Biology subjects

Gov, N.

Publications and source records attributed to Gov, N..

At least 19 recordsLinked to original sources

bioRxiv2026

A minimal physical model of adhesion-dependent protrusion explains confined haptotaxis and oscillatory cell migration

Haptotaxis is the directed migration of cells along gradients of substrate adhesion, and is an important guidance mechanism in biology. Recent experiments on fibronectin-patterned tracks show that cells typically migrate toward higher adhesion, then oscillate around the adhesion maximum, with substantial variability in speed and cell length. To explain these cellular shape and migration dynamics we present a minimal model for confined haptotaxis, built around one key physical ingredient: local adhesion strength directly enhances the recruitment of protrusive actin polymerization activity at the cell edge. This coupling creates a front-rear difference in protrusive activity, biasing the cell towards polarization in the direction of the higher adhesion. Quantitative comparison with experiment shows strong agreement at multiple levels: cell population-level directionality statistics and position-dependent changes in cell length and velocity. At the single-cell level, the model reproduces the full diversity of experimentally observed trajectories, including haptotactic bias and its dependence on adhesion-gradient strength, initial position, length and speed variations, myosin II inhibition, and migration on inverted adhesion gradients. Variability in experimental trajectories and migration speed is explained by differences in intrinsic actin polymerization activity and stochastic fluctuations, accounting for the full spectrum of observed migration patterns. Together, our results identify adhesion-dependent amplification of protrusive activity as a minimal and sufficient physical mechanism for understanding haptotaxis.

biophysics↗

bioRxiv2026

Cell Cluster Geometry and Fluidity Control the Transition from Single-Cell Chemorepulsion to Collective Chemotaxis

Directed migration along chemical gradients controls immune surveillance, development, and cancer invasion. However, the same chemical cue can produce different responses depending on its concentration and whether cells move alone or in groups. For example, in steep gradients, isolated malignant lymphocyte cells migrate away from the chemoattractant source, whereas clusters of the same cells continue to migrate toward it. Here, combining computational modeling and experimental observations, we show that this reversal is governed by coupled mechanisms acting across molecular, cellular, and collective scales. At the single-cell level, our model predicts that receptor endocytosis generates a feedback that produces a nonmonotonic surface receptor density with increasing chemoattractant concentration. Above a critical concentration that depends on the cells volume-to-sensing-area ratio, receptor depletion reverses cell polarity and drives chemorepulsion. However, in clusters, cell-cell contacts reduce the membrane area exposed to ligand, increasing the volume-to-sensing-area ratio, thus increasing the critical concentration and preserving chemotaxis. An agent-based model incorporating these mechanisms quantitatively reproduces the sign reversal of the migration index across gradient steepness and cluster size. We show that collective rearrangements further stabilize chemoattraction with exchanges between the cluster rim and core helping remove chemorepulsive cells from the leading edge, keeping their fraction below the threshold required to reverse cluster migration. The model further predicts, and experiments confirm, that increasing ambient ligand concentration while keeping the gradient fixed reduces cluster chemoattraction. Our results identify receptor trafficking, cell geometry, and cluster fluidity as physical determinants of collective directional decision-making, with implications for immune cell homing, tissue morphogenesis, and cancer dissemination.

biophysics↗

bioRxiv2025

In form for a swarm: programmable neutrophil swarming impacts infection outcome

Many migrating cells pattern signalling molecules to support their accumulation in target tissues. During inflammation, neutrophils achieve rapid swarming at sites of injury or infection by generating spatiotemporal gradients of chemoattractants. Whether these self-generated behaviours can be re-programmed to change disease course is unclear. Here, we show that neutrophil chemoattractant patterning machinery is subject to transcriptional reprogramming after microbial experience, leading to enhanced swarming and control of infection at subsequent wound sites in zebrafish. Through in vitro assays, we demonstrate that "trained swarming phenotypes" are cell-intrinsic and independent of the nature of the microbial target. Furthermore, genetic enhancement of 5-lipoxygenase in neutrophils is sufficient to improve neutrophil swarming and resistance to wound infection. Through mathematical modelling, we demonstrate that neutrophil-intrinsic alterations in chemoattractant release are sufficient to recapitulate trained swarming in infection-experienced animals. Together, these data suggest new routes for reprogramming cell migration in disease settings, via manipulating their ability to shape chemoattractant landscapes.

