A local uPAR-plasmin-TGFβ1 positive feedback loop in a qualitative computational model of angiogenic sprouting explains the in vitro effect of fibrinogen variants

Sonja E. M. Boas, Joao Carvalho, Marloes van den Broek, Ester M. Weijers, Marie-José Goumans, Pieter Koolwijk, Roeland M. H. Merks

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article numbere1006239
JournalPLoS Computational Biology
Volume14
Issue number7
DOIs
Publication statusPublished - 2018

Cite this

Boas, Sonja E. M. ; Carvalho, Joao ; van den Broek, Marloes ; Weijers, Ester M. ; Goumans, Marie-José ; Koolwijk, Pieter ; Merks, Roeland M. H. / A local uPAR-plasmin-TGFβ1 positive feedback loop in a qualitative computational model of angiogenic sprouting explains the in vitro effect of fibrinogen variants. In: PLoS Computational Biology. 2018 ; Vol. 14, No. 7.
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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.",
author = "Boas, {Sonja E. M.} and Joao Carvalho and {van den Broek}, Marloes and Weijers, {Ester M.} and Marie-Jos{\'e} Goumans and Pieter Koolwijk and Merks, {Roeland M. H.}",
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A local uPAR-plasmin-TGFβ1 positive feedback loop in a qualitative computational model of angiogenic sprouting explains the in vitro effect of fibrinogen variants. / Boas, Sonja E. M.; Carvalho, Joao; van den Broek, Marloes; Weijers, Ester M.; Goumans, Marie-José; Koolwijk, Pieter; Merks, Roeland M. H.

In: PLoS Computational Biology, Vol. 14, No. 7, e1006239, 2018.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - A local uPAR-plasmin-TGFβ1 positive feedback loop in a qualitative computational model of angiogenic sprouting explains the in vitro effect of fibrinogen variants

AU - Boas, Sonja E. M.

AU - Carvalho, Joao

AU - van den Broek, Marloes

AU - Weijers, Ester M.

AU - Goumans, Marie-José

AU - Koolwijk, Pieter

AU - Merks, Roeland M. H.

PY - 2018

Y1 - 2018

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