title: Mechanical cell-matrix feedback explains pairwise and collective endothelial cell behavior in vitro.
abstract: In vitro cultures of endothelial cells are a widely used model system of the collective behavior of endothelial cells during vasculogenesis and angiogenesis. When seeded in an extracellular matrix, endothelial cells can form blood vessel-like structures, including vascular networks and sprouts. Endothelial morphogenesis depends on a large number of chemical and mechanical factors, including the compliancy of the extracellular matrix, the available growth factors, the adhesion of cells to the extracellular matrix, cell-cell signaling, etc. Although various computational models have been proposed to explain the role of each of these biochemical and biomechanical effects, the understanding of the mechanisms underlying in vitro angiogenesis is still incomplete. Most explanations focus on predicting the whole vascular network or sprout from the underlying cell behavior, and do not check if the same model also correctly captures the intermediate scale: the pairwise cell-cell interactions or single cell responses to ECM mechanics. Here we show, using a hybrid cellular Potts and finite element computational model, that a single set of biologically plausible rules describing (a) the contractile forces that endothelial cells exert on the ECM, (b) the resulting strains in the extracellular matrix, and (c) the cellular response to the strains, suffices for reproducing the behavior of individual endothelial cells and the interactions of endothelial cell pairs in compliant matrices. With the same set of rules, the model also reproduces network formation from scattered cells, and sprouting from endothelial spheroids. Combining the present mechanical model with aspects of previously proposed mechanical and chemical models may lead to a more complete understanding of in vitro angiogenesis.
authors.affiliation: Life Sciences group, Centrum Wiskunde & Informatica, Amsterdam, The Netherlands; Netherlands Consortium for System Biology - Netherlands Institute for Systems Biology, Amsterdam, The Netherlands.
authors.forename: René F M
authors.initials: RF
authors.lastname: van Oers
authors.affiliation: Life Sciences group, Centrum Wiskunde & Informatica, Amsterdam, The Netherlands; Netherlands Consortium for System Biology - Netherlands Institute for Systems Biology, Amsterdam, The Netherlands.
authors.forename: Elisabeth G
authors.initials: EG
authors.lastname: Rens
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: LaValley
authors.affiliation: Department of Biomedical Engineering, Cornell University, Ithaca, New York, United States of America.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Reinhart-King
authors.affiliation: Life Sciences group, Centrum Wiskunde & Informatica, Amsterdam, The Netherlands; Netherlands Consortium for System Biology - Netherlands Institute for Systems Biology, Amsterdam, The Netherlands; Mathematical Institute, Leiden University, Leiden, The Netherlands.
authors.forename: Roeland M H
authors.initials: RM
authors.lastname: Merks
mesh_terms: D000818:Animals; D002417:Cattle; D002450:Cell Communication / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape / Q000502:physiology; D002478:Cells, Cultured; D003198:Computer Simulation; D042783:Endothelial Cells / Q000166:cytology*; D005109:Extracellular Matrix / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D018874:Spheroids, Cellular / Q000166:cytology / Q000502:physiology