Biology subjects

Weinberg, S. H.

Publications and source records attributed to Weinberg, S. H..

14 recordsLinked to original sources

bioRxiv2026

14-3-3 Enables β-Adrenergic Regulation of the Cardiac Sodium Channel at the Intercalated Disc

Background: Beta-Adrenergic stimulation enables the heart to adapt electrical activity to increased physiological demand. Although the cardiac sodium channel Nav1.5 is essential for impulse propagation, the mechanisms underlying its acute beta-adrenergic regulation, particularly within distinct cardiomyocyte membrane domains, remain poorly understood. We investigated whether the phosphorylation-sensitive adaptor protein 14-3-3 mediates this regulation. Methods and Results: Using automated patch-clamp electrophysiology in HEK293 cells and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we found that isoproterenol rapidly increased sodium current (INa) and promoted channel activation at more hyperpolarized potentials, whereas PKA inhibition reduced INa. Disruption of 14-3-3 function abolished these responses without substantially altering basal sodium current or Nav1.5 surface expression. Macropatch recordings from ventricular myocytes revealed that isoproterenol preferentially enhanced INa at the intercalated disc, an effect prevented by 14-3-3 inhibition. Proximity ligation assays further demonstrated increased Nav1.5/14-3-3 proximity following beta-adrenergic stimulation. Systematic mutagenesis identified S460 in the Nav1.5 DI-DII linker as a critical determinant of acute PKA-dependent regulation. Molecular modeling predicted that S460 phosphorylation stabilizes the Nav1.5/14-3-3 interaction. In CRISPR-engineered S460A iPSC-CMs, acute beta-adrenergic regulation of INa was abolished, whereas the isoproterenol-induced increase in conduction velocity was significantly attenuated. Computational simulations further predicted that enhanced intercalated-disc sodium current supports increased conduction velocity across varying conditions of electrical coupling and pacing rate. Conclusions: Our findings identify 14-3-3 and S460 as critical determinants of spatially selective beta-adrenergic regulation of Nav1.5 at the cardiac intercalated disc. This mechanism provides a molecular link between sympathetic signaling and cardiac sodium current regulation, supporting the concept that localized enhancement of Nav1.5 function contributes to the adaptation of cardiac conduction during increased sympathetic demand.

molecular biology↗

bioRxiv2026

Patient-Specific Heart Rate Modulates Developmental Electrophysiology in Transcriptomic-Guided In Silico Models of Pediatric Human Atrial Cardiomyocytes

Cardiac electrophysiology adapts throughout pediatric development, driven by factors including age-associated ion channel expression changes and decreasing heart rate. Our prior transcriptomic-guided simulations of human atrial cardiomyocytes predicted developmental-associated changes in electrophysiology biomarkers at a fixed pacing rate, leaving the contribution of age- and patient-specific heart rate unresolved. In this study, we incorporated intrinsic heart rate into gene expression-guided computational models to predict the interaction between developmental maturation and pacing rate to shape atrial electrophysiology. Virtual patient-specific populations of atrial cardiomyocytes were generated from the right atrial cardiomyocyte gene expression data from 117 patients, spanning neonates to young adults. We simulated each population at pacing rates corresponding to each patients intrinsic ECG-based heart rate and at fixed rates corresponding to the patient cohort minimum, median, and maximum. Action potential and calcium transient biomarkers were quantified, and partial least squares regression assessed key biomarker dependencies. For intrinsic-rate pacing conditions, action potential duration at 50% and 90% repolarization increased with age, whereas early repolarization shortened; maximum upstroke velocity increased, resting membrane potential became more negative, and alternans prevalence decreased. Developmental differences persisted during fixed-rate pacing conditions, indicating that differences were not explained solely by the faster heart rates of younger patients. Notably, intrinsic-rate simulations exhibited stronger age associations for upstroke velocity and alternans than fixed-rate simulations. Sensitivity analyses indicated that electrophysiological phenotypes arose from interactions among ionic conductances, calcium handling, age, and heart rate. Collectively, we find that pediatric atrial electrophysiology reflects both intrinsic developmental remodeling and rate-dependent modulation.

biophysics↗

bioRxiv2026

Dissecting Gap Junctional and Ephaptic Contributions to Electrical Conduction in a Novel Cardiomyocyte Pair Model

