Win, Lose, or Tie: Mathematical Modeling of Ligand Competition at the Cell-Extracellular Matrix Interface.

Zeynep Karagöz,Aurélie Carlier,Martijn Van Griensven,Vanessa L S Lapointe,Thomas Geuens

doi:10.3389/fbioe.2021.657244

Zeynep Karagöz, Aurélie Carlier + Show 3 more

Open Access

https://doi.org/10.3389/fbioe.2021.657244

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Abstract

Integrin transmembrane proteins conduct mechanotransduction at the cell–extracellular matrix (ECM) interface. This process is central to cellular homeostasis and therefore is particularly important when designing instructive biomaterials and organoid culture systems. Previous studies suggest that fine-tuning the ECM composition and mechanical properties can improve organoid development. Toward the bigger goal of fully functional organoid development, we hypothesize that resolving the dynamics of ECM–integrin interactions will be highly instructive. To this end, we developed a mathematical model that enabled us to simulate three main interactions, namely integrin activation, ligand binding, and integrin clustering. Different from previously published computational models, we account for the binding of more than one type of ligand to the integrin. This competition between ligands defines the fate of the system. We have demonstrated that an increase in the initial concentration of ligands does not ensure an increase in the steady state concentration of ligand-bound integrins. The ligand with higher binding rate occupies more integrins at the steady state than does the competing ligand. With cell type specific, quantitative input on integrin-ligand binding rates, this model can be used to develop instructive cell culture systems.

Highlights

The extracellular matrix (ECM) is a mesh of fibrous proteins that forms the basis of the tissue architecture and structurally supports the cells
Hudson et al (2017) studied the binding of fibronectin and von Willebrand Factor A to integrin αvβ3 as well as binding of collagen to α1β1 using an ordinary differential equation (ODE) model; they reported an increase in ligand-bound integrin at the steady state when there is an increase in the concentration of ligands
The mass-action kinetics scheme of the integrin–ligand competition model is given in Figure 1; here we present the differential equations for the model (Eqs 1–9): where i denotes the concentration of inactive integrins, I is the concentration of active integrins, IL1 and IL2 are the concentrations of L1- and L2-bound integrins, respectively

Summary

INTRODUCTION

The extracellular matrix (ECM) is a mesh of fibrous proteins that forms the basis of the tissue architecture and structurally supports the cells. Hudson et al (2017) studied the binding of fibronectin and von Willebrand Factor A (vWA) to integrin αvβ as well as binding of collagen to α1β1 using an ordinary differential equation (ODE) model; they reported an increase in ligand-bound integrin at the steady state when there is an increase in the concentration of ligands They simulate the integrin–ligand binding exclusively for each ligand, which overlooks the fact that the ligands of the same integrin are in a competition to bind when present at the same time. Our model consists of three reaction levels: (1) integrin activation, (2) ligand binding, and (3) ligand-bound integrin clustering (Figure 1) Using this model, we explore the changes in ligand-binding kinetics when the amount of ECM ligands changes over time, as in the case of kidney organoid cultures

MATERIALS AND METHODS

Design of in silico Experiments

RESULTS

DISCUSSION

DATA AVAILABILITY STATEMENT