Zhang2018 - Cell cycle commitment in hypoxia

  public model
Short description

Does not reproduce publication figure 3

Format
SBML (L2V4)
Related Publication
  • Mathematical modelling of interacting mechanisms for hypoxia mediated cell cycle commitment for mesenchymal stromal cells.
  • Yang A, Ye H
  • BMC systems biology , 4/ 2018 , Volume 12 , Issue 1 , pages: 35
  • Department of Engineering Science, University of Oxford, Oxford, UK.
  • Existing experimental data have shown hypoxia to be an important factor affecting the proliferation of mesenchymal stromal cells (MSCs), but the contrasting observations made at various hypoxic levels raise the questions of whether hypoxia accelerates proliferation, and how. On the other hand, in order to meet the increasing demand of MSCs, an optimised bioreactor control strategy is needed to enhance in vitro production.A comprehensive, single-cell mathematical model has been constructed in this work, which combines cellular oxygen sensing with hypoxia-mediated cell cycle progression to predict cell cycle commitment as a proxy to proliferation rate. With oxygen levels defined for in vitro cell culture, the model predicts enhanced proliferation under intermediate (2-8%) and mild (8-15%) hypoxia and cell quiescence under severe (< 2%) hypoxia. Global sensitivity analysis and quasi-Monte Carlo simulation revealed that within a certain range (+/- 100%), model parameters affect (with varying significance) the minimum commitment time, but the existence of a range of optimal oxygen tension could be preserved with the hypothesized effects of Hif2α and reactive oxygen species (ROS). It appears that Hif2α counteracts Hif1α and ROS-mediated protein deactivation under intermediate hypoxia and normoxia (20%), respectively, to regulate the response of cell cycle commitment to oxygen tension.Overall, this modelling study offered an integrative framework to capture several interacting mechanisms and allowed in silico analysis of their individual and collective roles in shaping the hypoxia-mediated commitment to cell cycle. The model offers a starting point to the establishment of a suitable mechanism that can satisfactorily explain the different existing experimental observations from different studies, and warrants future extension and dedicated experimental validation to eventually support bioreactor optimisation.
Contributors
Ashley Xavier

Metadata information

Curation status
Non-curated
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Model file

Zhang2018.xml SBML file 48.43 KB Preview | Download

Additional files

Zhang2018.cps copasi file 99.19 KB Preview | Download

  • Model originally submitted by : Ashley Xavier
  • Submitted: 06-Dec-2018 12:11:36
  • Last Modified: 06-Dec-2018 12:11:36
Revisions
  • Version: 4 public model Download this version
    • Submitted on: 06-Dec-2018 12:11:36
    • Submitted by: Ashley Xavier
    • With comment: Edited model metadata online.
Curator's comment:
(added: 06 Dec 2018, 12:10:35, updated: 06 Dec 2018, 12:10:35)
This is the simulated figure 3 and is quite different from the publication figure.