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Cell Invasion Dynamics into a Three Dimensional Extracellular Matrix Fibre Network.

Kim MC, Whisler J, Silberberg YR, Kamm RD, Asada HH - PLoS Comput. Biol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: BioSystems and Micromechanics IRG, Singapore MIT Alliance for Research and Technology, Singapore; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Experimental observations of filopodia state changes during penetration.A) 3-D confocal images showing filopodia protrusive, tugging, and contractile motions in GFP-transfected HUVECs, and remodeling of collagen fiber network at time points of 0, 2, 4, 6, 8 and 10 minutes. B) 3D collapsed images showing the crawling behavior of filopodial tip at time points 0, 2, 4, 6, 8 and 10 minutes. Blue sphere indicates a monitored location on the ECM, which was shown to be mechanically linked to the filopodial tip. Yellow arrows indicate directions of displacements of the blue sphere and the filopodial tip. Red arrows and red dots indicate filopodial tips and roots, respectively. C) Graph showing temporal variations of speeds at the tip of filopodium (Filo A in A) and blue sphere in B). D) Graphs showing filopodial length changes in Filo A and B over time. Graphs in E) and F) showing temporal variations in speedsn at both tip and root of the two filopodia: Filo A in E) and Filo B F). Note that plus and minus signs represent forward and backward movements of filopodium, respectively, and blue arrows in E) indicate fast oscillatory ‘load-and-fail’ traction dynamics during the retractile phase. T, C, and R in E) and F) indicate tugging, contractile, and retractile phases, respectively.
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pcbi.1004535.g005: Experimental observations of filopodia state changes during penetration.A) 3-D confocal images showing filopodia protrusive, tugging, and contractile motions in GFP-transfected HUVECs, and remodeling of collagen fiber network at time points of 0, 2, 4, 6, 8 and 10 minutes. B) 3D collapsed images showing the crawling behavior of filopodial tip at time points 0, 2, 4, 6, 8 and 10 minutes. Blue sphere indicates a monitored location on the ECM, which was shown to be mechanically linked to the filopodial tip. Yellow arrows indicate directions of displacements of the blue sphere and the filopodial tip. Red arrows and red dots indicate filopodial tips and roots, respectively. C) Graph showing temporal variations of speeds at the tip of filopodium (Filo A in A) and blue sphere in B). D) Graphs showing filopodial length changes in Filo A and B over time. Graphs in E) and F) showing temporal variations in speedsn at both tip and root of the two filopodia: Filo A in E) and Filo B F). Note that plus and minus signs represent forward and backward movements of filopodium, respectively, and blue arrows in E) indicate fast oscillatory ‘load-and-fail’ traction dynamics during the retractile phase. T, C, and R in E) and F) indicate tugging, contractile, and retractile phases, respectively.

Mentions: Experimental observation revealed additional behaviours of filopodia that support the mechanisms identified in our filopodia dynamic model as well as those of prior works [4–10]. Filopodial protrusive and contractile motions were recorded simultaneously with ECM fibers deformation and remodelling (Fig 5A and S11 Video). An example can be seen in Fig 5A: two filopodia extending in different directions and their proximal ECM fibers were tracked over time: ‘Filos A’ and ‘Filos B’. Filo A started crawling on collagen fibers at time 0, its tip was further protruded and branched along multiple collagen fibers in different directions (2 min, tugging phase); collagen fibers were stretched due to the contractile motion of filopodia (4 min, contractile phase); following that, fluctuating motions at the filopodial tip was further observed (6 min– 10 min, tugging phase).


Cell Invasion Dynamics into a Three Dimensional Extracellular Matrix Fibre Network.

Kim MC, Whisler J, Silberberg YR, Kamm RD, Asada HH - PLoS Comput. Biol. (2015)

Experimental observations of filopodia state changes during penetration.A) 3-D confocal images showing filopodia protrusive, tugging, and contractile motions in GFP-transfected HUVECs, and remodeling of collagen fiber network at time points of 0, 2, 4, 6, 8 and 10 minutes. B) 3D collapsed images showing the crawling behavior of filopodial tip at time points 0, 2, 4, 6, 8 and 10 minutes. Blue sphere indicates a monitored location on the ECM, which was shown to be mechanically linked to the filopodial tip. Yellow arrows indicate directions of displacements of the blue sphere and the filopodial tip. Red arrows and red dots indicate filopodial tips and roots, respectively. C) Graph showing temporal variations of speeds at the tip of filopodium (Filo A in A) and blue sphere in B). D) Graphs showing filopodial length changes in Filo A and B over time. Graphs in E) and F) showing temporal variations in speedsn at both tip and root of the two filopodia: Filo A in E) and Filo B F). Note that plus and minus signs represent forward and backward movements of filopodium, respectively, and blue arrows in E) indicate fast oscillatory ‘load-and-fail’ traction dynamics during the retractile phase. T, C, and R in E) and F) indicate tugging, contractile, and retractile phases, respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4593642&req=5

pcbi.1004535.g005: Experimental observations of filopodia state changes during penetration.A) 3-D confocal images showing filopodia protrusive, tugging, and contractile motions in GFP-transfected HUVECs, and remodeling of collagen fiber network at time points of 0, 2, 4, 6, 8 and 10 minutes. B) 3D collapsed images showing the crawling behavior of filopodial tip at time points 0, 2, 4, 6, 8 and 10 minutes. Blue sphere indicates a monitored location on the ECM, which was shown to be mechanically linked to the filopodial tip. Yellow arrows indicate directions of displacements of the blue sphere and the filopodial tip. Red arrows and red dots indicate filopodial tips and roots, respectively. C) Graph showing temporal variations of speeds at the tip of filopodium (Filo A in A) and blue sphere in B). D) Graphs showing filopodial length changes in Filo A and B over time. Graphs in E) and F) showing temporal variations in speedsn at both tip and root of the two filopodia: Filo A in E) and Filo B F). Note that plus and minus signs represent forward and backward movements of filopodium, respectively, and blue arrows in E) indicate fast oscillatory ‘load-and-fail’ traction dynamics during the retractile phase. T, C, and R in E) and F) indicate tugging, contractile, and retractile phases, respectively.
Mentions: Experimental observation revealed additional behaviours of filopodia that support the mechanisms identified in our filopodia dynamic model as well as those of prior works [4–10]. Filopodial protrusive and contractile motions were recorded simultaneously with ECM fibers deformation and remodelling (Fig 5A and S11 Video). An example can be seen in Fig 5A: two filopodia extending in different directions and their proximal ECM fibers were tracked over time: ‘Filos A’ and ‘Filos B’. Filo A started crawling on collagen fibers at time 0, its tip was further protruded and branched along multiple collagen fibers in different directions (2 min, tugging phase); collagen fibers were stretched due to the contractile motion of filopodia (4 min, contractile phase); following that, fluctuating motions at the filopodial tip was further observed (6 min– 10 min, tugging phase).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: BioSystems and Micromechanics IRG, Singapore MIT Alliance for Research and Technology, Singapore; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus