Biology subjects

Iglic, A.

Publications and source records attributed to Iglic, A..

8 recordsLinked to original sources

bioRxiv2026

From biting to engulfment: curvature-actin coupling controls phagocytosis of soft, deformable targets

Phagocytosis is a core innate immune process that clears targets spanning a wide range of mechanical properties, yet the role of target mechanics in recognition and engulfment remains unclear. Here, we combine theoretical modeling and experiments to reveal how target stiffness governs distinct modes of phagocyte-target interaction. We develop a membrane-based simulation framework in which both the engulfing cell and its target are deformable and undergo large shape changes, while actin-driven protrusions are regulated by curvature-sensitive membrane complexes. The model predicts three mechanical regimes with increasing target stiffness: (i) biting (trogocytosis), where part of the target is extracted; (ii) pushing, where the target is displaced rather than engulfed; and (iii) complete engulfment. We validate these predictions in epithelial clearance of apoptotic targets in vivo and macrophage engulfment of Giant Unilamellar Vesicles (GUVs) and lymphoma cells. Together, our results identify target mechanics as a key regulator of clearance and cell-cell interactions. Significance statementPhagocytosis is essential for immune defence, yet the physical principles governing engulfment of deformable targets remain poorly understood. Most theoretical models assume rigid particles, appropriate for phagocytosis of bacteria or fungi. When phagocytes engage dying cells or antibody-opsonised cancer cells, these targets undergo substantial shape changes during phagocytosis. We develop a theoretical model to simulate cell-cell interactions, enabling a mechanistic exploration of phagocytosis of soft targets. We utilize a model in which cytoskeletal protrusive activity is guided by curvature-sensitive membrane complexes, and show that target membrane rigidity dictates whether targets are fully engulfed, pushed away, or partially bitten. These mechanically driven dynamic regimes are validated experimentally using artificial elastic beads, GUVs, and lymphoma cells, both in vivo and in vitro.

biophysics↗

bioRxiv2024

Modelling how lamellipodia-driven cells maintain persistent migration and interact with external barriers

Cell motility is fundamental to many biological processes, and cells exhibit a variety of migration patterns. Many motile cell types follow a universal law that connects their speed and persistency, a property that can originate from the intracellular transport of polarity cues due to the global actin retrograde flow. This mechanism was termed the "Universal Coupling between cell Speed and Persistency"(UCSP). Here we implemented a simplified version of the UCSP mechanism in a coarse-grained "minimal-cell" model, which is composed of a three-dimensional vesicle that contains curved active proteins. This model spontaneously forms a lamellipodia-like motile cell shape, which is however sensitive and can depolarize into a non-motile form due to random fluctuations or when interacting with external obstacles. The UCSP implementation introduces long-range inhibition, which stabilizes the motile phenotype. This allows our model to describe the robust polarity observed in cells and explain a large variety of cellular dynamics, such as the relation between cell speed and aspect ratio, cell-barrier scattering, and cellular oscillations in different types of geometric confinements. Significance StatementCoupling curved membrane proteins to active protrusive forces that arise from recruited actin polymerization, can lead, in the presence of adhesion, to self-organization of a leading-edge cluster and a motile "minimal-cell". However, this polarized and motile shape can become unstable, and due to fluctuations or interactions with external perturbations transform to an immotile, symmetric shape. Here we couple the spatial organization of the curved active proteins to a global advection of a polarity cue along the cells activity axis. Introducing long-range inhibition, the resultant gradient of the polarity-cue stabilizes the motile, polarized "minimal-cell" vesicle. We thereby present a robust model of cell motility that can explain a variety of cellular shape-migration relations, cell-barrier scattering and spontaneous oscillations of confined cells.

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

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

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

Modelling cellular spreading and emergence of motility in the presence of curved membrane proteins and active cytoskeleton forces

Eukaryotic cells adhere to extracellular matrix during the normal development of the organism, forming static adhesion as well as during cell motility. We study this process by considering a simplified coarse-grained model of a vesicle that has uniform adhesion energy with a flat substrate, mobile curved membrane proteins and active forces. We find that a high concentration of curved proteins alone increases the spreading of the vesicle, by the self-organization of the curved proteins at the high curvature vesicle-substrate contact line, thereby reducing the bending energy penalty at the vesicle rim. This is most significant in the regime of low bare vesicle-substrate adhesion. When these curved proteins induce protrusive forces, representing the actin cytoskeleton, we find efficient spreading, in the form of sheet-like lamellipodia. Finally, the same mechanism of spreading is found to include a minimal set of ingredients needed to give rise to motile phenotypes.

biophysics↗

bioRxiv2018

Cell-extrinsic mechanical forces restore neutrophil polarization in the absence of branched actin assembly

Migratory cells use distinct motility modes to navigate different microenvironments, but it is unclear whether these modes rely on the same core set of polarity components. To investigate this, we disrupted Arp2/3 and WAVE complex, which assemble branched actin networks that are essential for neutrophil polarity and motility in standard adherent conditions. Surprisingly, confinement rescues polarity and movement of neutrophils lacking these components, revealing a processive bleb-based protrusion program that is mechanistically distinct from the branched actin-based protrusion program but shares some of the same core components and underlying molecular logic. We further find that the restriction of protrusion growth to one site does not always respond to membrane tension directly, as previously thought, but may rely on closely linked properties such as local membrane curvature. Our work reveals a hidden circuit for neutrophil polarity and indicates that cells have distinct molecular mechanisms for polarization that dominate in different microenvironments.

cell biology↗