Abstract
In experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting. More sprouts form on high molecular weight (HMW) than on low molecular weight (LMW) fibrin. It is unclear what mechanisms regulate the number and the positions of the vascular-like structures in cell cultures. To address this question, we propose a mechanistic simulation model of endothelial cell migration and fibrin proteolysis by the plasmin system. The model is a hybrid, cell-based and continuum, computational model based on the cellular Potts model and sets of partial-differential equations. Based on the model results, we propose that a positive feedback mechanism between uPAR, plasmin and transforming growth factor β1 (TGFβ1) selects cells in the monolayer for matrix invasion. Invading cells releases TGFβ1 from the extracellular matrix through plasmin-mediated fibrin degradation. The activated TGFβ1 further stimulates fibrin degradation and keeps proteolysis active as the sprout invades the fibrin matrix. The binding capacity for TGFβ1 of LMW is reduced relative to that of HMW. This leads to reduced activation of proteolysis and, consequently, reduced cell ingrowth in LMW fibrin compared to HMW fibrin. Thus our model predicts that endothelial cells in LMW fibrin matrices compared to HMW matrices show reduced sprouting due to a lower bio-availability of TGFβ1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Biological Availability
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Cell Movement
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Cells, Cultured
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Computer Simulation*
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Endothelial Cells / cytology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism
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Extracellular Matrix / metabolism
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Fibrin / chemistry
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Fibrin / metabolism
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Fibrinogen / metabolism*
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Fibrinolysin / metabolism*
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Fibrinolysis
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Humans
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In Vitro Techniques
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Molecular Weight
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Neovascularization, Physiologic / physiology*
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Proteolysis
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Receptors, Urokinase Plasminogen Activator / metabolism*
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Reproducibility of Results
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Transforming Growth Factor beta1 / metabolism*
Substances
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Receptors, Urokinase Plasminogen Activator
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TGFB1 protein, human
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Transforming Growth Factor beta1
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Fibrin
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Fibrinogen
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Fibrinolysin
Grants and funding
The work is part of the research programme “Innovational Research Incentives Scheme Vidi Cross-divisional 2010 ALW” with project number 864.10.009 to RMHM, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO;
http://www.nwo.nl). JC was financially supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal with grant SFRH/BSAB/113464/2015 and by Visitors Travel Grant 040.11.500 from the Netherlands Organisation for Scientific Research (NWO), Exacte Wetenschappen (EW). The Netherlands Institute for Regenerative Medicine (NIRM) supported MB, EW, MJG and PK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.