immunology↗

bioRxiv2025

Chemotaxis of branched cells in complex environments

Cell migration in vivo is often guided by chemical signals. Such chemotaxis, such as performed by immune cells migrating to a wound site, is complicated by the complex geometry inside living tissues. In this study, we extend our theoretical model of branched-cell migration on a network by introducing chemokine sources to explore the cellular response. The model predicts a speed-accuracy tradeoff, whereby slow cells are significantly more accurate and able to follow efficiently a weak chemoattractant signal. We then compare the models predictions with experimental observations of neutrophils migrating to the site of laser-inflicted wound in a zebrafish larva fin, and migrating in-vitro inside a regular lattice of pillars. We find that the model captures the details of the sub-cellular response to the chemokine gradient, as well as the large-scale migration response. This comparison suggests that the neutrophils behave as fast cells, compromising their chemotaxis accuracy, which explains the functionality of these immune cells.

biophysics↗

bioRxiv2025

Corrections in single cell migration path in vivo are controlled by pulses in polar Rac1 activation

Directed migration of single cells is central to a large number of processes in development and adult life. Corrections to the migration path of cells are often characterized by periodic loss of polarity that is followed by the generation of a new leading edge in response to guidance cues, a behavior termed run and tumble. While this phenomenon is essential for accurate arrival at migration targets, the precise molecular mechanisms responsible for the periodic changes in cell polarity are unknown. To investigate this issue, we employ germ cells in live zebrafish embryos as an in vivo model and show that a tunable molecular network controls periodic pulsations of Rac1 activity and actin polymerization. This process, which we term polar pulsations, is responsible for the transitions between the run and tumble phases. In addition, we provide evidence for the role of apolar blebbing activity during tumble phases in erasing the memory of the previous front-back polarity of the migrating cell. To understand how the molecular components give rise to this distinct behavior, we develop a minimal mathematical model of the biochemical network that accounts for the observed cell behavior. Together, our in vivo findings and the mathematical model suggest that a pulsatory signaling network regulates the accuracy of individual cell migration.

cell biology↗

bioRxiv2024

Integrated Ising Model with global inhibition for decision making

Humans and other organisms make decisions choosing between different options, with the aim to maximize the reward and minimize the cost. The main theoretical framework for modeling the decision-making process has been based on the highly successful drift-diffusion model, which is a simple tool for explaining many aspects of this process. However, new observations challenge this model. Recently, it was found that inhibitory tone increases during high cognitive load and situations of uncertainty, but the origin of this phenomenon is not understood. Motivated by this observation, we extend a recently developed model for decision making while animals move towards targets in real space. We introduce an integrated Ising-type model, that includes global inhibition, and use it to explore its role in decision-making. This model can explain how the brain may utilize inhibition to improve its decision-making accuracy. Compared to experimental results, this model suggests that the regime of the brains decision-making activity is in proximity to a critical transition line between the ordered and disordered. Within the model, the critical region near the transition line has the advantageous property of enabling a significant decrease in error with a small increase in inhibition and also exhibits unique properties with respect to learning and memory decay.

biophysics↗

bioRxiv2024

Actin turnover and myosin contractility determine emergent Thickness Robustness of Cell-Mimicking Cortex

