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Nanog在调节干细胞分化和重编程过程中诱导中间状态。

Nanog induced intermediate state in regulating stem cell differentiation and reprogramming.

作者信息

Yu Peijia, Nie Qing, Tang Chao, Zhang Lei

机构信息

Center for Quantitative Biology, Peking University, Beijing, 100871, China.

Department of Mathematics and Departmentof Developmental and Cell Biology, University of California Irvine, Irvine, CA, 92697, USA.

出版信息

BMC Syst Biol. 2018 Feb 27;12(1):22. doi: 10.1186/s12918-018-0552-3.

DOI:10.1186/s12918-018-0552-3
PMID:29486740
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6389130/
Abstract

BACKGROUND

Heterogeneous gene expressions of cells are widely observed in self-renewing pluripotent stem cells, suggesting possible coexistence of multiple cellular states with distinct characteristics. Though the elements regulating cellular states have been identified, the underlying dynamic mechanisms and the significance of such cellular heterogeneity remain elusive.

RESULTS

We present a gene regulatory network model to investigate the bimodal Nanog distribution in stem cells. Our model reveals a novel role of dynamic conversion between the cellular states of high and low Nanog levels. Model simulations demonstrate that the low-Nanog state benefits cell differentiation through serving as an intermediate state to reduce the barrier of transition. Interestingly, the existence of low-Nanog state dynamically slows down the reprogramming process, and additional Nanog activation is found to be essential to quickly attaining the fully reprogrammed cell state.

CONCLUSIONS

Nanog has been recognized as a critical pluripotency gene in stem cell regulation. Our modeling results quantitatively show a dual role of Nanog during stem cell differentiation and reprogramming, and the importance of the intermediate state during cell state transitions. Our approach offers a general method for analyzing key regulatory factors controlling cell differentiation and reprogramming.

摘要

背景

在自我更新的多能干细胞中广泛观察到细胞的异质基因表达，这表明可能存在具有不同特征的多种细胞状态的共存。尽管已经确定了调节细胞状态的因素，但这种细胞异质性的潜在动态机制和意义仍然难以捉摸。

结果

我们提出了一个基因调控网络模型来研究干细胞中双峰Nanog分布。我们的模型揭示了Nanog高表达和低表达细胞状态之间动态转换的新作用。模型模拟表明，低Nanog状态通过作为中间状态降低转变障碍而有利于细胞分化。有趣的是，低Nanog状态的存在动态地减缓了重编程过程，并且发现额外的Nanog激活对于快速达到完全重编程的细胞状态至关重要。

结论

Nanog已被认为是干细胞调控中的关键多能性基因。我们的建模结果定量地显示了Nanog在干细胞分化和重编程过程中的双重作用，以及中间状态在细胞状态转变过程中的重要性。我们的方法提供了一种分析控制细胞分化和重编程的关键调控因子的通用方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/d0088860bef3/12918_2018_552_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/4a663062c10e/12918_2018_552_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/02e346bf770f/12918_2018_552_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/e9d6bdbd1de9/12918_2018_552_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/9372a501e7c2/12918_2018_552_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/d0088860bef3/12918_2018_552_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/4a663062c10e/12918_2018_552_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/02e346bf770f/12918_2018_552_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/e9d6bdbd1de9/12918_2018_552_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/9372a501e7c2/12918_2018_552_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81a0/6389130/d0088860bef3/12918_2018_552_Fig5_HTML.jpg

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