Biology subjects

Doostmohammadi, A.

Publications and source records attributed to Doostmohammadi, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Higher-Order Mechanical Neighbourhood Sensing Governs Cell Fate in Complex Tissues

Adult tissues maintain precise architectures composed of multiple interspersed cell types, yet prevailing models of cell fate patterning rely on pairwise interactions between neighbouring cells that generate binary decisions. How local interactions encode higher-order, beyond pairwise, multicellular organization remains unclear. Here, using the Drosophila midgut as a model of adult tissue self-organization, we identify a higher-order neighbourhood-sensing mechanism that couples cell identity, mechanics and stem cell (SC) fate. We show that the receptors Cirl/Latrophilin and Toll-8 are expressed in complementary cellular compartments, restricting their engagement to heterotypic interfaces between progenitors and differentiated enterocytes (ECs). These interactions generate interface-specific myosin II-dependent tension that depends on EC neighbourhood composition and mechanically gates Delta-Notch signalling. Thus, although Delta-Notch acts through pairwise interactions, these fate decisions are modulated by a higher-order mechanical state integrating information from surrounding cell contacts. A mathematical model incorporating this coupling reproduces multicellular tissue architecture from first principles and predicts that loss of higher-order coupling destabilizes progenitor organization. This prediction is consistent with the excessive fate transitions, topological disorganization and regenerative defects observed after Cirl-Toll-8 disruption. These findings establish higher-order mechanical neighbourhood sensing as a general principle by which tissues integrate local cellular identities to maintain and restore complex architectures.

cell biology↗

bioRxiv2026

A principal-stress rule for cell division in epithelia

Dense active materials, from cellular tissues to jammed and glassy systems, must continuously relieve internal mechanical stress to remain structurally stable as they are driven far from equilibrium. In epithelial tissues, this relief occurs through cell division, yet what sets the geometry of this structural remodeling event has, for over a century, been attributed to a purely geometric principle: Hertwigs rule, whereby cells divide along their long axis. We show that as epithelial tissues densify and cell shape anisotropy collapses, this geometric rule is superseded by a mechanical one in which dense epithelia relieve anisotropic stress by cells dividing along their principal axis, independent of the tissues isotropic stress state. Using direct force measurement and stress inference, we show that stress orientation, rather than cell shape, governs the axis of cell division across mechanically distinct systems, from fluid-like to jammed monolayers and structurally heterogeneous organoids, remaining predictive precisely where the classical geometric rule fails. This stress-oriented remodeling is reciprocally coupled to the materials mechanical state: anisotropic stress accelerates the underlying remodeling rate, while each remodeling event locally dissipates the stress that triggered it, closing a negative feedback loop. This "principal-stress rule" recasts epithelial cell division as a stress-relief mechanism intrinsic to dense active matter, providing a general mechanical framework linking internal stress, structural remodeling, and homeostasis in living materials.

biophysics↗

bioRxiv2026

Mechanical Tension Actively Triggers RhoA-Mediated Cell Extrusion

Cell extrusion is a fundamental process in tissue homeostasis, morphogenesis, and cancer progression, facilitating the removal of cells either alive or through apoptosis. While biochemical signaling pathways are known to regulate extrusion, recent advances have underscored the importance of mechanical forces in this process. Here, using optogenetic control of RhoA activation in epithelial monolayers combined with Bayesian Inversion Stress Microscopy (BISM) and three-dimensional cell-based modeling, we uncover a counterintuitive mechanism whereby elevated tension, instead of stabilizing the monolayer, actively drives extrusion in highly contractile cells. We show that local RhoA activation enhances myosin II-dependent contractility and F-actin reorganization, which promotes cell stiffening, resulting in localized tension buildup. The ensuing tensile stress amplifies vertical mechanical fluctuations, which in turn trigger cell extrusion. Remarkably, these tension-induced extrusions occur both apically and basally. Furthermore, our findings show that RhoA-mediated contractility is not merely an effector of extrusion but also an active promoter of basal extrusion, independently of caspase activation. Our study demonstrates that tensile stress can directly initiate extrusion events and bias their outcome toward apical or basal fates. By identifying tension as a driver rather than a suppressor of extrusion, this work revises current models of epithelial homeostasis and highlights mechanical control as a targetable axis in disease and regeneration.

cell biology↗

bioRxiv2026

Mechanical memory of confinement pressure governs expansion size in epithelial monolayers

Epithelial tissues undergo rapid expansion during development, repair, and morphogenesis, yet how tissue-scale growth is coordinated to re-establish homeostasis remains unclear. Here, we show that large epithelial monolayers confined at a wide range of initial densities and mechanochemical states robustly converge to the same final size and density upon release, despite differences in initial cell size, YAP activity, and cell number dynamics. To investigate the underlying mechanism, we combined quantitative experiments with a mechanochemical agent-based model in which mechanical pressure arising from confinement acts as a tissue-scale signal that modulates intracellular cell-cycle activity over time. Using this framework, we show that transient mechanical relaxation during confinement selectively elevates cell-cycle activity in higher-density tissues at the time of release, accelerating early expansion without disrupting final homeostatic outcomes. Together, these results reveal how epithelial tissues coordinate collective growth and robustly restore homeostasis during expansion. SignificanceMechanisms that re-establish homeostasis and coordinate cell proliferation in expanding epithelial tissues such as during development and tissue regeneration remain poorly understood. Here, we used a large 2D epithelial expansion model and agent-based modelling to demonstrate history-dependent regulation of colony growth, mediated by pressure sensing. We find that, typically, equilibration of pressure during confinement just before the onset of expansion results in all expanding tissues of a given starting size reaching a target density and final size independent of starting cell numbers. By transiently reducing actomyosin contractility during confinement, we selectively accelerate the expansion of high-density tissues. Our findings provide key insights into physical mechanisms that govern organ development and tissue repair.

cell biology↗

bioRxiv2025

Packing-Driven Mechanotransduction: local crowding overrides adhesion and stiffness cues for YAP Activation in Cellular Collectives

The regulation of mechanotransduction is crucial for various cellular processes, including stem cell differentiation, wound healing, and cancer progression. While the activation of mechanotransduction has been extensively studied in single cells, it remains unclear whether similar mechanisms extend to mechanotransduction in multicellular collectives. Here, by focusing on Yes-associated protein (YAP), known as the master regulator of mechanotransduction, we reveal that the local packing fraction of cells acts as the primary determinant of YAP activation in cell collectives. We further show that local packing fraction modulates the isotropic stress landscape, with sparse regions experiencing large stress fluctuations and dense regions displaying stress equilibration. Remarkably, this packing fraction-dependent regulation persists even under conditions of disrupted force transmission through cell-cell and cell-substrate adhesion, suggesting a robust and conserved relation between YAP activation and local packing fraction in cell collectives. In particular, we show that local packing fraction-dependent activation of YAP in cell collectives is independent of substrate stiffness, E-cadherin expression, and myosin contractility, in stark contrast to YAP activation in single cells. Our results thus offer a new perspective on mechanotransduction, highlighting the critical role of local packing fraction of cells in dictating YAP dynamics within multicellular contexts. These insights have significant implications for tissue engineering and understanding tumour microenvironments, where cellular het-erogeneity often drives functional outcomes.

biophysics↗

bioRxiv2025

Quantifying the shape of cells - from Minkowski tensors to p-atic order

P-atic liquid crystal theories offer new perspectives on how cells self-organize and respond to mechanical cues. Understanding and quantifying the underlying orientational orders is therefore essential for unraveling the physical mechanisms that govern tissue dynamics. Due to the deformability of cells this requires quantifying their shape. We introduce rigorous mathematical tools and a reliable framework for such shape analysis. Applying this to segmented cells in MDCK monolayers and computational approaches for active vertex models and multiphase field models allows to demonstrate independence of shape measures and the presence of various p-atic orders at the same time. This challenges previous findings and opens new pathways for understanding the role of orientational symmetries and p-atic liquid crystal theories in tissue mechanics and development.

biophysics↗

bioRxiv2024

Force transmission is a master regulator of mechanical cell competition

Cell competition is a tissue surveillance mechanism for eliminating unwanted cells and as such is indispensable in development, infection and tumorigenesis. Although different biochemical mechanisms are proposed, due to the dearth of direct force measurements, how mechanical forces determine the competition outcome remains unclear. Here, using ex vivo tissues and different cell lines, we have discovered an unknown form of cell competition that is regulated by differences in force transmission capabilities, favoring cell types with stronger intercellular adhesion. Direct force measurements reveal increased mechanical activity at the interface of the two competing cell types in the form of large stress fluctuations which can lead to upward forces and cell elimination. We show how a winning cell type endowed with a stronger intercellular adhesion exhibits a higher resistance to elimination while benefiting from efficient force transmission to neighboring cells. This cell elimination mechanism could have broad implications of keeping strong force transmission ability for maintaining tissue boundaries and cell invasion pathology.

