Zhang Pengbo, Li Jian, Tan Zhijia, Wang Chengyan, Liu Ting, Chen Lin, Yong Jun, Jiang Wei, Sun Xiaomeng, Du Liying, Ding Mingxiao, Deng Hongkui
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China.
Blood. 2008 Feb 15;111(4):1933-41. doi: 10.1182/blood-2007-02-074120. Epub 2007 Nov 27.
Human embryonic stem cells (hES cells) have unlimited self-renewal capacity and can differentiate into most, if not all, possible cell types. This unique property makes them valuable not only for investigation of early developmental processes, but also for regenerative medicine. Mesoderm-derived cardiac cells and hematopoietic cells both have the potential for various therapeutic applications. However, efficient induction of hES cell differentiation into mesoderm remains a challenge. Here, we showed that treatment of hES cells with bone morphogenetic protein-4 (BMP-4) exhibited differential effects: long-term treatment results in trophoblast and extra-embryonic endoderm differentiation, whereas short-term treatment can promote early mesoderm induction. The induction of mesoderm in hES cells occurs at a high efficiency as measured using several markers, such as Brachyury, WNT3, and MIXL1 expression. Moreover, these mesoderm progenitor cells can differentiate into cardiac and hematopoietic lineages in vitro. Further analysis showed that the mesoderm-inducing capacity of BMP-4 requires endogenous FGF and TGF-beta/Nodal/activin signaling activities. Thus, our results uncover a novel role for BMP-4 in regulation of hES cell differentiation and should provide insights into the mechanism of mesoderm induction in hES cells.
人胚胎干细胞（hES细胞）具有无限的自我更新能力，并且能够分化成大多数（即便不是全部）可能的细胞类型。这种独特的特性使其不仅对于早期发育过程的研究具有价值，而且对于再生医学也具有价值。中胚层来源的心脏细胞和造血细胞都具有多种治疗应用的潜力。然而，将hES细胞高效诱导分化为中胚层仍然是一个挑战。在此，我们表明用骨形态发生蛋白-4（BMP-4）处理hES细胞会产生不同的效果：长期处理会导致滋养层和胚外内胚层分化，而短期处理则可促进早期中胚层诱导。使用几种标志物（如Brachyury、WNT3和MIXL1表达）测量发现，hES细胞中中胚层的诱导效率很高。此外，这些中胚层祖细胞能够在体外分化为心脏和造血谱系。进一步分析表明，BMP-4的中胚层诱导能力需要内源性FGF和TGF-β/Nodal/激活素信号活性。因此，我们的结果揭示了BMP-4在调控hES细胞分化中的新作用，并应为hES细胞中中胚层诱导机制提供见解。
