Roles of CDX2 and EOMES in human induced trophoblast progenitor cells
Roles of CDX2 and EOMES in human induced trophoblast progenitor cells
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DOI：
10.1016/j.bbrc.2012.12.135
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发表时间：
2013-02-08
影响因子：
3.1
通讯作者：
Leach, Richard
中科院分区：
文献类型：
--
作者：
Chen, Ying;Wang, Kai;Leach, Richard
妊娠早期滋养细胞增殖分化异常与妊娠胎盘疾病的发生有关。然而，由于有限的原代滋养层培养和永生化滋养层细胞系的保真度，在理解早期胎盘发育的分子机制方面仍然存在差距。滋养层干细胞（TS）是一种体外培养的滋养外胚层细胞模型，可分化为合体滋养层细胞和绒毛外滋养层细胞，是早期妊娠研究的一个有吸引力的工具。TS细胞在小鼠中很好地建立，但在人类中没有，这是由于对哪些滋养层谱系特异性转录因子参与人类滋养外胚层（TE）增殖和分化的知识不足。本研究应用诱导多能干细胞技术对人滋养层细胞系特异性转录因子进行研究。我们建立了人类诱导滋养层祖细胞（iTP）细胞直接重编程的成纤维细胞与小鼠滋养层细胞系特异性转录因子组成的CDX2，EOMES和ELF5的池。人iTP细胞表现出上皮形态，并且可以在体外维持超过2个月。这些细胞的基因表达谱与人滋养外胚层紧密聚集，但与人神经元祖细胞、间充质干细胞或内胚层细胞不紧密聚集。这些细胞能够分化成具有侵袭能力的细胞，这表明绒毛外滋养细胞。它们还形成分泌人绒毛膜促性腺激素和雌二醇的多核细胞，与合体滋养层表型一致。我们的研究结果提供了证据，转录因子CDX2和EOMES可能在人类iTP细胞生成中发挥关键作用。(C)2013 Elsevier Inc. All rights reserved.
Abnormal trophoblast lineage proliferation and differentiation in early pregnancy have been associated with the pathogenesis of placenta diseases of pregnancy. However, there is still a gap in understanding the molecular mechanisms of early placental development due to the limited primary trophoblast cultures and fidelity of immortalized trophoblast lines. Trophoblasts stem (TS) cells, an in vitro model of trophectoderm that can differentiate into syncytiotrophoblasts and extravillous trophoblasts, can be an attractive tool for early pregnancy research. TS cells are well established in mouse but not in humans due to insufficient knowledge of which trophoblast lineage-specific transcription factors are involved in human trophectoderm (TE) proliferation and differentiation. Here, we applied induced pluripotent stem cell technique to investigate the human trophoblast lineage-specific transcription factors. We established human induced trophoblast progenitor (iTP) cells by direct reprogramming the fibroblasts with a pool of mouse trophoblast lineage-specific transcription factors consisting of CDX2, EOMES, and ELF5. The human iTP cells exhibit epithelial morphology and can be maintained in vitro for more than 2 months. Gene expression profile of these cells was tightly clustered with human trophectoderm but not with human neuron progenitor cells, mesenchymal stem cells, or endoderm cells. These cells are capable of differentiating into cells with an invasive capacity, suggesting extravillous trophoblasts. They also form multi-nucleated cells which secrete human chorionic gonadotropin and estradiol, consistent with a syncytiotrophoblast phenotype. Our results provide the evidence that transcription factors CDX2 and EOMES may play critical roles in human iTP cell generation. (C) 2013 Elsevier Inc. All rights reserved.