近日，国际知名发育生物学期刊Development发表了生化与细胞所景乃禾研究组的最新研究成果，揭示了BMP信号通路在小鼠胚胎干细胞神经分化不同阶段的功能。
小鼠胚胎干细胞（Embryonic Stem Cells，ESCs）是用于研究哺乳动物早期胚胎发育很好的体外模型。胚胎干细胞的分化调控机制研究是当前干细胞研究的热点领域之一。但小鼠胚胎干细胞的体外神经诱导是否可以很好模拟体内胚胎发育过程并不清楚。BMP信号通路在小鼠胚胎早期神经诱导过程以及小鼠胚胎干细胞的神经分化中都发挥了重要的功能。但是BMP信号通路如何发挥这些功能也不清楚。
在这项研究中，景乃禾研究组博士生张克兢、李凌宇等发现在小鼠胚胎干细胞神经诱导的过程中有一个对BMP抑制敏感的时间段。该时期的细胞对应于小鼠早期胚胎的上胚层细胞，并可通过体外培养得到上胚层干细胞。这些来源于体外培养的上胚层干细胞 (ESC derived EpiSCs, ESD-EpiSCs)与来源于体内的上胚层干细胞，在基因表达、分化潜能等各方面都很相似。基于这种ESD-EpiSCs，可以将小鼠胚胎干细胞神经诱导过程分为两个阶段：从ESCs到ESD-EpiSCs阶段，以及从ESD-EpiSCs 到神经干细胞阶段。进一步的研究发现，BMP信号在小鼠胚胎干细胞神经诱导的两个阶段有不同的功能：它在前一个阶段通过抑制FGF/ERK信号通路以及上调Id基因抑制了ESCs分化为EpiSCs，而在后一个阶段则通过Id等基因促进ESD-EpiSCs向非神经组织分化。
该研究是首次将小鼠胚胎干细胞神经分化分为两个不同阶段，为小鼠胚胎神经分化的体内和体外对应关系提供了重要实验证据，为深入理解信号通路在维持干细胞全能性和命运决定之间的功能转换，并为分阶段研究早期胚胎发育过程的其他重要信号通路提供了一个全新的体外研究模型。
该项工作得到了国家科技部、国家自然科学基金委、中国科学院及上海市科委的经费支持。（生物谷Bioon.com）
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生物谷推荐原文出处：
Development doi: 10.1242/dev.049494
Distinct functions of BMP4 during different stages of mouse ES cell neural commitment
Kejing Zhang, Lingyu Li, Chengyang Huang, Chengyong Shen, Fangzhi Tan, Caihong Xia, Pingyu Liu, Janet Rossant and Naihe Jing*
Bone morphogenetic protein (BMP) signaling plays a crucial role in maintaining the pluripotency of mouse embryonic stem cells (ESCs) and has negative effects on ESC neural differentiation. However, it remains unclear when and how BMP signaling executes those different functions during neural commitment. Here, we show that a BMP4-sensitive window exists during ESC neural differentiation. Cells at this specific period correspond to the egg cylinder stage epiblast and can be maintained as ESC-derived epiblast stem cells (ESD-EpiSCs), which have the same characteristics as EpiSCs derived from mouse embryos. We propose that ESC neural differentiation occurs in two stages: first from ESCs to ESD-EpiSCs and then from ESD-EpiSCs to neural precursor cells (NPCs). We further show that BMP4 inhibits the conversion of ESCs into ESD-EpiSCs during the first stage, and suppresses ESD-EpiSC neural commitment and promotes non-neural lineage differentiation during the second stage. Mechanistic studies show that BMP4 inhibits FGF/ERK activity at the first stage but not at the second stage; and IDs, as important downstream genes of BMP signaling, partially substitute for BMP4 functions at both stages. We conclude that BMP signaling has distinct functions during different stages of ESC neural commitment.
