Mechanical Models of Complex Diseases

Thursday, June 17 at 04:15am (PDT)
Thursday, June 17 at 12:15pm (BST)
Thursday, June 17 08:15pm (KST)

SMB2021 SMB2021 Follow Wednesday (Thursday) during the "MS18" time block.
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Fabian Spill (University of Birmingham, USA)


Almost all complex diseases, including cancer, cardiovascular diseases, or asthma, have mechanical characteristics that were found to contribute to disease progression independently of well-studied molecular or genetic disease characteristics. Such mechanical characteristics include altered extracellular matrix properties or changes in cell mechanics. Mathematical models are developed to understand how cell and tissue mechanics change during disease progression, and, importantly, how cells are affected by these altered mechanical properties. Experiments and models have uncovered that almost all cell phenotypes can be affected by mechanical factors. Therefore, integrated mechano-chemical models are being developed that can lead to insights into the complex interplay of mechanical and non-mechanical disease signatures. Moreover, the importance of mechanics on disease progression makes interference with mechanics a promising therapeutic route for such diseases, where mathematical models can lead the way to identify novel treatment options.

Vijay Rajagopal

(University of Melbourne, Australia)
"Surface area-to-volume ratio, not cellular viscoelasticity is the major determinant of red blood cell traversal through small channels."
The remarkable deformability of red blood cells (RBCs) depends on the viscoelasticity of the plasma membrane and cell contents and the surface area to volume (SA:V) ratio; however, it remains unclear which of these factors is the key determinant for passage through small capillaries. We used a microfluidic device to examine the traversal of normal, stiffened, swollen, parasitised and immature RBCs. We show that dramatic stiffening of RBCs had no measurable effect on their ability to traverse small channels. By contrast, a moderate decrease in the SA:V ratio had a marked effect on the equivalent cylinder diameter that is traversable by RBCs of similar cellular viscoelasticity. We developed a finite element model that provides a coherent rationale for the experimental observations, based on the nonlinear mechanical behaviour of the RBC membrane skeleton. We conclude that the SA:V ratio should be given more prominence in studies of RBC pathologies.

Bindi Brook

(University of Nottingham, UK)
"Inflammation driven mechanical model of asthmatic airway remodelling"
Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we have developed a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. In this talk I will discuss our model predictions and in particular how they: (i) reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and pro- contractile cytokines; (ii) emergence of a persistent contractile tone observed in asthmatics; (iii) enable identification of various parameter combinations that may contribute to the existence of different asthma phenotypes, and combination of factors which may predispose severe asthmatics to fatal bronchospasms. Finally I will discuss how we plan to use this model to investigate how perturbations from a homoeostatic state might drive asthma pathogenesis.

Herbert Levine

(Northeastern University, USA)
"The role of extracellular matrix in motility and metastasis"
In order for cells to migrate from a primary tumor to the circulation as part of the metastatic cascade, it needs to traverse region of fibrous extracellular matrix (ECM). This material has interesting mechanical properties such as strain-stiffening and plasticity, and interesting effects on cells moving through it, such as contact guidance . And, cells themselves can secrete enzymes that modify the ECM, thereby engaging in 'reciprocal' communication with their microenvironment. Here we use simple computational models to try to better understand this set of phenomena.

Stephanie Fraley

(University of California San Diego, USA)
"A spatial model of YAP/TAZ mechanotransduction reveals new insights into how cells sense ECM dimensionality"
YAP/TAZ is a master regulator of mechanotransduction; cytoplasmic-to-nuclear translocation of YAP/TAZ responds to different physical cues, including substrate stiffness, substrate dimensionality, and cell shape, and is critical for cellular function and tissue homeostasis. However, the relative contributions and synergies of these biophysical signals to YAP/TAZ translocation remains unclear. For example, in 2D culture, YAP/TAZ nuclear localization correlates strongly with substrate stiffness while in 3D, YAP/TAZ translocation can increase with stiffness, decrease with stiffness, or remain unchanged. Here, we use spatial modeling of YAP/TAZ translocation in response to substrate stiffness to quantitatively analyze the relationships between substrate stiffness, cytosolic stiffness, nuclear mechanics, cell shape, and substrate dimensionality. Our model predicts that increasing substrate activation area through changes in culture dimensionality, while conserving cell volume, forces distinct shape changes that result in nonlinear effect on YAP/TAZ nuclear localization. Moreover, differences in substrate activation area versus total membrane area can account for counterintuitive trends in YAP/TAZ nuclear localization in 3D. Based on this multiscale investigation of the different system features of YAP/TAZ nuclear translocation, we predict that how a cell reads its environment is a complex information transfer function of multiple mechanical and biochemical factors. These predictions reveal design principles of cellular and tissue engineering for YAP/TAZ mechanotransduction.

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