Rigidity-driven growth and migration of epithelial cells on microstructured anisotropic substrates

Saez, Alexandre; Ghibaudo, Marion; Buguin, Axel; Silberzan, Pascal; Ladoux, Benoît

doi:10.1073/pnas.0702259104

Cited by 350 publications

(331 citation statements)

References 44 publications

(63 reference statements)

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“…1/K, the overall free energy, U, decreases with post stiffness, K p (equation (3.4) and figure 3d ). These predictions agree with the observations that cells prefer to migrate towards stiffer regions on a substrate with a stiffness gradient, which is known as durotaxis [28][29][30]: …”

Section: Cells Tend To Migrate Toward Stiffer Surroundingssupporting

confidence: 82%

A chemo-mechanical free-energy-based approach to model durotaxis and extracellular stiffness-dependent contraction and polarization of cells

Shenoy¹,

Wang²,

Xiao³

2016

Interface Focus.

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We propose a chemo-mechanical model based on stress-dependent recruitment of myosin motors to describe how the contractility, polarization and strain in cells vary with the stiffness of their surroundings and their shape. A contractility tensor, which depends on the distribution of myosin motors, is introduced to describe the chemical free energy of the cell due to myosin recruitment. We explicitly include the contributions to the free energy that arise from mechanosensitive signalling pathways (such as the SFX, Rho-Rock and MLCK pathways) through chemo-mechanical coupling parameters. Taking the variations of the total free energy, which consists of the chemical and mechanical components, in accordance with the second law of thermodynamics provides equations for the temporal evolution of the active stress and the contractility tensor. Following this approach, we are able to recover the well-known Hill relation for active stresses, based on the fundamental principles of irreversible thermodynamics rather than phenomenology. We have numerically implemented our free energy-based approach to model spatial distribution of strain and contractility in (i) cells supported by flexible microposts, (ii) cells on two-dimensional substrates, and (iii) cells in three-dimensional matrices. We demonstrate how the polarization of the cells and the orientation of stress fibres can be deduced from the eigenvalues and eigenvectors of the contractility tensor. Our calculations suggest that the chemical free energy of the cell decreases with the stiffness of the extracellular environment as the cytoskeleton polarizes in response to stress-dependent recruitment of molecular motors. The mechanical energy, which includes the strain energy and motor potential energy, however, increases with stiffness, but the overall energy is lower for cells in stiffer environments. This provides a thermodynamic basis for durotaxis, whereby cells preferentially migrate towards stiffer regions of the extracellular environment. Our models also explain, from an energetic perspective, why the shape of the cells can change in response to stiffness of the surroundings. The effect of the stiffness of the nucleus on its shape and the orientation of the stress fibres is also studied for all the above geometries. Along with making testable predictions, we have estimated the magnitudes of the chemo-mechanical coupling parameters for myofibroblasts based on data reported in the literature.

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Section: Cells Tend To Migrate Toward Stiffer Surroundingssupporting

confidence: 82%

A chemo-mechanical free-energy-based approach to model durotaxis and extracellular stiffness-dependent contraction and polarization of cells

Shenoy¹,

Wang²,

Xiao³

2016

Interface Focus.

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“…15 Cells can sense the mechanical properties of their environment and as a response to perceived mechanical stimuli, they generate biochemical activity along with the signal transduction mechanism called mechanotransduction. 16,17 The matrix stiffness can regulate cellular functions including adhesion, 18 spreading, 19 migration, 20 proliferation, 21 and differentiation. 13,22 One of the most commonly used synthetic polymers to investigate the effects of mechanical stimuli on cellular behavior is poly(ethylene glycol) (PEG), which provides precise control of material stiffness.…”

Section: ■ Introductionmentioning

confidence: 99%

Self-Assembled Peptide Amphiphile Nanofibers and PEG Composite Hydrogels as Tunable ECM Mimetic Microenvironment