biophysics↗

bioRxiv2024

Mechanical stresses govern myoblast fusion and myotube growth

Myoblast fusion into multinucleated myotubes is essential for skeletal muscle development and repair, yet how tissue-scale mechanics contributes to this process remains poorly understood. Here, we show that primary myoblasts behave as an evolving active nematic system in which actomyosin-dependent stresses, extracellular-matrix (ECM) remodeling and fusion-driven myotube growth are dynamically coupled. As myoblasts fuse into elongated myotubes, orientational order increases and the nematic field is progressively reshaped. We identify a strong coupling between cellular and ECM nematic organization, whereby cytoskeleton-dependent ECM remodeling stabilizes topological defects and reinforces their associated stress patterns. Fusion events preferentially accumulate near comet-shaped +1/2 defects, which correspond to regions of high compressive stress predicted by our theoretical model. Our findings support a model in which the intrinsic fusion machinery provides fusion competence, while ECM-stabilized nematic stress patterns spatially bias the localization of fusion events. Fusion-driven myotube growth then feeds back on the mechanical landscape, increasing nematogen length and stress magnitude. Together, these results reveal a self-reinforcing biomechanical mechanism that contributes to the organization of myoblast fusion and myotube growth, with potential relevance for developmental and regenerative morphogenesis.

biophysics↗

bioRxiv2024

Topological Excitations govern Ordering Kinetics in Endothelial Cell Layers

Many physiological processes, such as the shear flow alignment of endothelial cells in the vasculature, depend on the transition of cell layers between disordered and ordered phases. Here, we demonstrate that such a transition is driven by the non-monotonic evolution of nematic topological defects and the emergence of topological strings that bind the defects together, unveiling an intermediate phase of ordering kinetics in biological matter. We used time-resolved large-scale imaging and physical modeling to resolve the nature of the non-monotonic decrease in the number of defect pairs. The interaction of the intrinsic cell layer activity and the alignment field determines the occurrence of defect domains, which defines the nature of the transition. Defect pair annihilation is mediated by topological strings spanning multicellular scales within the cell layer. We propose that these long-range interactions in the intermediate ordering phase have significant implications for a wide range of biological phenomena in morphogenesis, tissue remodeling, and disease progression.

biophysics↗

bioRxiv2024

Cell aspect ratio is a mechanical winning strategy in microbial competition

Bacterial competition shapes community architecture, yet a universally conserved determinant remains elusive. We show that cell aspect ratio -a simple morphological feature- confers a competitive advantage. Using growth-based range expansion experiments, we show that longer bacteria conquer the expanding front, even when initially in minority. Using an agent-based model of dividing bacteria, to isolate the effect of aspect ratio, we reveal that the takeover mechanism is collective alignment: groups of locally aligned bacteria form "nematic arms" bridging the central region of the colony to the expanding front. Once at the front, bacteria align parallel to it and block shorter bacteria from access to nutrients and space. We confirm this observation with single-cell experiments and further generalise our findings by introducing a generic continuum model of alignment-dominated competition, explaining both experimental and cell-based model observations. Moreover, we extend our predictions to spherical range expansions and confirm the competitive advantage, even though the effect is less pronounced than in surface-attached colonies. Our results uncover a simple, yet hitherto overlooked, mechanical mechanism determining the outcome of bacterial competition, which is potentially ubiquitous among various bacteria. Current advances in genetic engineering enable aspect ratio tuning as a mechanism with broad implications for biofilm control.

biophysics↗

bioRxiv2022

Differential elasticity in lineage segregation of embryonic stem cells

The question of what guides lineage segregation is central to development, where cellular differentiation leads to segregated cell populations destined for specialized functions. Here, using optical tweezers measurements of mouse embryonic stem cells (mESCs), we reveal a mechanical mechanism based on differential elasticity in the second lineage segregation of the embryonic inner cell mass into epiblast (EPI) cells - that will develop into the fetus - and primitive endoderm (PrE) - which will form extraembryonic structures such as the yolk sac. Remarkably, we find that these mechanical differences already occur during priming and not just after a cell has committed to differentiation. Specifically, we show that the mESCs are highly elastic compared to any other reported cell type and that the PrE cells are significantly more elastic than EPI-primed cells. Using a model of two cell types differing only in elasticity we show that differential elasticity alone can lead to segregation between cell types, suggesting that the mechanical attributes of the cells contribute to the segregation process. Our findings present differential elasticity as a previously unknown mechanical contributor to the lineage segregation during the embryo morphogenesis.

