Biology subjects

Byrne, H. M.

Publications and source records attributed to Byrne, H. M..

4 recordsLinked to original sources

bioRxiv2017

The importance of geometry in the corneal micropocket assay

The corneal micropocket angiogenesis assay is an experimental protocol for studying vessel network formation, or neovascularization, in vivo. The assay is attractive due to the ease with which the developing vessel network can be observed in the same animal over time. Measurements from the assay have been used in combination with mathematical modeling to gain insights into the mechanisms of angiogenesis. While previous modeling studies have adopted planar domains to represent the assay, the hemispherical shape of the cornea and asymmetric positioning of the angiogenic source can be seen to affect vascular patterning in experimental images. As such, we aim to better understand: i) how the geometry of the assay influences vessel network formation and ii) how to relate observations from planar domains to those in the hemispherical cornea. To do so, we develop a three-dimensional, off-lattice mathematical model of neovascularization in the cornea, using a spatially resolved representation of the assay for the first time. Relative to the detailed model, we predict that the adoption of planar geometries has a noticeable impact on vascular patterning, leading to increased vessel merging, or anastomosis, in particular when circular geometries are adopted. Significant differences in the dynamics of diffusible aniogenesis simulators are also predicted between different domains. In terms of comparing predictions across domains, the distance of the vascular front to the limbus metric is found to have low sensitivity to domain choice, while metrics such as densities of tip cells and vessels and vascularized fraction are sensitive to domain choice. Given the widespread adoption and attractive simplicity of planar tissue domains, both in silico and in vitro, the differences identified in the present study should prove useful in relating the results of previous and future theoretical studies of neovascularization to in vivo observations in the cornea.\n\nAuthor summaryNeovascularization, or the formation of new blood vessels, is an important process in development, wound healing and cancer. The corneal micropocket assay is used to better understand the process and, in the case of cancer, how it can be controlled with drug therapies for improved patient outcomes. In the assay, the hemispherical shape of the cornea can influence the way the vessel network forms. This makes it difficult to directly compare results from experiments with the predictions of mathematical models or cell culture experiments, which are typically performed on flat substrates or planar matrices. In this study, we use mathematical modeling to investigate how the hemispherical shape of the cornea affects vessel formation and to identify how sensitive different measurements of neovascularization are to geometry.

physiology↗

bioRxiv2017

The evolution of tumour composition during fractionated radiotherapy: implications for outcome

Current protocols for delivering radiotherapy are based primarily on tumour stage and nodal and metastases status, even though it is well known that tumours and their microenvironments are highly heterogeneous. It is well established that the local oxygen tension plays an important role in radiation-induced cell death, with hypoxic tumour regions responding poorly to irradiation. Therefore, to improve radiation response, it is important to understand more fully the spatiotemporal distribution of oxygen within a growing tumour before and during fractionated radiation. To this end, we have extended a spatially-resolved mathematical model of tumour growth first proposed by Greenspan (Stud. Appl. Math., 1972) to investigate the effects of oxygen heterogeneity on radiation-induced cell death. In more detail, cell death due to radiation at each location in the tumour, as determined by the well-known linear-quadratic model, is assumed also to depend on the local oxygen concentration. The oxygen concentration is governed by a reaction-diffusion equation that is coupled to an integro-differential equation that determines the size of the assumed spherically-symmetric tumour. We combine numerical and analytical techniques to investigate radiation response of tumours with different intra-tumoral oxygen distribution profiles. Model simulations reveal a rapid transient increase in hypoxia upon re-growth of the tumour spheroid post-irradiation. We investigate the response to different radiation fractionation schedules and identify a tumour-specific relationship between inter-fraction time and dose per fraction to achieve cure. The rich dynamics exhibited by the model suggest that spatial heterogeneity may be important for predicting tumour response to radiotherapy for clinical applications.

cancer biology↗

bioRxiv2017

Microvessel Chaste: An Open Library for Spatial Modelling of Vascularized Tissues

Spatial models of vascularized tissues are widely used in computational physiology, to study for example, tumour growth, angiogenesis, osteogenesis, coronary perfusion and oxygen delivery. Composition of such models is time-consuming, with many researchers writing custom software for this purpose. Recent advances in imaging have produced detailed three-dimensional (3D) datasets of vascularized tissues at the scale of individual cells. To fully exploit such data there is an increasing need for software that allows user-friendly composition of efficient, 3D models of vascularized tissue growth, and comparison of predictions with in vivo or in vitro experiments and other models. Microvessel Chaste is a new open-source library for building spatial models of vascularized tissue growth. It can be used to simulate vessel growth and adaptation in response to mechanical and chemical stimuli, intra- and extra-vascular transport of nutrient, growth factor and drugs, and cell proliferation in complex 3D geometries. The library provides a comprehensive Python interface to solvers implemented in C++, allowing user-friendly model composition, and integration with experimental data. Such integration is facilitated by interoperability with a growing collection of scientific Python software for image processing, statistical analysis, model annotation and visualization. The library is available under an open-source Berkeley Software Distribution (BSD) licence at https://jmsgrogan.github.io/MicrovesselChaste. This article links to two reproducible example problems, showing how the library can be used to model tumour growth and angiogenesis with realistic vessel networks.

systems biology↗

bioRxiv2017

Bayesian inference of agent-based models: a tool for studying kidney branching morphogenesis

The adult mammalian kidney has a complex, highly-branched collecting duct epithelium that arises as a ureteric bud sidebranch from an epithelial tube known as the nephric duct. Subsequent branching of the ureteric bud to form the collecting duct tree is regulated by subcellular interactions between the epithelium and a population of mesenchymal cells that surround the tips of outgrowing branches. The mesenchymal cells produce glial cell-line derived neurotrophic factor (GDNF), that binds with RET receptors on the surface of the epithelial cells to stimulate several subcellular pathways in the epithelium. Such interactions are known to be a prerequisite for normal branching development, although competing theories exist for their role in morphogenesis. Here we introduce the first agent-based model of ex vivo kidney uretic branching. Through comparison with experimental data, we show that growth factor-regulated growth mechanisms can explain early epithelial cell branching, but only if epithelial cell division depends in a switch-like way on the local growth factor concentration; cell division occurring only if the driving growth factor level exceeds a threshold. We also show how a recently-developed method, \"Approximate Approximate Bayesian Computation\", can be used to infer key model parameters, and reveal the dependency between the parameters controlling a growth factor-dependent growth switch. These results are consistent with a requirement for signals controlling proliferation and chemotaxis, both of which are previously identified roles for GDNF.\n\nAuthor SummaryA number of important congenital disorders arise due to incomplete development of the mammalian kidney. Elucidating the cause of these conditions requires an understanding of the mechanisms that contribute to kidney morphogenesis. Whilst experimental work has suggested several candidate mechanisms, their importance is still not well understood. Here we develop a computational model of kidney morphogenesis at the individual cell level to compare these different hypotheses. Guided by existing experimental evidence we propose that a generic growth factor, that we term \"GDNF\", produced from the mesenchyme surrounding the epithelium, can drive a number of cellular responses. Simulations of our agent-based model reveal that diffusion of GDNF, coupled with GDNF-stimulated epithelial cell division, can generate the branching patterns seen in ex vivo kidney explant experiments. We also find that branching depends on the sensitivity of cell proliferation to changes in GDNF levels. In particular our model only generates realistic branching when there is significant variation in GDNF levels along the boundary of the epithelium, and most cells divide only if the local concentration of GDNF exceeds a threshold value. We conclude that feedback between mesenchymal cells that produce GDNF, and epithelial cells that consume it, is vital for normal kidney organogenesis.

developmental biology↗