周家喜课题组在Cell Research宣布人多精干细胞前期分解机理研讨成果

  2015年10月2日,最新一期的Cell Research期刊(*IF=12.417)在线宣布了周家喜课题组关于人多精干细胞前期分解机理的最新研讨成果。

  人多精干细胞理论上能够分解发生各种分解的功用细胞用于细胞医治和药物挑选等用处。可是,前期分解机理缺少深化的研讨,阻止了各种功用细胞的高效取得。BMP信号通路的激活可诱导人多精干细胞分解,可是其下流的要害调控基因以及BMP信号通路是否与OCT-4/SOX2/NANOG中心转录复合物之间存在彼此效果一向不知道。周家喜课题组经过基因芯片挑选发现转录因子MSX2在人多精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。经过CRISPR/CAS9技能进行基因敲除、DOX诱导过表达、CHIP以及RNA-SEQ等功用研讨和生物信息学手法,发现BMP信号激活之后MSX2直接结合SOX2的发动子然后特异性按捺SOX2,发动中内胚层的分解。此外,MSX2经过直接激活靶基因NODAL的表达进一步促进中内胚层分解。风趣的是,该研讨还发现SOX2一起对MSX2有拮抗效果,二者之间的彼此调控决议了人多精干细胞前期分解为中内胚层仍是神经外胚层细胞的命运挑选。上述发现提醒了人多精干细胞多能性保持与前期分解命运决议的重要调控机制。

  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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