biophysics↗

bioRxiv2021

Mechanics of cell integration in vivo

During embryonic development, regeneration and homeostasis, cells have to physically integrate into their target tissues, where they ultimately execute their function. Despite a significant body of research on how mechanical forces instruct cellular behaviors within the plane of an epithelium, very little is known about the mechanical interplay at the interface between migrating cells and their surrounding tissue, which has its own dynamics, architecture and identity. Here, using quantitative in vivo imaging and molecular perturbations, together with a theoretical model, we reveal that multiciliated cell (MCC) precursors in the Xenopus embryo form dynamic filopodia that pull at the vertices of the overlying epithelial sheet to probe their stiffness and identify the preferred positions for their integration into the tissue. Moreover, we report a novel function for a structural component of vertices, the lipolysis-stimulated lipoprotein receptor (LSR), in filopodia dynamics and show its critical role in cell intercalation. Remarkably, we find that pulling forces equip the MCCs to remodel the epithelial junctions of the neighboring tissue, enabling them to generate a permissive environment for their integration. Our findings reveal the intricate physical crosstalk at the cell-tissue interface and uncover previously unknown functions for mechanical forces in orchestrating cell integration.

biophysics↗

bioRxiv2021

Mechanics of live cell elimination

Cell layers eliminate unwanted cells through the extrusion process, which underlines healthy versus flawed tissue behaviors. Although several biochemical pathways have been identified, the underlying mechanical basis including the forces involved in cellular extrusion remain largely unexplored. Utilizing a phase-field model of a three-dimensional cell layer, we study the interplay of cell extrusion with cell-cell and cell-substrate interactions, in a monolayer. Independent tuning of cell-cell versus cell-substrate adhesion forces in the model reveals that a higher cell-substrate adhesion leads to a lower number of total extrusion events. We find extrusion events to be linked to both half-integer topological defects in the orientation field of the cells and to five-fold disclinations in cellular arrangements. We also show that increasing the relative cell-cell adhesion forces translates into a higher likelihood for an extrusion event to be associated with a five-fold disclination and a weaker correlation with +1/2 topological defects. We unify our findings by accessing mechanical stress fields: an extrusion event acts as a mechanism to relieve localized stress concentration.

biophysics↗

bioRxiv2021

Activity pulses induce spontaneous flow reversals in viscoelastic environments

Complex interactions between cellular systems and their surrounding extracellular matrices are emerging as important mechanical regulators of cell functions such as proliferation, motility, and cell death, and such cellular systems are often characterized by pulsating acto-myosin activities. Here, using an active gel model, we numerically explore the spontaneous flow generation by activity pulses in the presence of a viscoelastic medium. The results show that cross-talk between the activity-induced deformations of the viscoelastic surroundings with the time-dependent response of the active medium to these deformations can lead to the reversal of spontaneously generated active flows. We explain the mechanism behind this phenomenon based on the interaction between the active flow and the viscoelastic medium. We show the importance of relaxation timescales of both the polymers and the active particles and provide a phase-space over which such spontaneous flow reversals can be observed. Our results suggest new experiments investigating the role of controlled pulses of activity in living systems ensnared in complex mircoenvironments.

biophysics↗

bioRxiv2021

Machine learning based cellular contractile force detection: a new approach to predict cell mechanics by images

Combining experiments with artificial intelligence algorithms, we propose a new machine learning based approach to extract the cellular force distributions from the microscope images. The full process can be divided into three steps. First, we culture the cells on a special substrate allowing to measure both the cellular traction force on the substrate and the corresponding substrate wrinkles simultaneously. The cellular forces are obtained using the traction force microscopy (TFM), at the same time that cell-generated contractile forces wrinkle their underlying substrate. Second, the wrinkle positions are extracted from the microscope images. Third, we train the machine learning system with GAN (generative adversarial network) by using sets of corresponding two images, the traction field and the input images (raw microscope images or extracted wrinkle images), as the training data. The network understands the way to convert the input images of the substrate wrinkles to the traction distribution from the training. After sufficient training, the network is utilized to predict the cellular forces just from the input images. Our system provides a powerful tool to evaluate the cellular forces efficiently because the forces can be predicted just by observing the cells under the microscope, which is a way simpler method compared to the TFM experiment. Additionally, the machine learning based approach presented here has the profound potential for being applied to diverse cellular assays for studying mechanobiology of cells. Significance StatementCell-generated forces are indispensable determinants of fundamental cell functions such as motility and cell division. As such, quantifying how the forces change upon perturbations to the cells such as gene mutations and drug administration is of profound importance. Here we present a novel machine learning based system that allows for efficient estimations of the forces that are determined only by "observing" microscope images. Given that the cellular traction forces are regulated downstream of diverse signaling pathways, our system - that helps significantly improve the throughput of the measurements - presents a new, high throughput platform for real time analysis of the effects of a massive number of genetic and molecular perturbations on the forces and resulting cell mechanics.

