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1. Exploring cardiac form and function: A length‐scale computational biology approach

   https://doi.org/10.1002/wsbm.1470  

   Sherman, William F. ; Grosberg, Anna ( December 2019 , WIREs Systems Biology and Medicine)

   The ability to adequately pump blood throughout the body is the result of tightly regulated feedback mechanisms that exist across many spatial scales in the heart. Diseases which impede the function at any one of the spatial scales can cause detrimental cardiac remodeling and eventual heart failure. An overarching goal of cardiac research is to use engineered heart tissue in vitro to study the physiology of diseased heart tissue, develop cell replacement therapies, and explore drug testing applications. A commonality within the field is to manipulate the flow of mechanical signals across the various spatial scales to direct self‐organization and build functional tissue. Doing so requires an understanding of how chemical, electrical, and mechanical cues can be used to alter the cellular microenvironment. We discuss how mathematical models have been used in conjunction with experimental techniques to explore various structure–function relations that exist across numerous spatial scales. We highlight how a systems biology approach can be employed to recapitulate in vivo characteristics in vitro at the tissue, cell, and subcellular scales. Specific focus is placed on the interplay between experimental and theoretical approaches. Various modeling methods are showcased to demonstrate the breadth and power afforded to the systems biology approach. An overview of modeling methodologies exemplifies how the strengths of different scientific disciplines can be used to supplement and/or inspire new avenues of experimental exploration.

   This article is categorized under:

   Models of Systems Properties and Processes > Mechanistic Models

   Models of Systems Properties and Processes > Cellular Models

   Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

    

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2. Continuum interpretation of mechano-adaptation in micropatterned epithelia informed by in vitro experiments

   https://doi.org/10.1093/intbio/zyad009  

   Cook, Bernard L. ; Alford, Patrick W. ( August 2023 , Integrative Biology)

   Epithelial tissues adapt their form and function following mechanical perturbations, or mechano-adapt, and these changes often result in reactive forces that oppose the direction of the applied change. Tissues subjected to ectopic tensions, for example, employ behaviors that lower tension, such as increasing proliferation or actomyosin turnover. This oppositional behavior suggests that the tissue has a mechanical homeostasis. Whether attributed to maintenance of cellular area, cell density, or cell and tissue tensions, epithelial mechanical homeostasis has been implicated in coordinating embryonic morphogenesis, wound healing, and maintenance of adult tissues. Despite advances toward understanding the feedback between mechanical state and tissue response in epithelia, more work remains to be done to examine how tissues regulate mechanical homeostasis using epithelial sheets with defined micropatterned shapes. Here, we used cellular microbiaxial stretching (CμBS) to investigate mechano-adaptation in micropatterned tissues of different shape consisting of Madin–Darby canine kidney cells. Using the CμBS platform, tissues were subjected to a 30% stretch that was held for 24 h. We found that, following stretch, tissue stresses immediately increased then slowly evolved over time, approaching their pre-stretch values by 24 h. Organization of the actin cytoskeletal was found to play a role in this process: anisotropic ally structured tissues exhibited anisotropic stress patterns, and the cytoskeletal became more aligned following stretch and reorganized over time. Interestingly, in unstretched tissues, stresses also decreased, which was found to be driven by proliferation-induced cellular confinement and change in tissue thickness. We modeled these behaviors with a continuum-based model of epithelial growth that accounted for stress-induced actin remodeling and proliferation, and found this model to strongly capture experimental behavior. Ultimately, this combined experimental-modeling approach suggests that epithelial mechano-adaptation depends on cellular architecture and proliferation, which can be modeled with a field-averaged approach applicable to more specific contexts in which change is driven by epithelial mechanical homeostasis.

   Insight box Epithelial tissues adapt their form and function following mechanical perturbation, and it is thought that this ‘mechano-adaptation’ plays an important role in driving processes like embryonic morphogenesis, wound healing, and adult tissue maintenance. Here, we use cellular microbiaxial stretching to probe this process in vitro in small epithelial tissues whose geometries were both controlled and varied. By using a highly precise stretching device and a continuum mechanics modeling framework, we revealed that tissue mechanical state changes following stretch and over time, and that this behavior can be explained by stress-dependent changes in actin fibers and proliferation. Integration of these approaches enabled a systematic approach to empirically and precisely measure these phenomena.

