
中科院分区：
文献类型：
--
作者：
Inada, Mari;Follenzi, Antonia;Gupta, Sanjeev
了解胎儿干/祖细胞的生物学潜能将有助于确定肝脏发育和体内平衡的机制。我们分离了人胎肝上皮细胞，并在连续培养条件下建立了基因表达的表型特异性变化。胎儿人肝上皮细胞显示干细胞特性，具有多谱系基因表达、广泛增殖和间充质谱系细胞的产生，尽管最初的上皮表型在培养中迅速被中-内胚层表型所取代。这种中-内胚层表型通过细胞因子信号传导（包括转化生长因子β、骨形态发生蛋白、成纤维细胞生长因子和其他信号传导途径）进行遗传调节。HNF 3 α（FOXA 1）转录因子（原始内胚层中肝脏特化的驱动因子）的重新激活表明中-内胚层表型代表细胞的早期发育阶段。我们发现胎肝上皮细胞在体内形成成熟肝细胞，包括使用慢病毒载体进行遗传操作后，为进一步分析细胞分化和命运提供了方便的测定。总之，这些研究证明了胎肝上皮干细胞的可塑性，提供了定义干细胞谱系转换调节机制的范例，并为干细胞的应用（如细胞治疗）提供了调节细胞表型的潜在途径。
Understanding the biological potential of fetal stem/progenitor cells will help define mechanisms in liver development and homeostasis. We isolated epithelial fetal human liver cells and established phenotype-specific changes in gene expression during continuous culture conditions. Fetal human liver epithelial cells displayed stem cell properties with multilineage gene expression, extensive proliferation and generation of mesenchymal lineage cells, although the initial epithelial phenotype was rapidly supplanted by meso-endodermal phenotype in culture. This meso-endodermal phenotype was genetically regulated through cytokine signaling, including transforming growth factor beta, bone morphogenetic protein, fibroblast growth factor and other signaling pathways. Reactivation of HNF3 alpha (FOXA1) transcription factor, a driver of hepatic specification in the primitive endoderm, indicated that the meso-endodermal phenotype represented an earlier developmental stage of cells. We found that fetal liver epithelial cells formed mature hepatocytes in vivo, including after genetic manipulation using lentiviral vectors, offering convenient assays for analysis of further cell differentiation and fate. Taken together, these studies demonstrate plasticity in fetal liver epithelial stem cells, offer paradigms for defining mechanisms regulating lineage switching in stem cells, and provide potential avenues for regulating cell phenotypes for applications of stem cells, such as for cell therapy.