Multiscale Models Coupling Chemical Signaling and Mechanical Properties for Studying Tissue Growth

Velagala, Vijay; Chen, Weitao; Alber, Mark; Zartman, Jeremiah J.

doi:10.1016/b978-0-12-817931-4.00010-8

Cited by 7 publications

(5 citation statements)

References 172 publications

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“…proper SAM growth and stem cell maintenance. While the cellular basis of tissue homeostasis has been studied extensively, including in animal systems [55][56][57][58][59][60], the relationship between signaling pathways and mechanical cues requires further elucidation. Thus, quantitative studies utilizing experiments and multiscale computational models coupling cell mechanics and signal transduction have the potential to reveal important insights about the interplay between biochemical and mechanical processes regulating tissue growth and homeostasis.…”

Section: Plos Computational Biologymentioning

confidence: 99%

Combined computational modeling and experimental analysis integrating chemical and mechanical signals suggests possible mechanism of shoot meristem maintenance

et al. 2022

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Stem cell maintenance in multilayered shoot apical meristems (SAMs) of plants requires strict regulation of cell growth and division. Exactly how the complex milieu of chemical and mechanical signals interact in the central region of the SAM to regulate cell division plane orientation is not well understood. In this paper, simulations using a newly developed multiscale computational model are combined with experimental studies to suggest and test three hypothesized mechanisms for the regulation of cell division plane orientation and the direction of anisotropic cell expansion in the corpus. Simulations predict that in the Apical corpus, WUSCHEL and cytokinin regulate the direction of anisotropic cell expansion, and cells divide according to tensile stress on the cell wall. In the Basal corpus, model simulations suggest dual roles for WUSCHEL and cytokinin in regulating both the direction of anisotropic cell expansion and cell division plane orientation. Simulation results are followed by a detailed analysis of changes in cell characteristics upon manipulation of WUSCHEL and cytokinin in experiments that support model predictions. Moreover, simulations predict that this layer-specific mechanism maintains both the experimentally observed shape and structure of the SAM as well as the distribution of WUSCHEL in the tissue. This provides an additional link between the roles of WUSCHEL, cytokinin, and mechanical stress in regulating SAM growth and proper stem cell maintenance in the SAM.

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Section: Plos Computational Biologymentioning

confidence: 99%

Combined computational modeling and experimental analysis integrating chemical and mechanical signals suggests possible mechanism of shoot meristem maintenance

et al. 2022

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“…Further, we report that key experimental observations of the dynamics of tissue shape changes across the final stages of larval wing disc development can be controlled by specific hypothesized mechanisms based on model simulations combined with experiments (Fig. 4,5,6). Analysis of experimental data reveals that an increase in local ratio of apical to basal levels of pMyoII leads to a decline in basal tissue curvature and an increase in thickness of the pouch cells specific to the medial domain (Fig.…”

Section: Introductionmentioning

confidence: 77%

“…The final shape of an organ is a result of the dynamic interplay between several cell-level processes [1][2][3][4] . Progress in uncovering the regulation of organ shape control can be achieved by using systems-level, multi-scale approaches 5 .…”

Section: Introductionmentioning

confidence: 99%

Balancing competing effects of tissue growth and cytoskeletal regulation duringDrosophilawing disc development

Kumar

Tsai

Mim

et al. 2022

Preprint

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Cytoskeletal structure and force generation within cells must be carefully regulated as the developing organ grows to reach a final size and shape. However, how the complex regulation of multiple features of tissue architecture is simultaneously coordinated remains poorly understood. Through iterations between experiments and novel computational multi-scale model simulations, we investigate the combined regulation of cytoskeletal regulation and proliferation in the growing wing imaginal disc. First, we found through experiments and calibrated model simulations that the local curvature and nuclear positioning of cells in the growing wing disc are defined by patterning of nested spatial domains of peaks in apical and basal contractility. Additionally, predictions from model simulations that incorporate a mechanistic description of interkinetic nuclear migration demonstrate that cell proliferation increases the local basal curvature of the wing disc. This is confirmed experimentally as basal curvature increases when growth and proliferation are increased through insulin signaling. In surprising contrast, we experimentally found that Decapentaplegic (Dpp), the key morphogen involved in both growth control and patterning of the anterior-posterior axis, counteracts increases in tissue bending due to cell proliferation via a combined mechanism that balances the competing impacts of both proliferation and patterning of cell contractility. Overall, the high conservation of these regulatory interactions suggests an important balancing mechanism through dual regulation of proliferation and cytoskeleton to meet the multiple criteria defining tissue morphogenesis.

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“…The pipeline can be extended for organ-level drug screening, allowing for the study of new mechanical functions of genes due to genetic or pharmacological perturbations. Further, this framework can be extended to studying other physical and biochemical processes such as embryogenesis 70,71 and models of plant development 72 . Of note, it can also be used to study any models of organogenesis as it is independent of the modeling framework or package used in the physics-based simulation, which makes it attractive for more complex computational models that incorporate subcellular elements 22,29,73,74 .…”

Section: Discussionmentioning

confidence: 99%

Reverse engineering morphogenesis through Bayesian optimization of physics-based models

Kumar,

Dowling,

Zartman

2023

Preprint

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Morphogenetic programs direct the cell signaling and nonlinear mechanical interactions between multiple cell types and tissue layers to define organ shape and size. A key challenge for systems and synthetic biology is determining optimal combinations of intra- and inter-cellular interactions to predict an organ’s shape, size, and function. Physics-based mechanistic models that define the subcellular force distribution facilitate this, but it is extremely challenging to calibrate parameters in these models from data. To solve this inverse problem, we created a Bayesian optimization framework to determine the optimal cellular force distribution such that the predicted organ shapes match the desired organ shapes observed within the experimental imaging data. This integrative framework employs Gaussian Process Regression (GPR), a non-parametric kernel-based probabilistic machine learning modeling paradigm, to learn the mapping functions relating to the morphogenetic programs that generate and maintain the final organ shape. We calibrated and tested the method on cross-sections ofDrosophilawing imaginal discs, a highly informative model organ system, to study mechanisms that regulate epithelial processes that range from development to cancer. As a specific test case, the parameter estimation framework successfully infers the underlying changes in core parameters needed to match simulation data with time series imaging data of wing discs perturbed with collagenase. Unexpectedly, the framework also identifies multiple distinct parameter sets that generate shapes similar to wild-type organ shapes. This platform enables an efficient, global sensitivity analysis to support the necessity of both actomyosin contractility and basal ECM stiffness to generate and maintain the curved shape of the wing imaginal disc. The optimization framework, combined with fixed tissue imaging, identified that Piezo, a mechanosensitive ion channel, impacts fold formation by regulating the apical-basal balance of actomyosin contractility and elasticity of ECM. This framework is extensible toward reverse-engineering the morphogenesis of any organ system and can be utilized in real-time control of complex multicellular systems.

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Multiscale Models Coupling Chemical Signaling and Mechanical Properties for Studying Tissue Growth

Cited by 7 publications

References 172 publications

Combined computational modeling and experimental analysis integrating chemical and mechanical signals suggests possible mechanism of shoot meristem maintenance

Combined computational modeling and experimental analysis integrating chemical and mechanical signals suggests possible mechanism of shoot meristem maintenance

Balancing competing effects of tissue growth and cytoskeletal regulation duringDrosophilawing disc development

Reverse engineering morphogenesis through Bayesian optimization of physics-based models

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