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On the mechanics of actin and intermediate filament networks and their contribution to cellular mechanics
KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).ORCID iD: 0000-0002-6388-0995
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The mechanical behaviour of cells is essential in ensuring continued physiological function, and deficiencies therein can result in a variety of diseases. Also, altered mechanical response of cells can in certain cases be an indicator of a diseased state, and even actively promoting progression of pathology. In this thesis, methods to model cell and cytoskeletal mechanics are developed and analysed.

In Paper A, a constitutive model for the response of transiently cross-linked actin networks is developed using a continuum framework. A strain energy function is proposed and modified in terms of chemically activated cross-links.

In Paper B, a finite element framework was used to assess the influence of numerous geometrical and material parameters on the response of cross-linked actin networks, quantifying the influence of microstructural properties and cross-link compliance. Also, a micromechanically motivated constitutive model for cross-linked networks in a continuum framework was proposed.

In Paper C, the discrete model is extended to include the stochastic nature of cross-links. The strain rate dependence observed in experiments is suggested to depend partly on this.

In Paper D, the continuum model for cross-linked networks is extended to encompass more composite networks. Favourable comparisons to experiments indicate the interplay between phenomenological evolution laws to predict effects in biopolymer networks.

In Paper E, experimental and computational techniques are used to assess influence of the actin cytoskeleton on the mechanical response of fibroblast cells. The influence of cell shape is assessed, and experimental and computational aspects of cell mechanics are discussed.

In Paper F, the filament-based cytoskeletal model is extended with an active response to predict active force generation.  Importantly, experimentally observed stiffening of cells with applied stress is predicted.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. , 68 p.
Series
TRITA-HFL. Report / Royal Institute of Technology, Solid Mechanics, ISSN 1654-1472 ; 0583
Keyword [en]
actin, cell, mechanical, constitutive, intermediate, continuum, constitutive
National Category
Applied Mechanics
Research subject
Solid Mechanics
Identifiers
URN: urn:nbn:se:kth:diva-175748ISBN: 978-91-7595-752-4 (print)OAI: oai:DiVA.org:kth-175748DiVA: diva2:862607
Public defence
2016-01-29, Kollegiesalen, Brinellvägen 8, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, A0437201
Note

QC 20151209

Available from: 2015-12-09 Created: 2015-10-20 Last updated: 2015-12-09Bibliographically approved
List of papers
1. A chemo-mechanical constitutive model for transiently cross-linked actin networks and a theoretical assessment of their viscoelastic behaviour
Open this publication in new window or tab >>A chemo-mechanical constitutive model for transiently cross-linked actin networks and a theoretical assessment of their viscoelastic behaviour
2013 (English)In: Biomechanics and Modeling in Mechanobiology, ISSN 1617-7959, E-ISSN 1617-7940, Vol. 12, no 2, 373-382 p.Article in journal (Refereed) Published
Abstract [en]

Biological materials can undergo large deformations and also show viscoelastic behaviour. One such material is the network of actin filaments found in biological cells, giving the cell much of its mechanical stiffness. A theory for predicting the relaxation behaviour of actin networks cross-linked with the cross-linker alpha-actinin is proposed. The constitutive model is based on a continuum approach involving a neo-Hookean material model, modified in terms of concentration of chemically activated cross-links. The chemical model builds on work done by Spiros (Doctoral thesis, University of British Columbia, Vancouver, Canada, 1998) and has been modified to respond to mechanical stress experienced by the network. The deformation is split into a viscous and elastic part, and a thermodynamically motivated rate equation is assigned for the evolution of viscous deformation. The model predictions were evaluated for stress relaxation tests at different levels of strain and found to be in good agreement with experimental results for actin networks cross-linked with alpha-actinin.

Keyword
Viscoelasticity, alpha-actinin, Cross-link, Transient, Actin, Membrane
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-120524 (URN)10.1007/s10237-012-0406-7 (DOI)000316283900014 ()2-s2.0-84880729830 (Scopus ID)
Note

QC 20130411

Available from: 2013-04-11 Created: 2013-04-11 Last updated: 2017-12-06Bibliographically approved
2. Modelling of cross-linked actin networks - Influence of geometrical parameters and cross-link compliance
Open this publication in new window or tab >>Modelling of cross-linked actin networks - Influence of geometrical parameters and cross-link compliance
2014 (English)In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 350, 57-69 p.Article in journal (Refereed) Published
Abstract [en]