Cell shape deformation in eukaryotes, is primarily determined by the actin cortex, a thin network of actin filaments and myosin motors. This network is attached to the plasma membrane endowing cells with their mechanical stability and structural integrity. Since inside the cells hundreds of proteins are associated with the actin cortex, identifying the roles of the individual components and the mechanisms maintaining a functional cortex is highly challenging. Here, using a minimal set of components, we succeeded in recreating long-lasting dynamic treadmilling in an artificial actomyosin cortex on a bilayer membrane with cell-mimicking characteristics, both with and without myosin-II motors, replicating features observed in cells, such as myosin-induced increased cortical thickness and stress-dependent dynamics. We mechanistically reveal how treadmilling is regulated by actin network disassembly factors and myosin contractility, and the emergence of robustness of the cortical thickness to concentration fluctuations in cytoskeletal components. The robustness and responsiveness of the actin cortex which we found has a fundamental significance for the ability of Eukaryotic cells to maintain the mechanical integrity of their membrane, despite concentration fluctuation of the cytoskeleton components. Unlike complex biological cells, this system enables high-resolution and systematic studies of cortical dynamics under controlled conditions. It thus provides a cell-mimicking artificial system for designing interventions to modify the cellular cortex to improve our understanding of the basic mechanisms driving fundamental biological processes as well as for potential medical applications. SignificanceWe report a breakthrough in understanding the actin cortex, a key structure governing cell shape, stability, and motility. By reconstructing in-vitro a treadmilling actomyosin cortex on a lipid bilayer using minimal components, we replicate essential cellular features. This system reveals how cortical thickness is maintained despite concentration fluctuations, highlighting an actin turnover mechanism that buffers variability. The inclusion of myosin motors is found to modify the cortical dynamics, mimicking cellular properties such as the increased thickness and stress-dependent dynamics. Unlike complex living cells, this artificial system enables systematic studies of cortical behavior, with fine control over the components and high-resolution imaging. Our artificial system provides a platform for designing interventions to modify cortical dynamics, with broad implications for biology and medicine. One-Sentence SummaryIn-vitro recreation of a cell-like, membrane-bound cortical actin skeleton composed of a minimal set of building-blocks with continuous turnover and emergent robustness.

biophysics↗

bioRxiv2024

Shape dynamics and migration of branched cells on complex networks

Migrating cells often face microenvironmental constraints that force them to extend multiple, often highly dynamic, protrusions, that compete to choose the new direction. However, the analysis of how cells coordinate shape dynamics during this directional decision-making process has been restricted to single junctions. Here, we present a theoretical model and the corresponding experimental proof of concept using in vivo and in vitro live-cell microscopy and a neuronal network-based image analysis pipeline, to explore the shape and migration dynamics of highly bifurcated cells during spontaneous random migration. We found that macrophages and endothelial cells display different migration regimes in a hexagonal adhesive network, despite sharing a mesenchymal migratory strategy. Macrophages moved faster and presented larger changes in cell length in comparison to endothelial cells. The theoretical model describes the behavior of both cells during directional decision-making, and it reveals a trade-off between exploration for directional cues and long-range migration efficiency, showing the fine tune regulation of shape dynamics in complex geometries. TeaserHighly branched cells require precise control of their shape dynamics to ensure microenvironment exploration while keeping their motility.

biophysics↗

bioRxiv2024

How motility drives the glassy dynamics in confluent epithelial monolayers?

As wounds heal, embryos develop, cancer spreads, or asthma progresses, the cellular monolayer undergoes glass transition between solid-like jammed and fluid-like flowing states. During some of these processes, the cells undergo an epithelial-to-mesenchymal transition (EMT): they acquire in-plane polarity and become motile. Thus, how motility drives the glassy dynamics in epithelial systems is critical for the EMT process. However, no analytical framework that is indispensable for deeper insights exists. Here, we develop such a theory inspired by a well-known glass theory. One crucial result of this work is that the confluency affects the effective persistence time-scale of active force, described by its rotational diffusivity, [Formula]. [Formula] differs from the bare rotational diffusivity, Dr, of the motile force due to cell shape dynamics, which acts to rectify the force dynamics: [Formula] is equal to Dr when Dr is small and saturates when Dr is large. We test the theoretical prediction of [Formula] and how it affects the relaxation dynamics in our simulations of active Vertex model. This novel effect of [Formula] is crucial to understanding the new and previously published simulation data of active glassy dynamics in epithelial monolayers.

biophysics↗

bioRxiv2023

A minimal physical model for curvotaxis driven by curved protein complexes at the cell's leading edge