    

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3. A computational model of induced pluripotent stem‐cell derived cardiomyocytes incorporating experimental variability from multiple data sources

   https://doi.org/10.1113/JP277724  

   Kernik, Divya C. ; Morotti, Stefano ; Wu, HaoDi ; Garg, Priyanka ; Duff, Henry J. ; Kurokawa, Junko ; Jalife, José ; Wu, Joseph C. ; Grandi, Eleonora ; Clancy, Colleen E. ( July 2019 , The Journal of Physiology)

   Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) capture patient‐specific genotype–phenotype relationships, as well as cell‐to‐cell variability of cardiac electrical activity

   Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes

   We have developed a whole‐cell model of iPSC‐CMs, composed of single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM outputs

   We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC‐CMs

   This framework links molecular mechanisms to cellular‐level outputs by revealing unique subsets of model parameters linked to known iPSC‐CM phenotypes

   There is a profound need to develop a strategy for predicting patient‐to‐patient vulnerability in the emergence of cardiac arrhythmia. A promisingin vitromethod to address patient‐specific proclivity to cardiac disease utilizes induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs). A major strength of this approach is that iPSC‐CMs contain donor genetic information and therefore capture patient‐specific genotype–phenotype relationships. A cited detriment of iPSC‐CMs is the cell‐to‐cell variability observed in electrical activity. We postulated, however, that cell‐to‐cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole‐cell model of iPSC‐CMs composed of simple model components comprising ion channel models with single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM data for all major ionic currents. By optimizing ionic current model parameters to multiple experimental datasets, we incorporate experimentally‐observed variability in the ionic currents. The resulting population of cellular models predicts robust inter‐subject variability in iPSC‐CMs. This approach links molecular mechanisms to known cellular‐level iPSC‐CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyse the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacological interventions for studying the mechanisms of rare events, such as arrhythmia triggers.

    

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4. Cell-Based Model of the Generation and Maintenance of the Shape and Structure of the Multilayered Shoot Apical Meristem of Arabidopsis thaliana

   https://doi.org/10.1007/s11538-018-00547-z  

   Banwarth-Kuhn, Mikahl ; Nematbakhsh, Ali ; Rodriguez, Kevin W. ; Snipes, Stephen ; Rasmussen, Carolyn G. ; Reddy, G. Venugopala ; Alber, Mark ( December 2018 , Bulletin of Mathematical Biology)

   One of the central problems in animal and plant developmental biology is deciphering how chemical and mechanical signals interact within a tissue to produce organs of defined size, shape, and function. Cell walls in plants impose a unique constraint on cell expansion since cells are under turgor pressure and do not move relative to one another. Cell wall extensibility and constantly changing distribution of stress on the wall are mechanical properties that vary between individual cells and contribute to rates of expansion and orientation of cell division. How exactly cell wall mechanical properties influence cell behavior is still largely unknown. To address this problem, a novel, subcellular element computational model of growth of stem cells within the multilayered shoot apical meristem (SAM) of Arabidopsis thaliana is developed and calibrated using experimental data. Novel features of the model include separate, detailed descriptions of cell wall extensibility and mechanical stiffness, deformation of the middle lamella, and increase in cytoplasmic pressure generating internal turgor pressure. The model is used to test novel hypothesized mechanisms of formation of the shape and structure of the growing, multilayeredSAMbased onWUSconcentration of individual cells controlling cell growth rates and layer-dependent anisotropic mechanical properties of subcellular components of individual cells determining anisotropic cell expansion directions. Model simulations also provide a detailed prediction of distribution of stresses in the growing tissue which can be tested in future experiments. 

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5. Aligned human cardiac syncytium for in vitro analysis of electrical, structural, and mechanical readouts

   https://doi.org/10.1002/bit.27582  

   Napiwocki, B. N. ; Lang, D. ; Stempien, A. ; Zhang, J. ; Vaidyanathan, R. ; Makielski, J. C. ; Eckhardt, L. L. ; Glukhov, A. V. ; Kamp, T. J. ; Crone, W. C. ( October 2020 , Biotechnology and Bioengineering)

   Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) have emerged as an exciting new tool for cardiac research and can serve as a preclinical platform for drug development and disease modeling studies. However, these aspirations are limited by current culture methods in which hPSC‐CMs resemble fetal human cardiomyocytes in terms of structure and function. Herein we provide a novel in vitro platform that includes patterned extracellular matrix with physiological substrate stiffness and is amenable to both mechanical and electrical analysis. Micropatterned lanes promote the cellular and myofibril alignment of hPSC‐CMs while the addition of micropatterned bridges enable formation of a functional cardiac syncytium that beats synchronously over a large two‐dimensional area. We investigated the electrophysiological properties of the patterned cardiac constructs and showed they have anisotropic electrical impulse propagation, as occurs in the native myocardium, with speeds 2x faster in the primary direction of the pattern as compared to the transverse direction. Lastly, we interrogated the mechanical function of the pattern constructs and demonstrated the utility of this platform in recording the strength of cardiomyocyte contractions. This biomimetic platform with electrical and mechanical readout capabilities will enable the study of cardiac disease and the influence of pharmaceuticals and toxins on cardiomyocyte function. The platform also holds potential for high throughput evaluation of drug safety and efficacy, thus furthering our understanding of cardiovascular disease and increasing the translational use of hPSC‐CMs.

    

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