Electrical communication between excitable cells depends on both direct gap junction (GJ) currents and field-mediated ephaptic interactions, but their relative contributions have remained difficult to quantify experimentally, limiting mechanistic insight into arrhythmia and other disorders of bioelectric signaling in excitable tissues. Building on the concept of a nanoscale, sodium channel-rich perinexus at the cardiac intercalated disc, we developed a Single-on-Paired (SoP) preparation in which whole-cell sodium current is recorded from one adult ventricular myocyte that remains end-to-end coupled to an intact partner. This configuration revealed a composite two-cell sodium current characterized by a unique pre-peak waveform which exhibits two slopes in the rising phase, and a pronounced activation jump in sodium current amplitude between closely spaced voltage steps. This feature was absent in isolated single myocytes and interpretable as an Intercalated Disc Signature of intercellular activation. By combining graded GJ inhibition, perinexal widening via a Scn1b-derived competitive adhesion peptide, and controlled modulation of extracellular sodium, we show that low sodium conditions favor GJ-dominated activation, whereas at higher, more physiological sodium levels, perinexus-centered ephaptic mechanisms provide substantial support for intercellular activation. A complementary two-cell computational model, simulating our SoP model and incorporating lateral and junctional sodium channels, reproduces the two-cell Intercalated Disc Signature and predicts a shift from GJ-dominated activation at low sodium to ephaptic-dominated support at higher, more physiological sodium concentrations when GJ conductance is reduced. Together, these results provide direct experimental evidence for a specific structural and molecular substrate of ephaptic coupling in the heart and establish a framework for dissecting how nanoscale extracellular cleft geometry, channel organization, sodium level, and GJ conductance jointly tune electric-field-based mechanisms of activation in excitable tissues, with implications for paradoxical clinical responses to anti-arrhythmic interventions.

biophysics↗

bioRxiv2025

Hypernatremia Enhances Transient Outward Potassium and Late Sodium Currents in a Mouse Model of Long QT Syndrome Type 3

Cardiac voltage-gated sodium channel gain-of-function (NavGOF) is characterized by action potential duration (APD) prolongation. Hypernatremia and perinexal widening synergistically prolong cardiac APD in guinea pig. However, guinea pig lack the transient outward potassium current (Ito), which could be increased by hypernatremia and thereby shorten APD. ObjectiveDetermine whether hypernatremia and perinexal expansion synergistically prolong APD in an animal model functionally expressing Ito. MethodsWhole-cell Ito was measured in isolated genetically-modified NavGOF ({Delta}KPQ) mouse ventricular myocytes. Ventricular APD at 30 (APD30) and 90 (APD90) percent repolarization were measured from optically mapped, Langendorff-perfused wild-type (WT) and {Delta}KPQ mouse hearts at different perfusate sodium concentrations (145 or 160mM), without and with the perinexal adhesion antagonist {beta}adp1. ResultsIn isolated myocytes, hypernatremia (160mM sodium) increased Ito. In whole-heart, hypernatremia significantly decreased both APD30 and APD90 in WT but only APD30 in {Delta}KPQ preparations. Perinexal disruption with {beta}adp1 did not change APD30 or APD90 in WT hearts, however it decreased APD30 and increased APD90 in {Delta}KPQ hearts. Combination of hypernatremia and {beta}adp1 did not synergistically change APD in {Delta}KPQ hearts. Computational models predict that Ito activation can prevent synergistic APD prolongation in mouse during hypernatremia and perinexal expansion that was observed previously in a guinea pig NavGOF model lacking Ito. ConclusionsHypernatremia during NavGOF prevents early ventricular repolarization due to Ito activation (mouse) and prolongs repolarization in the absence of Ito (guinea pig). Future studies in animal models electrophysiologically similar to humans are needed to determine if hypernatremia and perinexal expansion are proarrhythmic during NavGOF.

physiology↗

bioRxiv2024

Calcium homeostatic feedback control predicts atrial fibrillation initiation, remodeling, and progression