Cells often migrate on curved surfaces inside the body, such as curved tissues, blood vessels or highly curved protrusions of other cells. Recent in-vitro experiments provide clear evidence that motile cells are affected by the curvature of the substrate on which they migrate, preferring certain curvatures to others, termed "curvotaxis". The origin and underlying mechanism that gives rise to this curvature sensitivity are not well understood. Here, we employ a "minimal cell" model which is composed of a vesicle that contains curved membrane protein complexes, that exert protrusive forces on the membrane (representing the pressure due to actin polymerization). This minimal-cell model gives rise to spontaneous emergence of a motile phenotype, driven by a lamellipodia-like leading edge. By systematically screening the behaviour of this model on different types of curved substrates (sinusoidal, cylinder and tube), we show that minimal ingredients and energy terms capture the experimental data. The model recovers the observed migration on the sinusoidal substrate, where cells move along the grooves (minima), while avoiding motion along the ridges. In addition, the model predicts the tendency of cells to migrate circumferentially on convex substrates and axially on concave ones. Both of these predictions are verified experimentally, on several cell types. Altogether, our results identify the minimization of membrane-substrate adhesion energy and binding energy between the membrane protein complexes as key players of curvotaxis in cell migration.

biophysics↗

bioRxiv2023

Modelling how curved active proteins and shear flow pattern cellular shape and motility

Cell spreading and motility on an adhesive substrate are driven by the active physical forces generated by the actin cytoskeleton. We have recently shown that coupling curved membrane complexes to protrusive forces, exerted by the actin polymerization that they recruit, provides a mechanism that can give rise to spontaneous membrane shapes and patterns. In the presence of an adhesive substrate, this model was shown to give rise to an emergent motile phenotype, resembling a motile cell. Here, we utilize this "minimal-cell" model to explore the impact of external shear flow on the cell shape and migration on a uniform adhesive flat substrate. We find that in the presence of shear the motile cell reorients such that its leading edge, where the curved active proteins aggregate, faces the shear flow. The flow-facing configuration is found to minimize the adhesion energy by allowing the cell to spread more efficiently over the substrate. For the non-motile vesicle shapes, we find that they mostly slide and roll with the shear flow. We compare these theoretical results with experimental observations, and suggest that the tendency of many cell types to move against the flow may arise from the very general, and non-cell-type-specific mechanism predicted by our model.

biophysics↗

bioRxiv2023

A simple cognitive model explains movement decisions during schooling in zebrafish

While moving, animals must frequently make decisions about their future travel direction, whether they are alone or in a group. Here we investigate this process for zebrafish (Danio rerio), which naturally move in cohesive groups. Employing state-of-the-art virtual reality, we study how real fish follow one or several moving, virtual conspecifics. These data are used to inform, and test, a model of social response that includes a process of explicit decision-making, whereby the fish can decide which of the virtual conspecifics to follow, or to follow some average direction. This approach is in contrast with previous models where the direction of motion was based on a continuous computation, such as directional averaging. Building upon a simplified version of this model [Sridhar et al., 2021], which has been shown to exhibit a spontaneous symmetry-breaking transition from moving along a "compromise" (average) direction, to deciding on following one of the virtual fish. This previously published simplified version was limited to a one-dimensional projection of the fish motion, while here we present a model that describes the motion of the real fish as it swims freely in two-dimensions. Here, we extend our proposed Ising-like model, which inherently describes a spontaneous symmetry-breaking transition from moving along a "compromise" (average) direction, to deciding on following one of the virtual fish. Motivated by experimental observations, the swim speed of the fish in this model uses a burst-and-coast swimming pattern, with the burst frequency being dependent on the distance of the fish from the followed conspecific(s). We demonstrate that this model is able to explain the observed spatial distribution of the real fish behind the virtual conspecifics in the experiments, as a function of their average speed and number. In particular, the model naturally explains the observed critical bifurcations for a freely swimming fish, which appear in the spatial distributions whenever the fish makes a decision to follow only one of the virtual conspecifics, instead of following them as an averaged group. This model can provide the foundation for modeling a cohesive shoal of swimming fish, while explicitly describing their directional decision-making process at the individual level.

