Crucial roles of mesodermal cell lineages in a murine embryonic stem cell-derived in vitro liver organogenesis system
Crucial roles of mesodermal cell lineages in a murine embryonic stem cell-derived in vitro liver organogenesis system
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DOI：
10.1634/stemcells.2004-0295
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发表时间：
2005-08-01
期刊：
影响因子：
5.2
通讯作者：
Miyagawa, S
中科院分区：
文献类型：
--
作者：
Ogawa, S;Tagawa, Y;Miyagawa, S
再生医学领域的最新研究利用胚胎干（ES）细胞的多能性来产生多种细胞谱系。然而，目标始终只是从其他分化细胞群中分离出来的单一谱系。在本研究中，我们选择了具有高分化能力的收缩心肌细胞亚系，并从亲本 ES 系中产生了种系嵌合小鼠。我们还成功地建立了由 ES 细胞制备的胚状体，该胚状体不仅分化为肝细胞，而且分化为至少两个中胚层谱系：支持肝脏发育的心肌细胞和对应于血窦的内皮细胞。这使得使用鼠 ES 细胞开发体外系统能够模拟体内肝脏发育的事件。分化的 ES 细胞中产生的心肌细胞中白蛋白的表达显着高于未分化的心肌细胞中的白蛋白表达。我们的体外肝脏器官发生系统由血液/正弦血管样网络和肝细胞层组成，与肝细胞系和小鼠成年肝细胞的原代培养物相比，显示出更高水平的肝功能，例如白蛋白产生和氨降解。这一创新系统将促进使用 ES 细胞的第二代再生医学技术的发展，预计将有助于生物人工肝系统和药物代谢测定的开发。
Recent studies in the field of regenerative medicine have exploited the pluripotency of embryonic stem (ES) cells to generate a variety of cell lineages. However, the target has always been only a single lineage, which was isolated from other differentiated cell populations. In the present study, we selected sublines with a high capability for differentiation to contracting cardiomyocytes and also produced germline chimeric mice from a parent ES line. We also succeed in establishing embryoid bodies prepared from the ES cells that differentiated into not only hepatocytes but also at least two mesodermal lineages: cardiomyocytes that supported liver development and endothelial cells corresponding to sinusoids. This allowed the development of an in vitro system using murine ES cells that approximated the events of liver development in vivo. The expression of albumin was significantly higher in cardiomyocytes that had arisen in differentiated ES cells than in those that had not. Our in vitro system for liver organogenesis consists of a blood/sinusoid vascular-like network and hepatocyte layers and shows higher levels of hepatic function, such as albumin production and ammonia degradation, than hepatic cell lines and primary cultures of murine adult hepatocytes. This innovative system will lead to the development of second-generation regenerative medicine techniques using ES cells and is expected to be useful for the development of bioartificial liver systems and drug-metabolism assays.