Atrial fibrillation (AF) is a progressive disorder, with arrhythmia episodes becoming increasingly longer and ultimately permanent. The chaotic electrical activity by itself is well-known to drive progression, a process classically summarized as "AF begets AF." However, the mechanisms underlying this progression are not yet well defined. We hypothesize that calcium homeostatic feedback regulating ion channel expression is a critical mechanistic component of this pathological process. We propose a modeling framework that tracks both short-term beat-to-beat electrical and calcium activity and long-term tissue substrate remodeling as a single coupled dynamical system. Importantly, the full AF progression from healthy to pathological remodeled tissue is reproduced, in contrast with prior studies that consider "snapshots" of various AF stages. Simulations predict that single cells respond to fast pacing by maintaining intracellular calcium concentrations through dynamic ion channel expression and electrical phenotype changes. In two-dimensional (2D) homogeneous tissue, spontaneous spiral waves stabilize into permanent re-entry. In 2D heterogeneous tissue, we observe the initiation of re-entrant activity in response to fast pacing, followed by increasingly longer intermittent, and then permanent, arrhythmic activity. Simulations predict critical properties of re-entrant wave locations, leading to a novel hypothesis: spiral wave activity itself drives underlying substrate remodeling and the emergence of remodeled tissue "niches" that support the stabilization of fast re-entrant activity. Thus, the model joins multiple lines of inquiry (i.e., long-term calcium regulation, ion channel co-expression and remodeling, and tissue-scale arrhythmia spatiotemporal organization) into a single coherent framework, and for the first time, captures the dynamics of the long-term natural history of AF.

physiology↗

bioRxiv2024

Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in the Human Pediatric Myocardium

BackgroundNearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models. MethodsRight atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. ResultsEnrichment of differentially expressed genes (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, with changes in calcium handling (INCX) and repolarization (IK1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We also note a shift in repolarization reserve, with lower IKr expression in younger patients, a finding likely tied to the increased amplitude of IKs triggered by elevated sympathetic activation in pediatric patients. ConclusionThis study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.

cell biology↗

bioRxiv2023

Indirect Correlative Light and Electron Microscopy (iCLEM): A Novel Pipeline for Multiscale Quantification of Structure from Molecules to Organs

Correlative light and electron microscopy (CLEM) methods are powerful methods which combine molecular organization (from light microscopy) with ultrastructure (from electron microscopy). However, CLEM methods pose high cost/difficulty barriers to entry and have very low experimental throughput. Therefore, we have developed an indirect correlative light and electron microscopy (iCLEM) pipeline to sidestep the rate limiting steps of CLEM (i.e., preparing and imaging the same samples on multiple microscopes) and correlate multiscale structural data gleaned from separate samples imaged using different modalities by exploiting biological structures identifiable by both light and electron microscopy as intrinsic fiducials. We demonstrate here an application of iCLEM, where we utilized gap junctions and mechanical junctions between muscle cells in the heart as intrinsic fiducials to correlate ultrastructural measurements from transmission electron microscopy (TEM), and focused ion beam scanning electron microscopy (FIB-SEM) with molecular organization from confocal microscopy and single molecule localization microscopy (SMLM). We further demonstrate how iCLEM can be integrated with computational modeling to discover structure-function relationships. Thus, we present iCLEM as a novel approach that complements existing CLEM methods and provides a generalizable framework that can be applied to any set of imaging modalities, provided suitable intrinsic fiducials can be identified.

systems biology↗

bioRxiv2023

Sodium channel subpopulations with distinct biophysical properties and subcellular localization enhance cardiac conduction

