A mathematical analysis of an activator-inhibitor Rho GTPase model

Juma, Victor Ogesa; Dehmelt, Leif; Portet, Stéphanie; Madzvamuse, Anotida

doi:10.3934/jcd.2021024

Cited by 6 publications

(4 citation statements)

References 42 publications

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“…We also observed that total levels of Rac1 and RhoA in healing monolayers are reduced in Yoda1-treated compared to DMSO-treated samples (S12 Fig) . While the downregulation of Rho GTPases provides an initial insight into the mechanism underlying PIEZO1-mediated inhibition of leader cells in collective migration, a detailed characterization of this relationship surpasses the scope of work covered within this paper. In future work, we can use mathematical modeling to investigate the relationship between PIEZO1 and Rho GTPases in keratinocyte collective migration by incorporating activator-inhibitor systems for Rho GTPase feedback networks [71] and spatial dynamics [72] into our modeling framework.…”

Section: Discussionmentioning

confidence: 99%

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

Holt

Chen

Evans

et al. 2022

Preprint

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The collective migration of keratinocytes during wound healing requires both the generation and transmission of mechanical forces for individual cellular locomotion as well as for the coordination of movement across cells. Leader cells initiated along the wound edge transmit mechanical and biochemical cues to ensuing follower cells, ensuring their uniform polarization and coordinated direction of migration, or directionality. Despite the observed importance of mechanical cues in leader cell formation and controlling directionality, the underlying biophysical mechanisms remain elusive. The mechanically activated ion channel PIEZO1 was recently identified to play an inhibitory role during the reepithelialization of wounds through retraction of keratinocytes located along the wound edge. Here, through an integrative experimental and mathematical modeling approach, we elucidate PIEZO1's contributions to collective migration. Time-lapse microscopy reveals that PIEZO1 activity inhibits leader cell formation along the wound edge. To probe the relationship between PIEZO1 activity, leader cell formation and inhibition of reepithelialization, we developed an integrative 2D-multiscale model of wound closure that links observations at the single cell and collective cell migration scales. Through numerical simulations and subsequent experimental validation, we found that directionality plays a key role during wound closure and is inhibited by PIEZO1 activity. We propose that PIEZO1-mediated retraction suppresses leader cell formation which inhibits the coordination of directionality between cells during collective migration.

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Section: Discussionmentioning

confidence: 99%

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

Holt

Chen

Evans

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…We also observed that total levels of Rac1 and RhoA in healing monolayers are reduced in Yoda1-treated compared to DMSOtreated samples (S12 Fig) . While the downregulation of Rho GTPases provides an initial insight into the mechanism underlying PIEZO1-mediated inhibition of leader cells in collective migration, a detailed characterization of this relationship surpasses the scope of work covered within this paper. In future work, we can use mathematical modeling to investigate the relationship between PIEZO1 and Rho GTPases in keratinocyte collective migration by incorporating activator-inhibitor systems for Rho GTPase feedback networks [71] and spatial dynamics [72] into our modeling framework.…”

Section: Plos Computational Biologymentioning

confidence: 99%

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

Chen,

Holt,

Evans

et al. 2024

PLoS Comput Biol

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The collective migration of keratinocytes during wound healing requires both the generation and transmission of mechanical forces for individual cellular locomotion and the coordination of movement across cells. Leader cells along the wound edge transmit mechanical and biochemical cues to ensuing follower cells, ensuring their coordinated direction of migration across multiple cells. Despite the observed importance of mechanical cues in leader cell formation and in controlling coordinated directionality of cell migration, the underlying biophysical mechanisms remain elusive. The mechanically-activated ion channel PIEZO1 was recently identified to play an inhibitory role during the reepithelialization of wounds. Here, through an integrative experimental and mathematical modeling approach, we elucidate PIEZO1’s contributions to collective migration. Time-lapse microscopy reveals that PIEZO1 activity inhibits leader cell formation at the wound edge. To probe the relationship between PIEZO1 activity, leader cell formation and inhibition of reepithelialization, we developed an integrative 2D continuum model of wound closure that links observations at the single cell and collective cell migration scales. Through numerical simulations and subsequent experimental validation, we found that coordinated directionality plays a key role during wound closure and is inhibited by upregulated PIEZO1 activity. We propose that PIEZO1-mediated retraction suppresses leader cell formation which inhibits coordinated directionality between cells during collective migration.

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“…The direct differential method (DDM) is used for carrying out local sensitivity analysis. The DDM allows us to fully characterize each sensitivity index as a function of the independent variable [ 56 , 57 ]. Therefore, given the analytic expression of the reproduction number, we differentiate it with respect to each parameter and evaluate the resulting derivatives with the estimated (nominal) parameters for each wave.…”

Section: Sensitivity Analysismentioning

confidence: 99%

COVID-19 transmission dynamics and the impact of vaccination: modelling, analysis and simulations

Malinzi,

Juma,

Madubueze

et al. 2023

R. Soc. open sci.

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Despite the lifting of COVID-19 restrictions, the COVID-19 pandemic and its effects remain a global challenge including the sub-Saharan Africa (SSA) region. Knowledge of the COVID-19 dynamics and its potential trends amidst variations in COVID-19 vaccine coverage is therefore crucial for policy makers in the SSA region where vaccine uptake is generally lower than in high-income countries. Using a compartmental epidemiological model, this study aims to forecast the potential COVID-19 trends and determine how long a wave could be, taking into consideration the current vaccination rates. The model is calibrated using South African reported data for the first four waves of COVID-19, and the data for the fifth wave are used to test the validity of the model forecast. The model is qualitatively analysed by determining equilibria and their stability, calculating the basic reproduction number R 0 and investigating the local and global sensitivity analysis with respect to R 0 . The impact of vaccination and control interventions are investigated via a series of numerical simulations. Based on the fitted data and simulations, we observed that massive vaccination would only be beneficial (deaths averting) if a highly effective vaccine is used, particularly in combination with non-pharmaceutical interventions. Furthermore, our forecasts demonstrate that increased vaccination coverage in SSA increases population immunity leading to low daily infection numbers in potential future waves. Our findings could be helpful in guiding policy makers and governments in designing vaccination strategies and the implementation of other COVID-19 mitigation strategies.

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A mathematical analysis of an activator-inhibitor Rho GTPase model

Cited by 6 publications

References 42 publications

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration

COVID-19 transmission dynamics and the impact of vaccination: modelling, analysis and simulations

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