Göktas

Çınar

Orujalipoor³

et al. 2015

Biomacromolecules

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Natural extracellular matrix (ECM) consists of complex signals interacting with each other to organize cellular behavior and responses. This sophisticated microenvironment can be mimicked by advanced materials presenting essential biochemical and physical properties in a synergistic manner. In this work, we developed a facile fabrication method for a novel nanofibrous self-assembled peptide amphiphile (PA) and poly(ethylene glycol) (PEG) composite hydrogel system with independently tunable biochemical, mechanical, and physical cues without any chemical modification of polymer backbone or additional polymer processing techniques to create synthetic ECM analogues. This approach allows noninteracting modification of multiple niche properties (e.g., bioactive ligands, stiffness, porosity), since no covalent conjugation method was used to modify PEG monomers for incorporation of bioactivity and porosity. Combining the self-assembled PA nanofibers with a chemically cross-linked polymer network simply by facile mixing followed by photopolymerization resulted in the formation of porous bioactive hydrogel systems. The resulting porous network can be functionalized with desired bioactive signaling epitopes by simply altering the amino acid sequence of the self-assembling PA molecule. In addition, the mechanical properties of the composite system can be precisely controlled by changing the PEG concentration. Therefore, nanofibrous self-assembled PA/ PEG composite hydrogels reported in this work can provide new opportunities as versatile synthetic mimics of ECM with independently tunable biological and mechanical properties for tissue engineering and regenerative medicine applications. In addition, such systems could provide useful tools for investigation of how complex niche cues influence cellular behavior and tissue formation both in two-dimensional and three-dimensional platforms.

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“…Thus, the behaviour of different normal cells has been examined using a large variety of micropatterned substrates such as columns [13,14], dots [15], pits [14,16], pores [3], gratings [17] and random surface roughness [18], created by a variety of microlithography and microfabrication techniques. Thus, the use of surfaces with patterned topologies and adhesivity to organise cells morphologies has become a common strategy in tissue engineering.…”

Section: Introductionmentioning

confidence: 99%

The motility of normal and cancer cells in response to the combined influence of the substrate rigidity and anisotropic microstructure

Tzvetkova-Chevolleau¹,

Stéphanou²,

Fuard³

et al. 2008

Biomaterials

160

110

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Cell adhesion and migration are strongly influenced by extracellular matrix (ECM) architecture and rigidity, but little is known about the concomitant influence of such environmental signals to cell responses, especially when considering cells of similar origin and morphology, but exhibiting a normal or cancerous phenotype. Using micropatterned polydimethylsiloxane substrates (PDMS) with tuneable stiffness (500kPa, 750kPa, 2000kPa) and topography (lines, pillars or unpatterned), we systematically analyse the differential response of normal (3T3) and cancer (SaI/N) fibroblastic cells. Our results demonstrate that both cells exhibit differential morphology and motility responses to changes in substrate rigidiy and microtopography. 3T3 polarization and spreading are influenced by substrate microtopography and rigidity. The cells exhibit a persistent type of migration, which depends on the substrate anisotropy. In contrast, the dynamic of SaI/N spreading is strongly modified by the substrate topography but not by substrate rigidity. SaI/N morphology and migration seem to escape from extracellular cues: the cells exhibit uncorrelated migration trajectories and a large dispersion of their migration speed, which increases with substrate rigidity. Abstract

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Rigidity-driven growth and migration of epithelial cells on microstructured anisotropic substrates

Cited by 350 publications

References 44 publications

A chemo-mechanical free-energy-based approach to model durotaxis and extracellular stiffness-dependent contraction and polarization of cells

A chemo-mechanical free-energy-based approach to model durotaxis and extracellular stiffness-dependent contraction and polarization of cells

Self-Assembled Peptide Amphiphile Nanofibers and PEG Composite Hydrogels as Tunable ECM Mimetic Microenvironment

The motility of normal and cancer cells in response to the combined influence of the substrate rigidity and anisotropic microstructure

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