Sodium (Na+) current is responsible for the rapid depolarization of cardiac myocytes that triggers the cardiac action potential upstroke. Recent studies have illustrated the presence of multiple "pools" of Na+ channels with distinct biophysical properties and subcellular localization, including clustering of channels at the intercalated disk and along the lateral membrane. Computational studies predict that Na+ channel clusters at the intercalated disk can regulate cardiac conduction via modulation of the narrow intercellular cleft between electrically coupled myocytes. However, these studies have primarily focused on the redistribution of Na+ channels between intercalated disk and lateral membranes and not considered the distinct biophysical properties of the Na+ channel subpopulations. In this study, we simulate computational models of single cardiac cells and one-dimensional cardiac tissues to predict the functional consequence of distinct Na+ channel subpopulations. Single cell simulations predict that a subpopulation of Na+ channels with shifted steady-state activation and inactivation voltage-dependency promote an earlier action potential upstroke. In cardiac tissues that account for distinct subcellular spatial localization, simulations predict that "shifted" Na+ channels contribute to faster and more robust conduction, with regards to sensitivity to tissue structural changes (i.e., cleft width), gap junctional coupling, and rapid pacing rates. Simulations predict that the intercalated disk-localized shifted Na+ channels provide a disproportionally larger contribution to total Na+ charge, relative to lateral membrane-localized Na+ channels. Importantly, our work supports the hypothesis that Na+ channel redistribution may be a critical mechanism by which cells can rapidly respond to perturbations to support fast and robust conduction. SummarySodium channels are organized in multiple "pools" with distinct biophysical properties and subcellular localization, but the role of these subpopulations is not well-understood. Computational modeling predicts that intercalated disk-localized sodium channels with shifted steady-state activation and inactivation voltage-dependence promote faster cardiac conduction.

physiology↗

bioRxiv2023

Unraveling Chamber-specific Differences in Intercalated Disc Ultrastructure and Molecular Organization and Their Impact on Cardiac Conduction

During each heartbeat, the propagation of action potentials through the heart coordinates the contraction of billions of individual cardiomyocytes and is thus, a critical life process. Unsurprisingly, intercalated discs, which are cell-cell contact sites specialized to provide electrical and mechanical coupling between adjacent cardiomyocytes, have been the focus of much investigation. Slowed or disrupted propagation leads to potentially life-threatening arrhythmias in a wide range of pathologies, where intercalated disc remodeling is a common finding. Hence, the importance and urgency of understanding intercalated disc structure and its influence on action potential propagation. Surprisingly, however, conventional modeling approaches cannot predict changes in propagation elicited by perturbations that alter intercalated disc ultrastructure or molecular organization, owing to lack of quantitative structural data at subcellular through nano scales. In order to address this critical gap in knowledge, we sought to quantify intercalated disc structure at these finer spatial scales in the healthy adult mouse heart and relate them to function in a chamber-specific manner as a precursor to understanding the impacts of pathological intercalated disc remodeling. Using super-resolution light microscopy, electron microscopy, and computational image analysis, we provide here the first ever systematic, multiscale quantification of intercalated disc ultrastructure and molecular organization. By incorporating these data into a rule-based model of cardiac tissue with realistic intercalated disc structure, and comparing model predictions of electrical propagation with experimental measures of conduction velocity, we reveal that atrial intercalated discs can support faster conduction than their ventricular counterparts, which is normally masked by inter-chamber differences in myocyte geometry. Further, we identify key ultrastructural and molecular organization features underpinning the ability of atrial intercalated discs to support faster conduction. These data provide the first stepping stone to elucidating chamber-specific impacts of pathological intercalated disc remodeling, as occurs in many arrhythmic diseases.

physiology↗

bioRxiv2022

Emergent Electrical Activity, Tissue Heterogeneity, and Robustness in a Calcium Feedback Regulatory Model of the Sinoatrial Node

The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN activity emerges at an early point in life and maintains a steady rhythm for the lifetime of the organism. The ion channel composition and currents of SAN cells can be influenced by a variety of factors. Therefore, the emergent activity and long-term stability imply some form of dynamical feedback control of SAN activity. We adapt a recent feedback model - previously utilized to describedion conductances in neurons - to a model of SAN cells and tissue. The model describes a minimal regulatory mechanism of ion channel conductances via feedback between intracellular calcium and an intrinsic target calcium level. By coupling a SAN cell to the calcium feedback model, we show that spontaneous electrical activity emerges from quiescence and is maintained at steady-state. In a 2D SAN tissue, spatial variability in intracellular calcium targets lead to significant, self-organized heterogeneous ion channel expression and calcium transients throughout the tissue. Further, multiple pacemaking regions appear, which interact and lead to time-varying cycle length, demonstrating that variability in heart rate is an emergent property of the feedback model. Finally, we demonstrate that the SAN tissue is robust to the silencing of leading cells or ion channel knockouts. Thus, the calcium feedback model can reproduce and explain many fundamental emergent properties of activity in the SAN that have been observed experimentally based on a minimal description of intracellular calcium and ion channel regulatory networks. Key Points SummaryO_LIThe robust function of the sinoatrial node (SAN) is reproduced in an intracellular calcium feedback model governing ion channel conductances C_LIO_LIThe feedback model predicts the emergence and long-term maintenance of spontaneous oscillatory electrical activity C_LIO_LIIntegrating the feedback model into a 2D SAN tissue leads to emergent spatial heterogeneity, multiple pacemaking regions, and variable cycle length C_LIO_LISAN cells and tissue with feedback are robust to cell injury and channel knock-outs C_LI

