Distinct Signaling Requirements for the Establishment of ESC Pluripotency in Late-Stage EpiSCs.
Distinct Signaling Requirements for the Establishment of ESC Pluripotency in Late-Stage EpiSCs.
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DOI：
10.1016/j.celrep.2016.03.073
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发表时间：
2016-04-26
期刊：
影响因子：
8.8
通讯作者：
Schöler HR
中科院分区：
文献类型：
--
作者：
Illich DJ;Zhang M;Ursu A;Osorno R;Kim KP;Yoon J;Araúzo-Bravo MJ;Wu G;Esch D;Sabour D;Colby D;Grassme KS;Chen J;Greber B;Höing S;Herzog W;Ziegler S;Chambers I;Gao S;Waldmann H;Schöler HR
先前已经报道，小鼠上胚层干细胞（EpiSC）系包含功能上等同于早期或晚期植入后发育的细胞的异质细胞群。迄今为止，通过广泛已知的MEK和GSK 3 β的化学抑制来建立胚胎干细胞（ESC）多能性基因调控网络在晚期EpiSC中是不切实际的。在这里，我们表明，化学抑制酪蛋白激酶1 α（CK 1 α）诱导的转化为ESC多能性的柠檬酸晚期EpiSCs。CK 1 α抑制直接导致WNT信号通路的同时激活，以及TGF β/SMAD 2信号通路的抑制，介导基因调控网络的重新布线，有利于ESC样状态。我们的发现揭示了一种通过直接调节WNT和TGF β信号将CK 1 α与ESC多能性联系起来的分子机制。抑制CK 1 α诱导EpiSC向2 i/LIF转化ESC转化通过WNT激活和TGF β/SMAD 2抑制发挥作用MEK抑制稳定转化并恢复种系能力CK 1抑制促进多能性网络的激活和维持Illich et al.通过用小分子Epiblastin A抑制酪蛋白激酶1 α（CK 1a），将2 i/LIF方法诱导的晚期EpiSC转化为生殖系感受态ESC样细胞。CK 1a的抑制导致WNT激活和TGF β/SMAD 2抑制，这促进了多能性网络的建立和维持。
It has previously been reported that mouse epiblast stem cell (EpiSC) lines comprise heterogeneous cell populations that are functionally equivalent to cells of either early- or late-stage postimplantation development. So far, the establishment of the embryonic stem cell (ESC) pluripotency gene regulatory network through the widely known chemical inhibition of MEK and GSK3beta has been impractical in late-stage EpiSCs. Here, we show that chemical inhibition of casein kinase 1alpha (CK1alpha) induces the conversion of recalcitrant late-stage EpiSCs into ESC pluripotency. CK1alpha inhibition directly results in the simultaneous activation of the WNT signaling pathway, together with inhibition of the TGFbeta/SMAD2 signaling pathway, mediating the rewiring of the gene regulatory network in favor of an ESC-like state. Our findings uncover a molecular mechanism that links CK1alpha to ESC pluripotency through the direct modulation of WNT and TGFbeta signaling. Inhibition of CK1alpha induces ESC conversion in EpiSCs recalcitrant to 2i/LIF The ESC conversion acts via WNT activation and TGFbeta/SMAD2 inhibition MEK inhibition stabilizes the conversion and restores germline competence CK1 inhibition promotes activation and maintenance of the pluripotency network Illich et al. convert late-stage EpiSCs recalcitrant to the 2i/LIF method into germline-competent ESC-like cells through inhibition of casein kinase 1 alpha (CK1a) with the small molecule Epiblastin A. Inhibition of CK1a leads to WNT activation and TGFbeta/SMAD2 inhibition, which promotes the establishment and maintenance of the pluripotency network.