周家喜课题组在Cell Research发表人多能干细胞早期分化机理研究成果

  2015年10月2日,最新一期的Cell Research期刊(*IF=12.417)在线发表了周家喜课题组关于人多能干细胞早期分化机理的最新研究成果。

  人多能干细胞理论上可以分化产生各种分化的功能细胞用于细胞治疗和药物筛选等用途。但是,早期分化机理缺乏深入的研究,阻碍了各种功能细胞的高效获得。BMP信号通路的激活可诱导人多能干细胞分化,但是其下游的关键调控基因以及BMP信号通路是否与OCT-4/SOX2/NANOG核心转录复合物之间存在相互作用一直未知。周家喜课题组通过基因芯片筛选发现转录因子MSX2在人多能干细胞中可特异性介导BMP信号,并可协同整合WNT信号的激活。通过CRISPR/CAS9技术进行基因敲除、DOX诱导过表达、CHIP以及RNA-SEQ等功能研究和生物信息学手段,发现BMP信号激活之后MSX2直接结合SOX2的启动子从而特异性抑制SOX2,启动中内胚层的分化。此外,MSX2通过直接激活靶基因NODAL的表达进一步促进中内胚层分化。有趣的是,该研究还发现SOX2同时对MSX2有拮抗作用,二者之间的相互调控决定了人多能干细胞早期分化为中内胚层还是神经外胚层细胞的命运选择。上述发现揭示了人多能干细胞多能性维持与早期分化命运决定的重要调控机制。

  Abstract

  How BMP signaling integrates into and destabilizes the pluripotency circuitry of human pluripotent stem cells (hPSCs) to initiate differentiation into individual germ layers is a long-standing puzzle. Here we report muscle segment homeobox 2 (MSX2), a homeobox transcription factor of msh family, as a direct target gene of BMP signaling and a master mediator of hPSCs' differentiation to mesendoderm. Enforced expression of MSX2 suffices to abolish pluripotency and induce directed mesendoderm differentiation of hPSCs, while MSX2 depletion impairs mesendoderm induction. MSX2 is a direct target gene of the BMP pathway in hPSCs, and can be synergistically activated by Wnt signals via LEF1 during mesendoderm induction. Furthermore, MSX2 destabilizes the pluripotency circuitry through direct binding to the SOX2 promoter and repression of SOX2 transcription, while MSX2 controls mesendoderm lineage commitment by simultaneous suppression of SOX2 and induction of NODAL expression through direct binding and activation of the Nodal promoter. Interestingly, SOX2 can promote the degradation of MSX2 protein, suggesting a mutual antagonism between the two lineage-specifying factors in the control of stem cell fate. Together, our findings reveal crucial new mechanisms of destabilizing pluripotency and directing lineage commitment in hPSCs.

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