bioengineering↗

bioRxiv2021

Effects of substrate stiffness and actin velocity on fibronectin fibril morphometry and mechanics

Assembly of the extracellular matrix protein fibronectin (FN) into insoluble, viscoelastic fibrils is a critical step during embryonic development and wound healing; misregulation of FN fibril assembly has been implicated in many diseases, including fibrotic diseases and cancer. We have previously developed a computational model of FN fibril assembly that recapitulates the morphometry and mechanics of cell-derived FN fibrils. Here we use this model to probe two important questions: how is FN fibril formation affected by the contractile phenotype of the cell, and how is FN fibril formation affected by the stiffness of the surrounding tissue? We show that FN fibril formation depends strongly on the contractile phenotype of the cell, but only weakly on tissue stiffness. These results are consistent with previous experimental data and provide a better insight into conditions that promote FN fibril assembly. We have also used the model to look at two distinct phenotypes of FN fibrils that we have previously identified; we show that the ratio of the two phenotypes depends on both tissue stiffness and contractile phenotype, with intermediate contractility and high tissue stiffness creating an optimal condition for stably stretched fibrils. Finally, we have investigated how re-stretch of a fibril affects cellular response. We probed how the contractile phenotype of the re-stretching cell affects the mechanics of the fibril; results indicate that the number of myosin motors only weakly affects the cellular response, but increasing actin velocity results in a decrease in the apparent stiffness of the fibril and a decrease in the stably-applied force to the fibril. Taken together, these results give novel insights into the combinatorial effects of tissue stiffness and cell contractility on FN fibril assembly.

biophysics↗

bioRxiv2019

A Predictive Model of Intercellular Tension and Cell-Matrix Mechanical Interactions in a Multicellular Geometry

Epithelial cells form continuous sheets of cells that exist in tensional homeostasis. Homeostasis is maintained through cell-to-cell adhesions that distribute tension and balance forces between cells and their underlying matrix. Disruption of tensional homeostasis can lead to Epithelial-Mesenchymal Transition (EMT), which is a transdifferentiation process in which epithelial cells adopt a mesenchymal phenotype, where cell-cell adhesion is lost and individual cell migration is acquired. This process is critical during embryogenesis and wound healing, but is also dysregulated in many disease states. To further understand the role of intercellular tension in spatial patterning of epithelial cell monolayers, we developed a multicellular computational model of cell-cell and cell-substrate forces. This work builds on a hybrid Cellular Potts-finite element model to evaluate cell-matrix mechanical feedback of an adherent multicellular cluster. Thermodynamically-constrained cells migrate by generating traction forces on a finite element substrate to minimize the total energy of the system. Junctional forces at cell-cell contacts balance these traction forces, thereby producing a mechanically stable epithelial monolayer. Simulations were compared to in vitro experiments using fluorescence-based junction force sensors in clusters of cells undergoing EMT. Results indicate that the multicellular CPM model can reproduce many aspects of EMT, including epithelial monolayer formation dynamics, changes in cell geometry, and spatial patterning of cell geometry and cell-cell forces in an epithelial colony.\n\nAuthor summaryEpithelial cells line all organs of the human body and act as a protective barrier by forming a continuous sheet. These cells exert force on both their neighboring cells as well as the underlying extracellular matrix, which is a network of proteins that creates the structure of tissues. Here we develop a model that encompasses both cell-cell forces and cell-matrix forces in an epithelial cell sheet. The model accounts for cell migration and proliferation, and regulates how cell-cell adhesions are formed. We demonstrate how the interplay between cell-cell forces and cell-matrix forces can regulate the formation of the epithelial cell sheet, the organization of cells within the sheet, and the pattern of cell geometries and cell forces within the sheet. We compare computational results with experiments in which epithelial cell sheets are disrupted and cell-cell junction forces are measured, and demonstrate that the model captures many aspects of epithelial cell dynamics observed experimentally.

