近日,，國際知名發(fā)育生物學(xué)期刊Development發(fā)表了生化與細(xì)胞所景乃禾研究組的最新研究成果，揭示了BMP信號通路在小鼠胚胎干細(xì)胞神經(jīng)分化不同階段的功能,。
小鼠胚胎干細(xì)胞（Embryonic Stem Cells，ESCs）是用于研究哺乳動物早期胚胎發(fā)育很好的體外模型,。胚胎干細(xì)胞的分化調(diào)控機(jī)制研究是當(dāng)前干細(xì)胞研究的熱點(diǎn)領(lǐng)域之一,。但小鼠胚胎干細(xì)胞的體外神經(jīng)誘導(dǎo)是否可以很好模擬體內(nèi)胚胎發(fā)育過程并不清楚。BMP信號通路在小鼠胚胎早期神經(jīng)誘導(dǎo)過程以及小鼠胚胎干細(xì)胞的神經(jīng)分化中都發(fā)揮了重要的功能,。但是BMP信號通路如何發(fā)揮這些功能也不清楚,。
在這項(xiàng)研究中，景乃禾研究組博士生張克兢,、李凌宇等發(fā)現(xiàn)在小鼠胚胎干細(xì)胞神經(jīng)誘導(dǎo)的過程中有一個對BMP抑制敏感的時間段,。該時期的細(xì)胞對應(yīng)于小鼠早期胚胎的上胚層細(xì)胞，并可通過體外培養(yǎng)得到上胚層干細(xì)胞,。這些來源于體外培養(yǎng)的上胚層干細(xì)胞 (ESC derived EpiSCs, ESD-EpiSCs)與來源于體內(nèi)的上胚層干細(xì)胞,，在基因表達(dá)、分化潛能等各方面都很相似,?；谶@種ESD-EpiSCs，可以將小鼠胚胎干細(xì)胞神經(jīng)誘導(dǎo)過程分為兩個階段：從ESCs到ESD-EpiSCs階段,，以及從ESD-EpiSCs 到神經(jīng)干細(xì)胞階段,。進(jìn)一步的研究發(fā)現(xiàn)，BMP信號在小鼠胚胎干細(xì)胞神經(jīng)誘導(dǎo)的兩個階段有不同的功能：它在前一個階段通過抑制FGF/ERK信號通路以及上調(diào)Id基因抑制了ESCs分化為EpiSCs,，而在后一個階段則通過Id等基因促進(jìn)ESD-EpiSCs向非神經(jīng)組織分化,。
該研究是首次將小鼠胚胎干細(xì)胞神經(jīng)分化分為兩個不同階段，為小鼠胚胎神經(jīng)分化的體內(nèi)和體外對應(yīng)關(guān)系提供了重要實(shí)驗(yàn)證據(jù),，為深入理解信號通路在維持干細(xì)胞全能性和命運(yùn)決定之間的功能轉(zhuǎn)換,，并為分階段研究早期胚胎發(fā)育過程的其他重要信號通路提供了一個全新的體外研究模型。
該項(xiàng)工作得到了國家科技部,、國家自然科學(xué)基金委,、中國科學(xué)院及上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
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生物谷推薦原文出處：
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.
