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

TL;DR

This paper presents a mathematical model of HIF-1α dynamics in single cells and 3D cultures, capturing transient responses to hypoxia and predicting effects of repetitive hypoxic pulses on gene regulation.

Contribution

The study develops a novel differential equation model that incorporates feedback mechanisms and heterogeneity to describe HIF-1α dynamics in different cellular contexts.

Findings

HIF-1α exhibits non-monotone responses to oxygen levels.

Heterogeneity affects HIF-1α transient behavior.

Predictions made for HIF-1α dynamics under repetitive hypoxia.

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-1{\alpha} 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-1{\alpha} and Prolyl Hydroxylases (PHD) oxygen sensors. Heterogeneity in the single-cell data is accounted for through parameter variation in the model. We previously identified the PHD2 isoform as the main PHD responsible for controlling the HIF-1{\alpha} transient response, and make here testable predictions regarding HIF-1{\alpha} dynamics subject to repetitive hypoxic pulses. The model is further developed to describe the dynamics of HIF-1{\alpha} in cells cultured as 3D spheroids, with oxygen dynamics parameterized using experimental measurements of oxygen within spheroids. We show that the dynamics of HIF-1{\alpha} and transcriptional targets of HIF-1{\alpha} display a non-monotone response to the oxygen dynamics. Specifically we demonstrate that the dynamic transient behavior of HIF-1{\alpha} results in differential dynamics in transcriptional targets.