cell biology↗

bioRxiv2019

Cell fate forecasting: a data assimilation approach to predict epithelial-mesenchymal transition

Epithelial-mesenchymal transition (EMT) is a fundamental biological process that plays a central role in embryonic development, tissue regeneration, and cancer metastasis. Transforming growth factor-{beta} (TGF{beta}) is a major and potent inducer of this cellular transition, which is comprised of transitions from an epithelial state to an intermediate or partial EMT state, then to a mesenchymal state. Using computational models to predict state transitions in a specific experiment is inherently difficult for many reasons, including model parameter uncertainty and the error associated with experimental observations. In this study, we demonstrate that a data-assimilation approach using an ensemble Kalman filter, which combines limited noisy observations with predictions from a computational model of TGF{beta}-induced EMT, can reconstruct the cell state and predict the timing of state transitions. We used our approach in proof-of-concept \"synthetic\" in silico experiments, in which experimental observations were produced from a known computational model with the addition of noise. We mimic parameter uncertainty in in vitro experiments by incorporating model error that shifts the TGF{beta} doses associated with the state transitions. We performed synthetic experiments for a wide range of TGF{beta} doses to investigate different cell steady state conditions, and we conducted a parameter study varying several properties of the data-assimilation approach, including the time interval between observations, and incorporating multiplicative inflation, a technique to compensate for underestimation of the model uncertainty and mitigate the influence of model error. We find that cell state can be successfully reconstructed in synthetic experiments, even in the setting of model error, when experimental observations are performed at a sufficiently short time interval and incorporate multiplicative inflation. Our study demonstrates a feasible proof-of-concept for a data assimilation approach to forecasting the fate of cells undergoing EMT.\n\nAuthor summaryEpithelial-mesenchymal transition (EMT) is a biological process in which an epithelial cell loses core epithelial-like characteristics, such as tight cell-to-cell adhesion, and gains core mesenchymal-like characteristics, such as an increase in cell motility. EMT is a multistep process, in which the cell undergoes transitions from epithelial state to a partial or intermediate state, and then from a partial state to a mesenchymal state. In this study, we apply data assimilation to improve prediction of these state transitions. Data assimilation is an approach well known in the weather forecasting community, in which experimental observations are iteratively combined with predictions from a dynamical model to provide an improved estimation of both observed and unobserved system states. We show that this data assimilation approach can reconstruct cell state measurements and predict state transition dynamics using noisy observations, while minimizing the error produced by the limitations and imperfections of the dynamical model.

cell biology↗

bioRxiv2019

Mechanochemical coupling and junctional forces during collective cell migration

Cell migration, a fundamental physiological process in which cells sense and move through their surrounding physical environment, plays a critical role in development and tissue formation, as well as pathological processes, such as cancer metastasis and wound healing. During cell migration, dynamics are governed by the bidirectional interplay between cell-generated mechanical forces and the activity of Rho GTPases, a family of small GTP-binding proteins that regulate actin cytoskeleton assembly and cellular contractility. These interactions are inherently more complex during the collective migration of mechanically coupled cells, due to the additional regulation of cell-cell junctional forces. In this study, we present a minimal modeling framework to simulate the interactions between mechanochemical signaling in individual cells and interactions with cell-cell junctional forces during collective cell migration. We find that migration of individual cells depends on the feedback between mechanical tension and Rho GTPase activity in a biphasic manner. During collective cell migration, waves of Rho GTPase activity mediate mechanical contraction/extension and thus synchronization throughout the tissue. Further, cell-cell junctional forces exhibit distinct spatial patterns during collective cell migration, with larger forces near the leading edge. Larger junctional force magnitudes are associated with faster collective cell migration and larger tissue size. Simulations of heterogeneous tissue migration exhibit a complex dependence on the properties of both leading and trailing cells. Computational predictions demonstrate that collective cell migration depends on both the emergent dynamics and interactions between cellular-level Rho GTPase activity and contractility, and multicellular-level junctional forces.

biophysics↗