LIF-mediated control of embryonic stem cell self-renewal emerges due to an autoregulatory loop
LIF-mediated control of embryonic stem cell self-renewal emerges due to an autoregulatory loop
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DOI：
10.1096/fj.06-7852com
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发表时间：
2007-07-01
期刊：
影响因子：
4.8
通讯作者：
Zandstra, Peter W.
中科院分区：
文献类型：
--
作者：
Davey, Ryan E.;Onishi, Kento;Zandstra, Peter W.
干细胞将分级刺激转化为全有或全无的细胞命运反应。我们研究了胚胎干细胞（ESC）如何将白血病抑制因子（LIF）浓度转化为全或无细胞命运决定（自我更新）。使用相结合的实验/计算方法，我们展示了意想不到的开关样（开/关）信号响应LIF。这种行为随着时间的推移而出现，这是由于正反馈环控制LIF信号传导途径组分的转录表达。自调节环在足够浓度的外源性LIF下维持稳健的通路响应性（“开启”），而自分泌信号传导和低浓度的外源性LIF导致ESC采用分化细胞的弱响应性（“关闭”）状态。我们证明了配体反应性的丧失是可逆的，并且先于ESC转录因子Oct 4和Nanog的丧失，这表明分化的分级控制的早期步骤。虽然内源性产生的配体不足以维持“开启”状态，但它们缓冲了这种状态，影响了分化的时机。这些结果证明了一种新的开关样行为，建立了ESC自我更新的LIF阈值。
Stem cells convert graded stimuli into all-or-nothing cell-fate responses. We investigated how embryonic stem cells (ESCs) convert leukemia inhibitory factor (LIF) concentration into an all-or-nothing cell-fate decision (self-renewal). Using a combined experimental/computational approach we demonstrate unexpected switch-like (on/off) signaling in response to LIF. This behavior emerges over time due to a positive feedback loop controlling transcriptional expression of LIF signaling pathway components. The autoregulatory loop maintains robust pathway responsiveness ("on") at sufficient concentrations of exogenous LIF, while autocrine signaling and low concentrations of exogenous LIF cause ESCs to adopt the weakly responsive ("off") state of differentiated cells. We demonstrate that loss of ligand responsiveness is reversible and precedes loss of the ESC transcription factors Oct4 and Nanog, suggesting an early step in the hierarchical control of differentiation. While endogenously produced ligands were insufficient to sustain the "on" state, they buffer it, influencing the timing of differentiation. These results demonstrate a novel switch-like behavior, which establishes the LIF threshold for ESC self-renewal.