Cell Invasion Dynamics into a Three Dimensional Extracellular Matrix Fibre Network

PLoS Comput Biol. 2015 Oct 5;11(10):e1004535. doi: 10.1371/journal.pcbi.1004535. eCollection 2015 Oct.

Abstract

The dynamics of filopodia interacting with the surrounding extracellular matrix (ECM) play a key role in various cell-ECM interactions, but their mechanisms of interaction with the ECM in 3D environment remain poorly understood. Based on first principles, here we construct an individual-based, force-based computational model integrating four modules of 1) filopodia penetration dynamics; 2) intracellular mechanics of cellular and nuclear membranes, contractile actin stress fibers, and focal adhesion dynamics; 3) structural mechanics of ECM fiber networks; and 4) reaction-diffusion mass transfers of seven biochemical concentrations in related with chemotaxis, proteolysis, haptotaxis, and degradation in ECM to predict dynamic behaviors of filopodia that penetrate into a 3D ECM fiber network. The tip of each filopodium crawls along ECM fibers, tugs the surrounding fibers, and contracts or retracts depending on the strength of the binding and the ECM stiffness and pore size. This filopodium-ECM interaction is modeled as a stochastic process based on binding kinetics between integrins along the filopodial shaft and the ligands on the surrounding ECM fibers. This filopodia stochastic model is integrated into migratory dynamics of a whole cell in order to predict the cell invasion into 3D ECM in response to chemotaxis, haptotaxis, and durotaxis cues. Predicted average filopodia speed and that of the cell membrane advance agreed with experiments of 3D HUVEC migration at r(2) > 0.95 for diverse ECMs with different pore sizes and stiffness.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Adhesion / physiology*
  • Cell Movement / physiology*
  • Computer Simulation
  • Elastic Modulus / physiology
  • Extracellular Matrix / physiology*
  • Humans
  • Mechanotransduction, Cellular / physiology*
  • Models, Biological*
  • Pseudopodia / physiology*
  • Stress, Mechanical

Grant support

This research was supported by the National Research Foundation Singapore through the Singapore MIT Alliance for Research and Technology's BioSyM IRG research program. This material is based upon work supported by the National Science Foundation (NSF), Science and Technology Center (STC), and Emergent Behaviors in Integrated Cellular Systems (EBICS) under Grant No. EFRI-0735997, Grant No. STC-0902396 and Grant CBET-0939511. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.