Matrix compliance and the regulation of cytokinesis.

Savitha Sambandamoorthy,Scott Varney,Susan E Laflamme,Livingston Van De Water,Jonathan M Zuidema,Ryan J Gilbert,Shomita Mathew-Steiner

doi:10.1242/bio.011825

Savitha Sambandamoorthy, Scott Varney + Show 5 more

Open Access

https://doi.org/10.1242/bio.011825

Copy DOI

Abstract

ABSTRACTIntegrin-mediated cell adhesion to the ECM regulates many physiological processes in part by controlling cell proliferation. It is well established that many normal cells require integrin-mediated adhesion to enter S phase of the cell cycle. Recent evidence indicates that integrins also regulate cytokinesis. Mechanical properties of the ECM can dictate entry into S phase; however, it is not known whether they also can affect the successful completion of cell division. To address this issue, we modulated substrate compliance using fibronectin-coated acrylamide-based hydrogels. Soft and hard substrates were generated with approximate elastic moduli of 1600 and 34,000 Pascals (Pa) respectively. Our results indicate that dermal fibroblasts successfully complete cytokinesis on hard substrates, whereas on soft substrates, a significant number fail and become binucleated. Cytokinesis failure occurs at a step following the formation of the intercellular bridge connecting presumptive daughter cells, suggesting a defect in abscission. Like dermal fibroblasts, mesenchymal stem cells require cell-matrix adhesion for successful cytokinesis. However, in contrast to dermal fibroblasts, they are able to complete cytokinesis on both hard and soft substrates. These results indicate that matrix stiffness regulates the successful completion of cytokinesis, and does so in a cell-type specific manner. To our knowledge, our study is the first to demonstrate that matrix stiffness can affect cytokinesis. Understanding the cell-type specific contribution of matrix compliance to the regulation of cytokinesis will provide new insights important for development, as well as tissue homeostasis and regeneration.

Highlights

Proliferation of adherent mammalian cells is tightly regulated by a number of factors including cell adhesion to the extracellular matrix (ECM) and the binding of soluble growth factors to their receptors (Assoian and Schwartz, 2001; Schwartz and Assoian, 2001)
Cell-matrix adhesion and β1 integrins promote the successful completion of cytokinesis in primary human dermal fibroblasts (HDFs) To examine the role of matrix compliance in the regulation of cytokinesis, we used primary human dermal fibroblasts (HDFs), as these cells are known to develop tension and pull against their ECM (Hinz, 2010)
We demonstrate that matrix stiffness regulates the successful completion of cytokinesis and does so in a cell type-dependent manner

Summary

Introduction

Proliferation of adherent mammalian cells is tightly regulated by a number of factors including cell adhesion to the extracellular matrix (ECM) and the binding of soluble growth factors to their receptors (Assoian and Schwartz, 2001; Schwartz and Assoian, 2001). Integrins coordinate with growth factor receptors to control entry into S phase (Assoian and Schwartz, 2001; Schwartz and Assoian, 2001). Studies from our lab and others have demonstrated that integrins can promote the successful completion of cytokinesis (Aszodi et al, 2003; Kittler et al, 2007; Mathew et al, 2014; Pellinen et al, 2008; Reverte et al, 2006; Thullberg et al, 2007)

Methods

Results

Conclusion