Biology subjects

Garcia-Aznar, J. M.

Publications and source records attributed to Garcia-Aznar, J. M..

7 recordsLinked to original sources

bioRxiv2025

Discrete viscoelastic model of deformable immune cell migration through confined tumor microchannels

Understanding the mechanical behavior of immune cells as they migrate through the complex environment of solid tumors may be crucial for improving immunotherapy strategies. In this work, we present a particle-based model that captures the large deformations of single immune cells migrating through confined microchannels, which mimic the narrow tumor micropores. In our model, the nucleus, cytoplasm, and membrane are simulated through discrete particles with varying interacting forces that account for the differences in the mechanical properties of the discrete parts of the cell. We compare and validate the model with experimental measurements from microfluidic devices, providing relevant mechanistic conclusions into the effects of changes in cellular stiffness on migration efficiency.

bioengineering↗

bioRxiv2025

Leveraging agent-based models and deep reinforcement learning to predict taxis in cell migration: Insights from barotaxis

We present a novel computational framework that combines Agent-Based Modeling (ABM) with Reinforcement Learning (RL) using the Double Deep Q-Network (DDQN) algorithm to determine cellular behavior in response to environmental signals. We showcase its potential by modeling how pressure gradients direct cell migration in confined environments, a phenomenon known as barotaxis. By integrating RL, the model allows cells to learn and adapt their migration behavior based on sensed pressure gradients, capturing the dynamic, environment-dependent nature of cell behavior. We validate the framework using real microfluidic devices and experimental data, demonstrating the models ability to predict barotactic migration. Thus, this approach introduces a novel direction for modeling how cells sense and transduce environmental cues into biological behaviors.

bioengineering↗

bioRxiv2022

Tumour growth: Bayesian parameter calibration of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment

To unravel processes that lead to the growth of solid tumours, it is necessary to link knowledge of cancer biology with the physical properties of the tumour and its interaction with the surrounding microenvironment. Our understanding of the underlying mechanisms is however still imprecise. We therefore developed computational physics-based models, which incorporate the interaction of the tumour with its surroundings based on the theory of porous media. However, the experimental validation of such models represents a challenge to its clinical use as a prognostic tool. This study combines a physics-based model with in vitro experiments based on microfluidic devices used to mimic a 3D tumour microenvironment. By conducting a global sensitivity analysis, we identify the most influential input parameters and infer their posterior distribution based on Bayesian calibration. The resulting probability density is in agreement with the scattering of the experimental data and thus validates the modelling approach. Using the proposed workflow, we demonstrate that we can indirectly characterise the mechanical properties of neuroblastoma spheroids that cannot feasibly be measured experimentally.

bioengineering↗

bioRxiv2021

Modeling the three-way feedback between cellular contractility, actin polymerization, and adhesion turnover resolves the contradictory effects of RhoA and Rac1 on endothelial junction dynamics

The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to atherosclerosis and tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the maintenance of endothelial junctions as dependent on the crosstalk between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Our theoretical model reveals that active cell tension can stabilize cadherin bonds within an adhesion, but excessive RhoA signaling can drive bond dissociation and junction failure. While Rac1-mediated actin polymerization aids gap closure, high levels of Rac1 may also facilitate junction weakening. Combining the modeling framework with novel experiments, we identify how dynamic rupture and heal cycles emerge and, further, describe why gaps tend to localize at multi-cell contacts. Beyond, our analysis also indicates that a critical balance between RhoA and Rac1 expression is required to maintain junction stability and limit endothelial dysfunction. The model predicts how pharmacological modulation of actin polymerization and cell contractility impacts junction stability, with predictions subsequently validated experimentally. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.

biophysics↗

bioRxiv2020

Conserved cysteines in titin sustain the mechanical function of cardiomyocytes

The protein titin determines cardiomyocyte contraction and truncating variants in the titin gene (TTN) are the most common cause of dilated cardiomyopathy (DCM). Different to truncations, missense variants in TTN are currently classified as variants of uncertain significance due to their high frequency in the population and the absence of functional annotation. Here, we report the regulatory role of conserved, mechanically active titin cysteines, which, contrary to current views, we uncover to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics. Building on our functional studies, we demonstrate that missense mutations targeting a conserved titin cysteine alter myocyte contractile function and cause DCM in humans. Our findings have a direct impact on genetic counselling in clinical practice. One sentence summaryMutations targeting cysteines key to the mechanoredox control of titin cause human dilated cardiomyopathy

physiology↗

bioRxiv2020

Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially-infected epithelial cells

Multiple distinct types of intracellular bacterial pathogens have been shown to alter the mechanics of their mammalian host cells to promote cell-to-cell spread. Conversely, host cells may respond by altering their own mechanical behavior to limit infection. We monitored epithelial cell monolayers sparsely infected with the intracellular bacterial pathogens Listeria monocytogenes or Rickettsia parkeri over the course of several days. Under conditions where these pathogens were able to trigger innate immune signaling through the NF-{kappa}B pathway and to use actin-based motility to spread non-lytically from cell to cell, domains of infected cells formed enormous three-dimensional mounds, where uninfected cells surrounding the infected cells became stiffer and actively moved toward the site of infection, collectively squeezing the softer and weaker infected cells up and ejecting them from the epithelial monolayer. Bacteria in mounds were less able to spread laterally in the monolayer, limiting the growth of the focus, while mounded cells eventually underwent cell death. Cells in infected monolayers exhibited behavioral and molecular signatures of the epithelial to mesenchymal transition (EMT), such that coordinated forceful action by uninfected bystander cells actively eliminated large domains of infected cells, consistent with the hypothesis that this collective cell response represents an innate immune response.

microbiology↗

bioRxiv2018

Balance of Mechanical Forces Drives Endothelial Gap Formation and May Facilitate Cancer and Immune-Cell Extravasation

The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolayer and show that the dynamic nature of the endothelium leads to spontaneous gap formation, even without intervention from the transmigrating cells. These gaps preferentially appear at the vertices between three endothelial cells, as opposed to the border between two cells. We quantify the frequency and lifetime of these gaps, and validate our predictions experimentally. Interestingly, we find experimentally that cancer cells also preferentially extravasate at vertices, even when they first arrest on borders. This suggests that extravasating cells, rather than initially signaling to the endothelium, might exploit the autonomously forming gaps in the endothelium to initiate transmigration.

bioengineering↗