Modeling the dynamics of hypoxia inducible factor-1α (HIF-1α) within single cells and 3D cell culture systems



Leedale, Joe ORCID: 0000-0001-9010-4126, Herrmann, Anne ORCID: 0000-0002-0858-419X, Bagnall, James, Fercher, Andreas, Papkovsky, Dmitri, See, Violaine ORCID: 0000-0001-6384-8381 and Bearon, Rachel ORCID: 0000-0001-8461-0823
(2014) Modeling the dynamics of hypoxia inducible factor-1α (HIF-1α) within single cells and 3D cell culture systems. Mathematical Biosciences, 258. 33 - 43.

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Abstract

HIF (hypoxia inducible factor) is an oxygen-regulated transcription factor that mediates the intracellular response to hypoxia in human cells. There is increasing evidence that cell signaling pathways encode temporal information, and thus cell fate may be determined by the dynamics of protein levels. We have developed a mathematical model to describe the transient dynamics of the HIF-1α protein measured in single cells subjected to hypoxic shock. The essential characteristics of these data are modeled with a system of differential equations describing the feedback inhibition between HIF-1α and prolyl hydroxylases (PHD) oxygen sensors. Heterogeneity in the single-cell data is accounted through parameter variation in the model. We previously identified the PHD2 isoform as the main PHD sensor responsible for controlling the HIF-1α transient response, and make here testable predictions regarding HIF-1α dynamics subject to repetitive hypoxic pulses. The model is further developed to describe the dynamics of HIF-1α in cells cultured as 3D spheroids, with oxygen dynamics parameterized using experimental measurements of oxygen within spheroids. We show that the dynamics of HIF-1α and transcriptional targets of HIF-1α display a non-monotone response to the oxygen dynamics. Specifically we demonstrate that the dynamic transient behaviour of HIF-1α results in differential dynamics in transcriptional targets.

Item Type: Article
Uncontrolled Keywords: hypoxia, HIF (hypoxia inducible factor), prolyl hydroxylase, spheroids, mathematical modeling, oxygen nanoprobes
Depositing User: Symplectic Admin
Date Deposited: 13 Jan 2015 16:57
Last Modified: 12 Aug 2022 07:10
DOI: 10.1016/j.mbs.2014.09.007
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/2005002