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          周家喜課題組在Cell Research發表人多能干細胞早期分化機理研究成果

            2015年10月2日,最新一期的Cell Research期刊(*IF=12.417)在線發表了周家喜課題組關于人多能干細胞早期分化機理的最新研究成果。

            人多能干細胞理論上可以分化產生各種分化的功能細胞用于細胞治療和藥物篩選等用途。但是,早期分化機理缺乏深入的研究,阻礙了各種功能細胞的高效獲得。BMP信號通路的激活可誘導人多能干細胞分化,但是其下游的關鍵調控基因以及BMP信號通路是否與OCT-4/SOX2/NANOG核心轉錄復合物之間存在相互作用一直未知。周家喜課題組通過基因芯片篩選發現轉錄因子MSX2在人多能干細胞中可特異性介導BMP信號,并可協同整合WNT信號的激活。通過CRISPR/CAS9技術進行基因敲除、DOX誘導過表達、CHIP以及RNA-SEQ等功能研究和生物信息學手段,發現BMP信號激活之后MSX2直接結合SOX2的啟動子從而特異性抑制SOX2,啟動中內胚層的分化。此外,MSX2通過直接激活靶基因NODAL的表達進一步促進中內胚層分化。有趣的是,該研究還發現SOX2同時對MSX2有拮抗作用,二者之間的相互調控決定了人多能干細胞早期分化為中內胚層還是神經外胚層細胞的命運選擇。上述發現揭示了人多能干細胞多能性維持與早期分化命運決定的重要調控機制。

            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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