biophysics↗

bioRxiv2023

Theoretical model of membrane protrusions driven by curved active proteins

Eukaryotic cells intrinsically change their shape, by changing the composition of their membrane and by restructuring their underlying cytoskeleton. We present here further studies and extensions of a minimal physical model, describing a closed vesicle with mobile curved membrane protein complexes. The cytoskeletal forces describe the protrusive force due to actin polymerization which is recruited to the membrane by the curved protein complexes. We characterize the phase diagrams of this model, as function of the magnitude of the active forces, nearest-neighbor protein interactions and the proteins spontaneous curvature. It was previously shown that this model can explain the formation of lamellipodia-like flat protrusions, and here we explore the regimes where the model can also give rise to filopodia-like tubular protrusions. We extend the simulation with curved components of both convex and concave species, where we find the formation of complex ruffled clusters, as well as internalized invaginations that resemble the process of endocytosis and macropinocytosis. We alter the force model representing the cytoskeleton to simulate the effects of bundled instead of branched structure, resulting in shapes which resemble filopodia.

biophysics↗

bioRxiv2022

Coiling of cellular protrusions around extracellular fibers

Protrusions at the leading-edge of a cell play an important role in sensing the extracellular cues, during cellular spreading and motility. Recent studies provided indications that these protrusions wrap (coil) around the extra-cellular fibers. The details of this coiling process, and the mechanisms that drive it, are not well understood. We present a combined theoretical and experimental study of the coiling of cellular protrusions on fibers of different geometry. Our theoretical model describes membrane protrusions that are produced by curved membrane proteins that recruit the protrusive forces of actin polymerization, and identifies the role of bending and adhesion energies in orienting the leading-edges of the protrusions along the azimuthal (coiling) direction. Our model predicts that the cells leading-edge coils on round fibers, but the coiling ceases for a fiber of elliptical (flat) cross-section. These predictions are verified by 3D visualization and quantitation of coiling on suspended fibers using Dual-View light-sheet microscopy (diSPIM). Overall, we provide a theoretical framework supported by high spatiotemporal resolution experiments capable of resolving coiling of cellular protrusions around extracellular fibers of varying diameters. Significance StatementCells adhere and migrate in environments that are composed of fibrous structures, such as the thin filaments of the extracellular matrix, or the wider axons and dendrites of neurons. In recent experiments, cells have been observed to form leading edge protrusions on such surfaces, that seem to coil around the extracellular fibers. However, the mechanism responsible for the formation of such coiling protrusions is not understood. Here, we provide a combined experimental and theoretical approach to explain the emergence of coiling protrusions. Our model is based on the self-organization of curved proteins that recruit actin polymerization at the leading edge of the cell, when spreading over an adhesive fiber.

biophysics↗

bioRxiv2022

Actin filaments couple the protrusive tips to the nucleus through the I-BAR domain protein IRSp53 for migration of elongated cells on 1D fibers

The cell migration cycle proceeds with shaping the membrane to form new protrusive structures and redistribution of contractile machinery. The molecular mechanisms of cell migration are well-studied in 2D, but membrane shape-driven molecular migratory landscape in 3D fibrous matrices remains poorly described. 1D fibers recapitulate 3D migration, and here, we examined the role of membrane curvature regulator IRSp53 as a coupler between actin filaments and plasma membrane during cell migration on suspended 1D fibers. Cells attached, elongated, and migrated on the 1D fibers with the coiling of their leading-edge protrusions. IRSp53 depletion reduced cell-length spanning actin stress fibers, reduced protrusive activity, and contractility, leading to uncoupling of the nucleus from cellular movements. Using a theoretical model, the observed transition of IRSp53 depleted cells from rapid stick-slip migration to smooth, and slower migration was predicted to arise from reduced actin polymerization at the cell edges, which was verified by direct measurements of retrograde actin flow using speckle microscopy. Overall, we trace the effects of IRSp53 deep inside the cell from its actin-related activity at the cellular tips, thus demonstrating a unique role of IRSp53 in controlling cell migration in 3D.

cell biology↗

bioRxiv2022

Theoretical model of efficient phagocytosis driven by curved membrane proteins and active cytoskeleton forces

