Biology subjects

Ford, H. Z.

Publications and source records attributed to Ford, H. Z..

6 recordsLinked to original sources

bioRxiv2025

Intermittent attachments form three-dimensional cell aggregates with emergent fluid properties

In living systems across developmental and cancer biology, populations of cells on surfaces organize themselves into aggregates that mediate function and disease. Recent experimental studies have identified that such aggregates can have emergent fluid-like properties such as surface tension, yet the physical origin of these properties is not clear. Here, we develop a minimal cell-based model in which cell-cell and cell-substrate interactions are governed by active intermittent attachments. We explain the transition of cells from a dilute population to a dense aggregate, and quantify the emergent material properties underpinning this transition. We use our model to interpret experiments on dewetting of aggregates of MDA-MDB-231 cancer cells and shape fluctuations of surface-associated OVCAR3 cell aggregates. Finally, we show how spatial heterogeneity in attachments governs collective chemotaxis of cell aggregates. Together, these results reveal how active intermittent attachments generate cell aggregates with emergent material properties, with broad implications for development and cancer.

biophysics↗

bioRxiv2024

Pattern formation along signaling gradients driven by active droplet behaviour of cell groups

Gradients of extracellular signals organise cells in tissues. Although there are several models for how gradients can pattern cell behaviour, it is not clear how cells react to gradients when the population is undergoing 3D morphogenesis, in which cell-cell and cell-signal interactions are continually changing. Dictyostelium cells follow gradients of their nutritional source to feed and maintain their undifferentiated state. Using light sheet imaging to simultaneously monitor signaling, single cell and population dynamics, we show that the cells migrate towards nutritional gradients in swarms. As swarms advance, they deposit clumps of cells at the rear, triggering differentiation. Clump deposition is explained by a physical model in which cell swarms behave as active droplets: cells proliferate within the swarm, with clump shedding occurring at a critical population size, at which cells at the rear no longer perceive the gradient and are not retained by the emergent surface tension of the swarm. The droplet model predicts vortex motion of the cells within the swarm emerging from the local transfer of propulsion forces, a prediction validated by 3D tracking of single cells. This active fluid behaviour reveals a developmental mechanism we term "musical chairs" decision-making, in which the decision to proliferate or differentiate is determined by the position of a cell within the group as it bifurcates.

biophysics↗

bioRxiv2022

Signalling centre vortices coordinate collective behaviour in social amoebae

Cells use signal relay to transmit information across tissue scales. However, the production of information carried by signal relay remains poorly characterised. To determine how the coding features of signal relay are generated, we used the classic system for long-range signalling: the periodic cAMP waves that drive Dictyostelium collective migration. Combining imaging and optogenetic perturbation of cell signalling states, we find that migration is triggered by an increase in wave frequency generated at the signalling centre. Wave frequency is regulated by cAMP wave circulation, which organises the long-range signal. To determine the mechanisms modulating wave circulation, we combined mathematical modelling, the general theory of excitable media and mechanical perturbations to test competing models. Models in which cell density and spatial patterning modulate the wave frequency cannot explain the temporal evolution of signalling waves. Instead, our evidence leads to a model where wave circulation increases the ability for cell to relay the signal, causing further increase in the circulation rate. This implies that information driving a morphogenetic transition gradually unfolds due to positive feedback between cell signalling state and signalling pattern. This demonstrates how the coding properties of a long-range signal arise from self-organised wave dynamics at the signalling centre.

biophysics↗

bioRxiv2020

Viral-structured models of dividing cells shows cell-virus coexistence via viral load partitioning between cell progeny

The present study develops and analyses a system of partial differential equations that model a single population of dividing cells infected by lytic viruses in a closed system. This mean-field model stratifies cells by cell size (continuous) and number of virus particles per cell (discrete) to couple the cell cycle and the lytic cycle under mass conservation. We present numerical solutions to the mean-field model and an equivalent stochastic model for parameter values representative of Escherichia Coli and lytic bacteriophages such as Escherichia virus T4. This analysis suggests that dividing cells and lytic virus populations in isolation can coexist in the absence of evolutionary, ecological and biochemical processes. Coexistence emerges because viral load dilution via cell growth and viral load partitioning via cell division both counteract viral load growth via viral synthesis and hence cell death by lysis. Furthermore, we analytically determine the quasi-steady state solution of the mean-field model in the continuum limit with respect to viral loads. From this solution we derive a condition for cell-virus coexistence through viral load partitioning: that the product of the viral synthesis rate, cell lysis rate and the time between cell divisions must be less than the product of log(2) and the cell growth rate. Overall, the present study provides a theoretical argument for a stable relationship between cells and lytic viruses simply by virtue of cell growth and division.

systems biology↗

bioRxiv2019

Efferocytosis perpetuates substance accumulation inside macrophage populations

In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored. Here we take mathematical and experimental approaches to study the relationship between cannibalistic efferocytosis and substance accumulation in macrophages. Through mathematical modelling, we deduce that substances which transfer between individuals through cannibalism will concentrate inside the population via a coalescence process. This prediction was confirmed for macrophage populations inside a closed system. We used image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages (104 - 105 cells) following their stimulation into an inflammatory state ex vivo. While the total number of phagocytosed beads remained constant, cell death reduced cell numbers and efferocytosis concentrated the beads among the surviving macrophages. Since lipids are also conserved during efferocytosis, these cells accumulated lipid derived from the membranes of dead and consumed macrophages (becoming macrophage foam cells). Consequently, enhanced macrophage cell death increased the rate and extent foam cell formation. Our results demonstrate that cannibalistic efferocytosis perpetuates exogenous (e.g. beads) and endogenous (e.g. lipids) substance accumulation inside macrophage populations. As such, cannibalism has similar detrimental consequences in both cells and animals.

immunology↗

bioRxiv2019

A lipid-structured model for macrophage populations in atherosclerotic plaques

Atherosclerosis is a chronic inflammatory disease driven by the accumulation of pro-inflammatory, lipid-loaded macrophages at sites inside artery walls. These accumulations lead to the development of atherosclerotic plaques. The rupture of plaques that contain lipid-rich necrotic cores can trigger heart attacks and strokes via occlusion of blood vessels. We construct and analyse a system of partial integro-differential equations that model lipid accumulation by macrophages, including generating apoptotic cells and a necrotic core. The model includes the following cell behaviours: recruitment of macrophages into the plaque; macrophage ingestion of low density lipoproteins LDL and of apoptotic cells and necrotic material; lipid offloading to high density lipoproteins (HDL); macrophage emigration; and macrophage apoptosis and necrosis of apoptotic cells. With this model, we study how changes in parameters predict the characteristic features of plaque pathology. In particular, we find the qualitative form of lipid distribution across the macrophage population and show that high lipid loads can occur in the absence of LDL ingestion. We also demonstrate the importance of macrophage emigration in the model in mitigating and resolving inflammation and plaque lipid accumulation. ContributionsO_LIHZF: conceptualisation, formal analysis, investigation, methodology, visualisation, writing-- original draft preparation, writing--review and editing. C_LIO_LIHMB: conceptualisation, funding acquisition, methodology, project administration, resources, supervision, writing--review and editing. C_LIO_LIMRM: conceptualisation, funding acquisition, methodology, project administration, resources, supervision, writing--original draft, writing--review and editing. C_LI

immunology↗