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

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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.

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          Most cited references50

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          Integrin ligands at a glance.

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            Integrins: bidirectional, allosteric signaling machines.

            In their roles as major adhesion receptors, integrins signal across the plasma membrane in both directions. Recent structural and cell biological data suggest models for how integrins transmit signals between their extracellular ligand binding adhesion sites and their cytoplasmic domains, which link to the cytoskeleton and to signal transduction pathways. Long-range conformational changes couple these functions via allosteric equilibria.
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              Designer matrices for intestinal stem cell and organoid culture.

              Epithelial organoids recapitulate multiple aspects of real organs, making them promising models of organ development, function and disease. However, the full potential of organoids in research and therapy has remained unrealized, owing to the poorly defined animal-derived matrices in which they are grown. Here we used modular synthetic hydrogel networks to define the key extracellular matrix (ECM) parameters that govern intestinal stem cell (ISC) expansion and organoid formation, and show that separate stages of the process require different mechanical environments and ECM components. In particular, fibronectin-based adhesion was sufficient for ISC survival and proliferation. High matrix stiffness significantly enhanced ISC expansion through a yes-associated protein 1 (YAP)-dependent mechanism. ISC differentiation and organoid formation, on the other hand, required a soft matrix and laminin-based adhesion. We used these insights to build a fully defined culture system for the expansion of mouse and human ISCs. We also produced mechanically dynamic matrices that were initially optimal for ISC expansion and subsequently permissive to differentiation and intestinal organoid formation, thus creating well-defined alternatives to animal-derived matrices for the culture of mouse and human stem-cell-derived organoids. Our approach overcomes multiple limitations of current organoid cultures and greatly expands their applicability in basic and clinical research. The principles presented here can be extended to identify designer matrices that are optimal for long-term culture of other types of stem cells and organoids.
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                Author and article information

                Contributors
                Journal
                Front Bioeng Biotechnol
                Front Bioeng Biotechnol
                Front. Bioeng. Biotechnol.
                Frontiers in Bioengineering and Biotechnology
                Frontiers Media S.A.
                2296-4185
                29 April 2021
                2021
                : 9
                : 657244
                Affiliations
                Department of Cell Biology–Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University , Maastricht, Netherlands
                Author notes

                Edited by: Ben Goult, University of Kent, United Kingdom

                Reviewed by: William Richardson, Clemson University, United States; Pontus Nordenfelt, Lund University, Sweden

                *Correspondence: Aurélie Carlier, a.carlier@ 123456maastrichtuniversity.nl

                This article was submitted to Tissue Engineering and Regenerative Medicine, a section of the journal Frontiers in Bioengineering and Biotechnology

                Article
                10.3389/fbioe.2021.657244
                8117103
                1e119253-af9a-4090-a639-4ca50145d1ba
                Copyright © 2021 Karagöz, Geuens, LaPointe, van Griensven and Carlier.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 January 2021
                : 07 April 2021
                Page count
                Figures: 6, Tables: 2, Equations: 20, References: 50, Pages: 14, Words: 0
                Funding
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek 10.13039/501100003246
                Categories
                Bioengineering and Biotechnology
                Original Research

                integrin,ligand competition,computational model,extracellular matrix,ordinary differential equation

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