Multiscale mechanobiology: Coupling models of adhesion kinetics and nonlinear tissue mechanics

Guo, Yifan; Calve, Sarah; Tepole, Adrián Buganza

doi:10.1016/j.bpj.2022.01.012

Cited by 21 publications

(27 citation statements)

References 91 publications

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“…7). On the other hand, extensive recent work in cell mechanobiology has highlighted a strong sensitivity of fibroblast activity to ECM stiffness [76–78, 86] through a pathway involving integrin-mediated adhesion [77, 87, 88], which we have also recently used to explain stretch-mediated mechanosensitivity in cells by combining Bell’s adhesion kinetics with the typical nonlinear strain-stiffening of collagenous ECMs [89]. Indeed, considering stiffness-driven cell mechanosensitivity (Fig.…”

Section: Discussionmentioning

confidence: 99%

Mechano-biological and bio-mechanical pathways in cutaneous wound healing

Pensalfini

Tepole

2022

Preprint

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Skin injuries heal through coordinated action of fibroblast-mediated extracellular matrix (ECM) deposition, ECM remodeling, and wound contraction. Defects involving the dermis result in fibrotic scars featuring increased stiffness and altered collagen content and organization. Although computational models are crucial to unravel the underlying biochemical and biophysical mechanisms, simulations of the evolving wound biomechanics are seldom benchmarked against measurements. Here, we leverage recent quantifications of local tissue stiffness in murine wounds to refine a previously-proposed systems bio-chemo mechanobiological finite-element model. Fibroblasts are considered as the main cell type involved in ECM remodeling and wound contraction. Tissue rebuilding is coordinated by the release and diffusion of a cytokine wave, e.g. TGF-beta, itself developed in response to an earlier inflammatory signal triggered by platelet aggregation. We calibrate a model of the evolving wound biomechanics through a custom-developed hierarchical Bayesian inverse analysis. Further calibration is based on published biochemical and morphological murine wound healing data over a 21-day healing period. The calibrated model recapitulates the temporal evolution of: inflammatory signal, fibroblast infiltration, collagen buildup, and wound contraction. Moreover, it enables in silico hypothesis testing, which we explore by: (i) quantifying the alteration of wound contraction profiles corresponding to the measured variability in local wound stiffness; (ii) proposing alternative constitutive links connecting the dynamics of the biochemical fields to the evolving mechanical properties; (iii) discussing the plausibility of a stretch- vs. stiffness-mediated mechanobiological coupling. Ultimately, our model challenges the current understanding of wound biomechanics and mechanobiology, beside offering a versatile tool to explore and eventually control scar fibrosis after injury.

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Section: Discussionmentioning

confidence: 99%

Mechano-biological and bio-mechanical pathways in cutaneous wound healing

Pensalfini

Tepole

2022

Preprint

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“…An outstanding challenge in the field is relating measurable macroscale mechanics to microscale properties of cells and ECM cross-talk [Sree and Tepole, 2020]. ECM fiber network models can adequately address this challenge in sparse networks [Eichinger et al, 2021, Wang and Xu, 2020] or when populations at high cell density can be approximated with a continuum [Guo et al, 2022]. When individual cell behavior and ECM fiber dynamics are non-negligible, a more detailed model of both is needed [Eichinger et al, 2021, Guo et al, 2022, Sree and Tepole, 2020].…”

Section: Discussionmentioning

confidence: 99%

“…ECM fiber network models can adequately address this challenge in sparse networks [Eichinger et al, 2021, Wang and Xu, 2020] or when populations at high cell density can be approximated with a continuum [Guo et al, 2022]. When individual cell behavior and ECM fiber dynamics are non-negligible, a more detailed model of both is needed [Eichinger et al, 2021, Guo et al, 2022, Sree and Tepole, 2020]. We here provide such a model by introducing a coarse-grained discrete mechanical model of ECM fibers hybridized with CPM cells, and demonstrate the potential to calibrate it to biomechanical measurements, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…First, they oversimplify biological behavior of cells that are embedded into and interact with the fiber network [Sree and Tepole, 2020]. Second, they struggle with the mesoscale: They can only capture cell-ECM mechanobiology when cell density is very low [Eichinger et al, 2021, Guo et al, 2022], or, conversely, when cell density is very high such that multicellular collectives can be approximated by a continuum [Guo et al, 2022]. Cell-based models are naturally well-adapted to address both of these limitations.…”

Section: Introductionmentioning

confidence: 99%

“…Generally, these models treat cell-ECM mechanobiology implicitly by coarse-graining ECM fibers as a homogeneous material exerting uniform friction [Daub and Merks, 2013, Drasdo and Hoehme, 2012], or explicitly with a finite element model [Rens and Merks, 2017, 2020, Scott et al, 2020, Van Oers et al, 2014]. However, the characteristic length scale of ECM fibers is large compared to the cell size; thus, coarse-graining fails to capture some material properties, and a discrete representation is needed [Davidson et al, 2019, Guo et al, 2022, Wang and Xu, 2020]. Several cell-based models represent the ECM discretely, e.g.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modelling the mechanical cross-talk between cells and fibrous extracellular matrix using hybrid cellular Potts and molecular dynamics methods

Tsingos

Bakker

Keijzer

et al. 2022

Preprint

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Cell-based modelling frameworks such as cellular Potts are well-established tools to spatially model cell behavior and tissue morphogenesis. These models generally represent the extracellular matrix (ECM) with mean-field approaches, which assume substrate homogeneity. This assumption breaks down with fibrous ECM, which has non-trivial topology and mechanics. Here, we extend the cellular Potts software library Tissue Simulation Toolkit with the molecular mechanics framework hoomd-blue. We model cells mechanically interacting through discrete focal adhesion-like sites with an ECM fiber network modelled as bead-spring chains. Using a case study of an isolated contractile cell straining a randomly-oriented fiber network, we demonstrate agreement with experimental fiber densification and displacement dynamics. Further, we apply in silico atomic force microscopy to show local cell-induced network stiffening consistent with experiments. Our model overcomes the limitation of mean-field approaches to modelling ECM, and lays the foundation to investigate biomechanical cell-ECM interactions in a multicellular context.

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