Biology subjects

Osborne, J. M.

Publications and source records attributed to Osborne, J. M..

8 recordsLinked to original sources

bioRxiv2026

A mechanical model of multicellular remodelling in epithelial monolayers

Epithelial monolayers are the foundation of many mammalian organs and have a significant impact on numerous biological processes, including the secretion of cytokines, absorption of waste products and barrier function. During organ development epithelia are subject to many external forces due to the growth of the surrounding tissues. They exhibit complex responses to such forces, with deformation occurring on short timescales (seconds), and relaxation and remodelling occurring on longer timescales (minutes or hours). Existing mathematical and computational models do not typically account for subcellular remodelling, assuming instead that the response to an applied force or strain acts on a single timescale. In this paper we extend an off-lattice, cell-centre modelling framework to account for subcellular and tissue remodelling by introducing a Dynamic Reference Frame (DRF). The DRF provides a discrete, cell-based analogue of morpho-elasticity: it decouples the evolution of each cell's mechanical reference configuration from its instantaneous deformation, providing a phenomenological description of subcellular remodelling processes - cytoskeletal reorganisation, myosin turnover and adhesion bond remodelling - at the cellular scale. Using this extended multicellular model, we reproduce multiscale responses to external mechanical forces, including creep and stress relaxation experiments, and demonstrate that the history of applied deformation influences tissue recovery upon release. Additionally we identify and quantify where and how these multiscale responses occur. The resulting framework allows for more detailed descriptions and analyses of the development and function of biological tissues.

biophysics↗

bioRxiv2025

Quantifying biological heterogeneity in nano-engineered particle-cell interaction experiments

Nano-engineered particles are a promising tool for medical diagnostics, biomedical imaging, and targeted drug delivery. Fundamental to the assessment of particle performance are in vitro particle-cell interaction experiments. These experiments can be summarised with key parameters that facilitate objective comparisons across various cell and particle pairs, such as the particle-cell association rate. Previous studies often focus on point estimates of such parameters and neglect heterogeneity in routine measurements. In this study, we develop an ordinary differential equation-based mechanistic mathematical model that incorporates and exploits the heterogeneity in routine measurements. Connecting this model to data using approximate Bayesian computation parameter inference and prediction tools, we reveal the significant role of heterogeneity in parameters that characterise particle-cell interactions. We then generate predictions for key quantities, such as the time evolution of the number of particles per cell. Finally, by systematically exploring how the choice of experimental time points influences estimates of key quantities, we identify optimal experimental time points that maximise the information that is gained from particle-cell interaction experiments.

biophysics↗

bioRxiv2024

Understanding the mechanisms causing buckling of epithelial monolayers

A model using the rigid body multi-cellular framework (RBMCF) is implemented to investigate the mechanisms of buckling of an epithelial mono-layer. Specifically, the deformation of a monolayer of epithelial cells which are attached to a basement membrane and the surrounding stromal tissue. The epithelial monolayer, supporting basement membrane and stromal tissue are modelled using two separate vertex dynamics models (one for the epithelial monolayer layer and one for the basement membrane and stromal tissue combined) and interactions between the two are considered using the RBMCF to ensure biologically realistic interactions. Model simulations are used to investigate the effects of cell-stromal attachment and membrane rigidity on buckling behaviour. We demonstrate that there are two competing modes of buckling, stromal deformation and stromal separation. HighlightsO_LIA rigid body multi-cellular framework allows for the simulation of an epithelial monolayer which is connected to a basement membrane and surrounding tissue stroma. C_LIO_LIInteraction with basement membrane and tissue stroma allows epithelial cells to migrate forming a confluent monolayer. C_LIO_LIBuckling of monolayer can occur through separation from or deformation of the basement membrane. C_LI

biophysics↗

bioRxiv2024

An adaptive numerical method for multi-cellular simulations of organ development and disease

In recent years, multi-cellular models, where cells are represented as individual interacting entities, are becoming ever popular. This has led to a proliferation of novel methods and simulation tools. The first aim of this paper is to review the numerical methods utilised by multi-cellular modelling tools and to demonstrate which numerical methods are appropriate for simulations of tissue and organ development and disease. The second aim is to introduce an adaptive time-stepping algorithm and to demonstrate its efficiency and accuracy. We focus on off-lattice, mechanics based, models where cell movement is defined by a series of first order ordinary differential equations, derived by assuming over-damped motion and balancing forces. We see that many numerical methods have been used, ranging from simple Forward Euler approaches through to higher order single-step methods like Runge-Kutta 4 and multi-step methods like Adams-Bashforth 2. Through a series of exemplar multi-cellular simulations, we see that if: care is taken to have events (births deaths and re-meshing/re-arrangements) occur on common time-steps; and boundaries are imposed on all sub-steps of numerical methods or implemented using forces, then all numerical methods can converge with the correct order. We introduce an adaptive time-stepping method and demonstrate that the best compromise between L{infty} error and run-time is to use Runge-Kutta 4 with an increased time-step and moderate adaptivity. We see that a judicious choice of numerical method can speed the simulation up by a factor of 10-60 from the Forward Euler methods seen in Osborne et. al. [2017, https://doi.org/10.1371/journal.pcbi.1005387] and a further speed up by a factor of 4 can be achieved by using an adaptive time-step.