biophysics↗

bioRxiv2020

Spatiotemporal model of cellular mechanotransduction via Rho and YAP

How cells sense and respond to mechanical stimuli remains an open question. Recent advances have identified the translocation of Yes-associated protein (YAP) between nucleus and cytoplasm as a central mechanism for sensing mechanical forces and regulating mechanotransduction. We formulate a spatiotemporal model of the mechanotransduction signalling pathway that includes coupling of YAP with the cell force-generation machinery through the Rho family of GTPases. Considering the active and inactive forms of a single Rho protein (GTP/GDP-bound) and of YAP (non-phosphorylated/phosphorylated), we study the cross-talk between cell polarization due to active Rho and YAP activation through its nuclear localization. For fixed mechanical stimuli, our model predicts stationary nuclear-to-cytoplasmic YAP ratios consistent with experimental data at varying adhesive cell area. We further predict damped and even sustained oscillations in the YAP nuclear-to-cytoplasmic ratio by accounting for recently reported positive and negative YAP-Rho feedback. Extending the framework to time-varying mechanical stimuli that simulate cyclic stretching and compression, we show that the YAP nuclear-to-cytoplasmic ratios time dependence follows that of the cyclic mechanical stimulus. The model presents one of the first frameworks for understanding spatiotemporal YAP mechanotransduction, providing several predictions of possible YAP localization dynamics, and suggesting new directions for experimental and theoretical studies.

biophysics↗

bioRxiv2020

Nature of active forces in tissues: how contractile cells can form extensile monolayers

Actomyosin machinery endows cells with contractility at a single cell level. However, at a tissue scale, cells can show either contractile or extensile behaviour based on the direction of pushing or pulling forces due to neighbour interactions or substrate interactions. Previous studies have shown that a monolayer of fibroblasts behaves as a contractile system1 while a monolayer of epithelial cells2,3 or neural crest cells behaves as an extensile system.4 How these two contradictory sources of force generation can coexist has remained unexplained. Through a combination of experiments using MDCK (Madin Darby Canine Kidney) cells, and in-silico modeling, we uncover the mechanism behind this switch in behaviour of epithelial cell monolayers from extensile to contractile as the weakening of intercellular contacts. We find that this switch in active behaviour also promotes the buildup of tension at the cell-substrate interface through an increase in actin stress fibers and higher traction forces. This in turn triggers a mechanotransductive response in vinculin translocation to focal adhesion sites and YAP (Yes-associated protein) transcription factor activation. Our studies also show that differences in extensility and contractility act to sort cells, thus determining a general mechanism for mechanobiological pattern formation during cell competition, morphogenesis and cancer progression.

biophysics↗

bioRxiv2020

Filopodia rotate and coil by actively generating twist in their actin shaft

Filopodia are actin-rich structures, present on the surface of practically every known eukaryotic cell. These structures play a pivotal role in specific cell-cell and cell-matrix interactions by allowing cells to explore their environment, generate mechanical forces, perform chemical signaling, or convey signals via intercellular tunneling nano-bridges. The dynamics of filopodia appear quite complex as they exhibit a rich behavior of buckling, pulling, length and shape changes. Here, we find that filopodia additionally explore their 3D extracellular space by combining growth and shrinking with axial twisting and buckling of their actin rich core. Importantly, we show the rotational dynamics of the filamentous actin inside filopodia for a range of highly distinct and cognate cell types spanning from earliest development to highly differentiated tissue cells. Non-equilibrium physical modeling of actin and myosin confirm that twist, and hence rotation, is an emergent phenomenon of active filaments confined in a narrow channel which points to a generic mechanism present in all cells. Our measurements confirm that filopodia exert traction forces and form helical buckles in a range of different cell types that can be ascribed to accumulation of sufficient twist. These results lead us to conclude that activity induced twisting of the actin shaft is a general mechanism underlying fundamental functions of filopodia.

biophysics↗