Phagocytosis is the process of engulfment and internalization of comparatively large particles by the cell, that plays a central role in the functioning of our immune system. We study the process of phagocytosis by considering a simplified coarse grained model of a three-dimensional vesicle, having uniform adhesion interaction with a rigid particle, in the presence of curved membrane proteins and active cytoskeletal forces. Complete engulfment is achieved when the bending energy cost of the vesicle is balanced by the gain in the adhesion energy. The presence of curved (convex) proteins reduces the bending energy cost by self-organizing with higher density at the highly curved leading edge of the engulfing membrane, which forms the circular rim of the phagocytic cup that wraps around the particle. This allows the engulfment to occur at much smaller adhesion strength. When the curved proteins exert outwards protrusive forces, representing actin polymerization, at the leading edge, we find that engulfment is achieved more quickly and at lower protein density. We consider spherical as well as non-spherical particles, and find that non-spherical particles are more difficult to engulf in comparison to the spherical particles of the same surface area. For non-spherical particles, the engulfment time crucially depends upon the initial orientation of the particles with respect to the vesicle. Our model offers a mechanism for the spontaneous self-organization of the actin cytoskeleton at the phagocytic cup, in good agreement with recent high-resolution experimental observations. Significance StatementPhagocytosis is an important process that plays a central role in our immune system, and also during nutrient uptake, drug delivery and pathogen invasion. Despite its biological importance, it is still not understood how the actin cytoskeleton is coordinated spatio-temporally during the phagocytosis process. We present a simple model that explains the dynamics and self-organization of the membrane and the actin cytoskeleton during the engulfment process, based on curved membrane activators of actin polymerization.

biophysics↗

bioRxiv2021

Mitotic Outcomes in Fibrous Environments

During mitosis, cells round up and generate outward forces to create space and orient the mitotic spindles. Here, using suspended ECM-mimicking nanofiber networks, we recapitulate in vivo adhesion organization and confinement to interrogate mitotic outcomes for various interphase cell shapes. Elongated cells attached to single fibers through two focal adhesion clusters (FACs) at their extremities result in perfect spherical mitotic cell bodies that undergo large 3D displacement while being held by retraction fibers. Increasing the number of parallel fibers increases cellular extremity FACs and retraction fiber-driven stability, leading to reduced 3D cell-body movement, metaphase plate rotations, and significantly faster division times. Interestingly, interphase kite shapes on a crosshatch pattern of four fibers undergo mitosis resembling single-fiber outcomes due to rounded bodies being primarily held in position by retraction fibers from two perpendicular suspended fibers. We develop a cortex-astral microtubule analytical friction and force model to capture retraction-fiber-driven stability of the metaphase plate rotations. We report that reduced orientational stability results in increased monopolar mitotic defects. In the case of cells attached to two parallel fibers, rounded mitotic cells can get confined between the suspended fibers, allowing estimation of the mitotic forces through measurement of the outward deflection of the fibers. Interestingly, confinement causes rotated mitotic spindles similar to those reported in dense tissues. Overall, we establish dynamics of mitosis in fibrous environments governed by fiber arrangement and architecture-driven differences in interphase cell shapes, adhesion geometries, and varying levels of mechanical confinement.

cell biology↗

bioRxiv2021

Cytoplasmic forces functionally reorganize nuclear condensates in oocytes

Cells remodel their cytoplasm with force-generating cytoskeletal motors1. Their activity generates random forces that stir the cytoplasm, agitating and displacing membrane-bound organelles like the nucleus in somatic2-4 and germ5-7 cells. These forces are transmitted inside the nucleus4,7, yet their consequences on liquid-like biomolecular condensates8-10 residing in the nucleus remain unexplored. Here, we probe experimentally and computationally diverse nuclear condensates, that include nuclear speckles, Cajal bodies, and nucleoli, during cytoplasmic remodeling of female germ cells named oocytes. We discover that growing mammalian oocytes deploy cytoplasmic forces to timely impose multiscale reorganization of nuclear condensates for the success of meiotic divisions. These cytoplasmic forces accelerate nuclear condensate collision-coalescence and molecular kinetics within condensates. Inversely, disrupting the forces decelerates nuclear condensate reorganization on both scales, compromising condensate-associated mRNA processing and consequently hindering oocyte divisions that drive female fertility. We establish that cytoplasmic forces can reorganize nuclear condensates in an evolutionary conserved fashion in insects. Our work implies that cells evolved a mechanism, based on cytoplasmic force tuning, to functionally regulate a broad range of nuclear condensates across scales. This finding opens new perspectives when studying condensate-associated pathologies like cancer, neurodegeneration and viral infections11-13.

cell biology↗