A major structural component of the cell is the actin cytoskeleton, in which actin subunits are polymerised into actin filaments. These networks can be cross-linked by various types of ABPs (Actin Binding Proteins), such as Filamin A. In this paper, the passive response of cross-linked actin filament networks is evaluated, by use of a numerical and continuum network model. For the numerical model, the influence of filament length, statistical dispersion, cross-link compliance (including that representative of Filamin A) and boundary conditions on the mechanical response is evaluated and compared to experimental results. It is found that the introduction of statistical dispersion of filament lengths has a significant influence on the computed results, reducing the network stiffness by several orders of magnitude. Actin networks have previously been shown to have a characteristic transition from an initial bending-dominated to a stretching-dominated regime at larger strains, and the cross-link compliance is shown to shift this transition. The continuum network model, a modified eight-chain polymer model, is evaluated and shown to predict experimental results reasonably well, although a single set of parameters cannot be found to predict the characteristic dependence of filament length for different types of cross-links. Given the vast diversity of cross-linking proteins, the dependence of mechanical response on cross-link compliance signifies the importance of incorporating it properly in models to understand the roles of different types of actin networks and their respective tasks in the cell.

Keyword
Filamin, Actin, Cross-link, Network, Cytoskeleton
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-145566 (URN)10.1016/j.jtbi.2014.01.032 (DOI)000334821000007 ()2-s2.0-84896842750 (Scopus ID)
Note

QC 20140611

Available from: 2014-06-11 Created: 2014-05-23 Last updated: 2017-12-05Bibliographically approved
3. Cross-link debonding in actin networks: influence on mechanical properties
Open this publication in new window or tab >>Cross-link debonding in actin networks: influence on mechanical properties
2015 (English)In: International Journal of Experimental and Computational Biomechanics, ISSN 1755-8743, Vol. 3, no 1, 16-26 p., b778558v5j17h4n8Article in journal (Refereed) Published
Abstract [en]

The actin cytoskeleton is essential for the continued function and survival of the cell. A peculiar mechanical characteristic of actin networks is their remodelling ability, providing them with a time-dependent response to mechanical forces. In cross-linked actin networks, this behaviour is typically tuned by the binding affinity of the cross-link. We propose that the debonding of a cross-link between filaments can be modelled using a stochastic approach, in which the activation energy for a bond is modified by a term to account for mechanical strain energy. By use of a finite element model, we perform numerical analyses in which we first compare the model behaviour to experimental results. The computed and experimental results are in good agreement for short time scales, but over longer time scales the stress is overestimated. However, it does provide a possible explanation for experimentally observed strain-rate dependence as well as strain-softening at longer time scales.

National Category
Applied Mechanics
Research subject
Solid Mechanics
Identifiers
urn:nbn:se:kth:diva-164408 (URN)10.1504/IJECB.2015.067679 (DOI)
Note

QC 20150506. QC 20160211. QC 20160314

Available from: 2015-04-16 Created: 2015-04-16 Last updated: 2016-03-14Bibliographically approved
4. Constitutive modelling of composite biopolymer networks
Open this publication in new window or tab >>Constitutive modelling of composite biopolymer networks
2016 (English)In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 395, 51-61 p.Article in journal (Refereed) Published
Abstract [en]

The mechanical behaviour of biopolymer networks is to a large extent determined at a microstructural level where the characteristics of individual filaments and the interactions between them determine the response at a macroscopic level. Phenomena such as viscoelasticity and strain-hardening followed by strain-softening are observed experimentally in these networks, often due to microstructural changes (such as filament sliding, rupture and cross-link debonding). Further, composite structures can also be formed with vastly different mechanical properties as compared to the indivudal networks. In this present paper, we present a constitutive model presented in a continuum framework aimed at capturing these effects. Special care is taken to formulate thermodynamically consistent evolution laws for dissipative effects. This model, incorporating possible anisotropic network properties, is based on a strain energy function, split into an isochoric and a volumetric part. Generalisation to three dimensions is performed by numerical integration over the unit sphere. Model predictions indicate that the constitutive model is well able to predict the elastic and viscoelastic response of biological networks, and to an extent also composite structures.

Place, publisher, year, edition, pages
Elsevier, 2016
Keyword
Composite, Actin, Intermediate, Neurofilament, Constitutive
National Category
Biophysics
Research subject
Solid Mechanics; Biological Physics
Identifiers
urn:nbn:se:kth:diva-173936 (URN)10.1016/j.jtbi.2016.01.034 (DOI)000373096700006 ()2-s2.0-84957991341 (Scopus ID)
Funder
Swedish Research Council, A0437201
Note

Updated from "Manuscript" to "Article".

