Godwin, S., Ward, D., Pedone, E. et al. (3 more authors) (2017) An extended model for culture-dependent heterogenous gene expression and proliferation dynamics in mouse embryonic stem cells. npj Systems Biology and Applications, 3. 19.
Abstract
During development, pluripotency is a transient state describing a cell's ability to give rise to all three germ layers and germline. Recent studies have shown that, in vitro, pluripotency is highly dynamic: exogenous stimuli provided to cultures of mouse embryonic stem cells, isolated from pre-implantation blastocysts, significantly affect the spectrum of pluripotency. 2i/LIF, a recently defined serum-free medium, forces mouse embryonic stem cells into a ground-state of pluripotency, while serum/LIF cultures promote the co-existence of ground-like and primed-like mouse embryonic stem cell subpopulations. The latter heterogeneity correlates with temporal fluctuations of pluripotency markers, including the master regulator Nanog, in single cells. We propose a mathematical model of Nanog dynamics in both media, accounting for recent experimental data showing the persistence of a small Nanog Low subpopulation in ground-state pluripotency mouse embryonic stem cell cultures. The model integrates into the core pluripotency Gene Regulatory Network both inhibitors present in 2i/LIF (PD and Chiron), and feedback interactions with genes found to be differentially expressed in the two media. Our simulations and bifurcation analysis show that, in ground-state cultures, Nanog dynamics result from the combination of reduced noise in gene expression and the shift of the system towards a monostable, but still excitable, regulation. Experimental data and agent-based modelling simulations indicate that mouse embryonic stem cell proliferation dynamics vary in the two media, and cannot be reproduced by accounting only for Nanog-dependent cell-cycle regulation. We further demonstrate that both PD and Chiron play a key role in regulating heterogeneity in transcription factor expression and, ultimately, mouse embryonic stem cell fate decision.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. |
Keywords: | Dynamical systems; Stem cells |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Mathematics and Statistics (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 24 Aug 2017 12:22 |
Last Modified: | 24 Aug 2017 12:22 |
Published Version: | https://doi.org/10.1038/s41540-017-0020-5 |
Status: | Published |
Publisher: | Nature Publishing Group |
Refereed: | Yes |
Identification Number: | 10.1038/s41540-017-0020-5 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:120495 |