Inada Mari, Follenzi Antonia, Cheng Kang, Surana Manju, Joseph Brigid, Benten Daniel, Bandi Sriram, Qian Hong, Gupta Sanjeev
Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
J Cell Sci. 2008 Apr 1;121(Pt 7):1002-13. doi: 10.1242/jcs.019315. Epub 2008 Mar 4.
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 HNF3alpha (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.
了解胎儿干细胞/祖细胞的生物学潜能将有助于明确肝脏发育和内稳态的机制。我们分离了胎儿人肝细胞，并确定了在连续培养条件下基因表达的表型特异性变化。胎儿人肝上皮细胞表现出具有多谱系基因表达、广泛增殖以及产生间充质谱系细胞的干细胞特性，尽管在培养过程中初始的上皮表型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通路进行基因调控，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通路。原始内胚层中肝脏特异性决定因子HNF3α（FOXA1）转录因子的重新激活表明，中内胚层表型代表了细胞的一个更早发育阶段。我们发现胎儿肝上皮细胞在体内可形成成熟肝细胞，包括在使用慢病毒载体进行基因操作后，这为进一步分析细胞分化和命运提供了便利的检测方法。综上所述，这些研究证明了胎儿肝上皮干细胞的可塑性，为定义调控干细胞谱系转换的机制提供了范例，并为调控细胞表型以应用于干细胞治疗等提供了潜在途径。