QC 20160311

Available from: 2015-09-24 Created: 2015-09-24 Last updated: 2017-12-01Bibliographically approved
5. Experimental and computational assessment of F-actin influence in regulating cellular stiffness and relaxation behaviour of fibroblasts
Open this publication in new window or tab >>Experimental and computational assessment of F-actin influence in regulating cellular stiffness and relaxation behaviour of fibroblasts
Show others...
2016 (English)In: Journal of The Mechanical Behavior of Biomedical Materials, ISSN 1751-6161, E-ISSN 1878-0180, Vol. 59, 168-184 p.Article in journal (Refereed) Published
Abstract [en]

In biomechanics, a complete understanding of the structures and mechanisms that regulate cellular stiffness at a molecular level remain elusive. In this paper, we have elucidated the role of filamentous actin (F-actin) in regulating elastic and viscous properties of the cytoplasm and the nucleus. Specifically, we performed colloidal-probe atomic force microscopy (AFM) on BjhTERT fibroblast cells incubated with Latrunculin B (LatB), which results in depolymerisation of F-actin, or DMSO control. We found that the treatment with LatB not only reduced cellular stiffness, but also greatly increased the relaxation rate for the cytoplasm in the peripheral region and in the vicinity of the nucleus. We thus conclude that F-actin is a major determinant in not only providing elastic stiffness to the cell, but also in regulating its viscous behaviour. To further investigate the interdependence of different cytoskeletal networks and cell shape, we provided a computational model in a finite element framework. The computational model is based on a split strain energy function of separate cellular constituents, here assumed to be cytoskeletal components, for which a composite strain energy function was defined. We found a significant influence of cell geometry on the predicted mechanical response. Importantly, the relaxation behaviour of the cell can be characterised by a material model with two time constants that have previously been found to predict mechanical behaviour of actin and intermediate filament networks. By merely tuning two effective stiffness parameters, the model predicts experimental results in cells with a partly depolymerised actin cytoskeleton as well as in untreated control. This indicates that actin and intermediate filament networks are instrumental in providing elastic stiffness in response to applied forces, as well as governing the relaxation behaviour over shorter and longer time-scales, respectively.

Place, publisher, year, edition, pages
Elsevier, 2016
Keyword
Actin, relaxation, constitutive
National Category
Biophysics
Research subject
Solid Mechanics; Biological Physics
Identifiers
urn:nbn:se:kth:diva-173937 (URN)10.1016/j.jmbbm.2015.11.039 (DOI)2-s2.0-84952934669 (Scopus ID)
Funder
Swedish Research Council, A0437201
Note

Updated from "Manuscript" to "Article". QC 20160201

Available from: 2015-09-24 Created: 2015-09-24 Last updated: 2017-12-01Bibliographically approved
6. Implementing cell contractility in filament-based cytoskeletal models
Open this publication in new window or tab >>Implementing cell contractility in filament-based cytoskeletal models
2016 (English)In: Cytoskeleton, ISSN 1949-3584, Vol. 73, no 2, 12 p.93-106 p.Article in journal (Other (popular science, discussion, etc.)) Published
Abstract [en]

Cells are known to respond over time to mechanical stimuli, even actively generating force at longer times. In this paper, a microstructural filament-based cytoskeletal network model is extended to incorporate this active response, and a computational study to assess the influence on relaxation behaviour was performed. The incorporation of an active response was achieved by including a strain energy function of contractile activity from the cross-linked actin filaments. A four-state chemical model and strain energy function was adopted, and generalisation to three dimensions and the macroscopic deformation field was performed by integration over the unit sphere. Computational results in MATLAB and ABAQUS/Explicit indicated an active cellular response over various time-scales, dependent on contractile parameters. Important features such as force generation and increasing cell stiffness due to prestress are qualitatively predicted. The work in this paper can easily be extended to encompass other filament-based cytoskeletal models as well.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016. 12 p.
Keyword
Contractility, cell, constitutive, actin, cytoskeleton
National Category
Biophysics Materials Engineering
Research subject
Biological Physics; Solid Mechanics
Identifiers
urn:nbn:se:kth:diva-175408 (URN)10.1002/cm.21279 (DOI)000371414800004 ()26899417 (PubMedID)2-s2.0-84959460849 (Scopus ID)
Note

Updated from submitted to published.

QC 20160311. QC 20160407

Available from: 2015-10-14 Created: 2015-10-14 Last updated: 2016-12-02Bibliographically approved

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Citation style
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  • modern-language-association-8th-edition
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  • nn-NO
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  • Other locale
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Output format
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