Confinement and substrate topography control cell migration in a 3D computational model

Benjamin Winkler,Igor S Aranson,Falko Ziebert

doi:10.1038/s42005-019-0185-x

Abstract

Cell movement in vivo is typically characterized by strong confinement and heterogeneous, three-dimensional environments. Such external constraints on cell motility are known to play important roles in many vital processes e.g. during development, differentiation, and the immune response, as well as in pathologies like cancer metastasis. Here we develop a physics-driven three-dimensional computational modeling framework that describes lamellipodium-based motion of cells in arbitrarily shaped and topographically structured surroundings. We use it to investigate the primary in vitro model scenarios currently studied experimentally: motion in vertical confinement, confinement in microchannels, as well as motion on fibers and on imposed modulations of surface topography. We find that confinement, substrate curvature and topography modulate the cell’s speed, shape and actin organization and can induce changes in the direction of motion along axes defined by the constraints. Our model serves as a benchmark to systematically explore lamellipodium-based motility and its interaction with the environment.

Highlights

Cell movement in vivo is typically characterized by strong confinement and heterogeneous, three-dimensional environments
Recent studies demonstrated that several aspects of the seemingly complex dynamics of migrating cells and tissues can be rationalized in the framework of relatively simple physics-driven models[1,2,3,4]
Due to the relative ease in observation, data analysis, and modeling, quantitative physics-driven studies of cell motion have in the past focused almost exclusively on cells crawling along flat substrates[5]

Summary

Introduction

Cell movement in vivo is typically characterized by strong confinement and heterogeneous, three-dimensional environments. We develop a physics-driven three-dimensional computational modeling framework that describes lamellipodium-based motion of cells in arbitrarily shaped and topographically structured surroundings We use it to investigate the primary in vitro model scenarios currently studied experimentally: motion in vertical confinement, confinement in microchannels, as well as motion on fibers and on imposed modulations of surface topography. Cells migrate in rather complex three-dimensional (3D) environments that in addition are strongly inhomogeneous and reorganized by both forces and chemical action from the cells Both leukocytes[7] and metastatic cancer cells[8] move along or within blood vessels until they reach a target site, where they need to squeeze through epithelial layers, or extracellular matrix (ECM). A direct mapping from these model systems to the full in vivo case is in no way direct or obvious, these systems are in well-controlled conditions that allow to isolate different generic features of topography and/or confinement and their influence on cell motion

Methods

Results

Conclusion