CaltechAUTHORS
  A Caltech Library Service

A Computational Model for Understanding Stem Cell, Trophectoderm and Endoderm Lineage Determination

Chickarmane, Vijay and Peterson, Carsten (2008) A Computational Model for Understanding Stem Cell, Trophectoderm and Endoderm Lineage Determination. PLoS ONE, 3 (10). e3478. ISSN 1932-6203. http://resolver.caltech.edu/CaltechAUTHORS:CHIplosone08

[img]
Preview
PDF - Published Version
Creative Commons Attribution.

193Kb

Use this Persistent URL to link to this item: http://resolver.caltech.edu/CaltechAUTHORS:CHIplosone08

Abstract

Background: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4. Methodology/Principal Findings: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4–Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6. Conclusions: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pone.0003478DOIUNSPECIFIED
Additional Information:© 2008 Chickarmane et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received May 23, 2008; Accepted September 11, 2008; Published October 22, 2008. We would like to thank Elliot Meyerowitz and members of his laboratory for insightful discussions and Henrik Jönsson for valuable comments on the manuscript. Author Contributions: Conceived and designed the experiments: VC CP. Performed the experiments: VC. Analyzed the data: VC CP. Wrote the paper: VC CP. Funding: This research was in part supported by the Swedish Foundation for Strategic Research through a Senior Individual Grant and the National Science Foundation-FIBR Award EF-0330786. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
Funders:
Funding AgencyGrant Number
Swedish Foundation for Strategic ResearchUNSPECIFIED
National Science FoundationEF-0330786
Record Number:CaltechAUTHORS:CHIplosone08
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:CHIplosone08
Official Citation:Chickarmane V, Peterson C (2008) A Computational Model for Understanding Stem Cell, Trophectoderm and Endoderm Lineage Determination. PLoS ONE 3(10): e3478. doi:10.1371/journal.pone.0003478
Usage Policy:This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ID Code:12186
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:28 Oct 2008 18:30
Last Modified:26 Dec 2012 10:28

Repository Staff Only: item control page