developmental biology↗

bioRxiv2022

Free and interfacial boundaries in individual-based models of multicellular biological systems

Coordination of cell behaviour is key to a myriad of biological processes including tissue morphogenesis, wound healing, and tumour growth. As such, individual-based computational models, which explicitly describe inter-cellular interactions, are commonly used to model collective cell dynamics. However, when using individual-based models, it is unclear how descriptions of cell boundaries affect overall population dynamics. In order to investigate this we define three cell boundary descriptions of varying complexities for each of three widely used off-lattice individual-based models: overlapping spheres, Voronoi tessellation, and vertex models. We apply our models to multiple biological scenarios to investigate how cell boundary description can influence tissue-scale behaviour. We find that the Voronoi tessellation model is most sensitive to changes in the cell boundary description with basic models being inappropriate in many cases. The timescale of tissue evolution when using an overlapping spheres model is coupled to the boundary description. The vertex model is demonstrated to be the most stable to changes in boundary description, though still exhibits timescale sensitivity. When using individual-based computational models one should carefully consider how cell boundaries are defined. To inform future work, we provide an exploration of common individual-based models and cell boundary descriptions in frequently studied biological scenarios and discuss their benefits and disadvantages.

biophysics↗

bioRxiv2021

A rigid body framework for multi-cellular modelling

Multi-cellular modelling, where tissues and organs are represented by a collection of individual interacting agents, is a well established field, encapsulating several different approaches. In particular, off-lattice models, which represent cells using points that are free to move in space, have been applied to numerous biological problems in both two and three dimensions. The fact that a cell can be represented by point objects is useful in a wide range of settings, particularly when large populations are involved. However, a purely point-based representation is not naturally equipped to deal with objects that inherently have length like cell boundaries or external membranes. In this paper we introduce a novel off-lattice modelling framework that exploits rigid body mechanics to represent cells using a collection of one-dimensional edges (rather than zero-dimensional points) in a viscosity-dominated system. The rigid body framework can be used, among other things, to represent cells as free moving polygons, to allow epithelial layers to smoothly interact with themselves, and to model rod shaped cells like bacteria. We demonstrate the value of our new framework by using it in these three applications, showing that this approach can replicate established results, as well as offer solutions to problems that limit the scope of current off-lattice multi-cellular models.

systems biology↗

bioRxiv2019

Skip segment Hirschsprung disease: modelling the trans-mesenteric origin of the enteric nervous system in the human colon

Skip segment Hirschsprung disease is a difficult to explain human enteric neuropathy where a ganglionated region lies within a region of total colonic aganglionosis.. Recently, trans-mesenteric migration was described in the mouse intestine whereby neural crest cells migrate via the mesentery across a U-shape gut loop from the midgut to the hindgut: this could explain skip segment Hirschsprung disease. To investigate this, human intestinal growth parameters were derived from published sources and correlated with enteric neural crest cell migration. These processes were then simulated using agent based mathematical models scaled to human intestinal growth. A Hirschsprung-associated slowing of migration was imposed and trans-mesenteric migration was allowed. From the developmental anatomy we conclude that trans-mesenteric migration is unlikely in normal human embryogenesis, but with a Hirschsprung-associated slowing of enteric neural crest cell migration it could occur at Carnegie stages 17 and 18. By varying the division rate of enteric neural crest agents we could reproduce full colonisation, short segment, long segment and skip segment Hirschsprung and hypoganglionic segments. Summary StatementSkip segment Hirschsprung disease in humans challenges current explanations. Mathematical modelling shows how this birth defect could develop.

developmental biology↗

bioRxiv2017

Postmitotic Separation Enables Selective Niche Retention Of One Daughter Cell In Intestinal Crypts And Is Facilitated By Interkinetic Nuclear Migration And Basal Tethering

Homeostasis of renewing tissues requires balanced proliferation, differentiation and movement. This is particullary important in the intestinal epithelium where lineage tracing suggests that stochastic differentiation choices are intricately coupled to position. To determine how position is achieved we followed proliferating cells in intestinal organoids and discovered that behaviour of mitotic sisters predicted long-term positioning. Normally, 70% of sisters remain neighbours while 30% lose contact separating after cytokinesis. Postmitotic placements predict differences in positions of sisters later: adjacent sisters reach similar positions; one separating sister remains close to its birthplace, the other moves upward. Computationally modelling crypt dynamics confirmed post-mitotic separation as a mechanism for placement of sisters into different niches. Separation depends on interkinetic nuclear migration, cell size, and asymmetric tethering by a basal process. These processes are altered when Adenomatous polyposis coli (Apc) is mutant and separation is lost. We conclude that post-mitotic placement enables stochastic niche exit and when defective, supports the clonal expansion of Apc mutant cells.

cancer biology↗