Multicellular tissues are the building blocks of many biological systems and organs. These tissues are not static, but dynamically change over time. Even if the overall structure remains the same there is a turnover of cells within the tissue. This dynamic homeostasis is maintained by numerous governing mechanisms which are finely tuned in such a way that the tissue remains in a homeostatic state, even across large timescales. Some of these governing mechanisms include cell motion, and cell fate selection through inter cellular signalling. However, it is not yet clear how to link these two processes, or how they may affect one another across the tissue. In this paper, we present a multicellular, multiscale model, which brings together the two phenomena of cell motility, and inter cellular signalling, to describe cell fate selection on a dynamic tissue. We find that the affinity for cellular signalling to occur greatly influences a cells ability to differentiate. We also find that our results support claims that cell differentiation is a finely tuned process within dynamic tissues at homeostasis, with excessive cell turnover rates leading to unhealthy (undifferentiated and unpatterned) tissues.
After injury, if regeneration can be observed in hydra, planaria and some vertebrates, regeneration is rare in mammals and particularly in humans. In this paper, we investigate the mechanisms by which biological tissues recover after injury. We explore this question on adipose tissue, using the mathematical framework recently developed in Peurichard et al, J. Theoret. Biol. 429 (2017), pp. 61-81. Our assumption is that simple mechanical cues between the Extra-Cellular Matrix (ECM) and differentiated cells can explain adipose tissue morphogenesis and that regeneration requires after injury the …
The emergence of complex organs is driven by the coordinated proliferation, migration and differentiation of precursor cells. The fate behaviour of these cells is reflected in the time evolution their progeny, termed clones, which serve as a key experimental observable. In adult tissues, where cell dynamics is constrained by the condition of homeostasis, clonal tracing studies based on transgenic animal models have advanced our understanding of cell fate behaviour and its dysregulation in disease. But what can be learned from clonal dynamics in development, where the spatial cohesiveness of cl…
Using formal asymptotic methods we derive a free boundary problem representing one of the simplest mathematical descriptions of the growth and death of a tumour or other biological tissue. The mathematical model takes the form of a closed interface evolving via forced mean curvature flow (together with a `kinetic under-cooling' regularisation) where the forcing depends on the solution of a PDE that holds in the domain enclosed by the interface. We perform linear stability analysis and derive a diffuse-interface approximation of the model. Finite-element discretisations of two closely related m…
Starting from kinetic transport equations and subcellular dynamics we deduce a multiscale model for glioma invasion relying on the go-or-grow dichotomy and the influence of vasculature, acidity, and brain tissue anisotropy. Numerical simulations are performed for this model with multiple taxis, in order to assess the solution behavior under several scenarios of taxis and growth for tumor and endothelial cells. An extension of the model to incorporate the macroscopic evolution of normal tissue and necrotic matter allows us to perform tumor grading.
Spatial variations in the electrical properties of cardiac tissue can occur because of cardiac diseases. We introduce such gradients into mathematical models for cardiac tissue and then study, by extensive numerical simulations, their effects on reentrant electrical waves and their stability in both two and three dimensions. We explain the mechanism of spiral- and scroll-wave instability, which entails anisotropic thinning in the wavelength of the waves because of anisotropic variation in its electrical properties.
Plant hormone auxin has critical roles in plant growth, dependent on its heterogeneous distribution in plant tissues. Exactly how auxin transport and developmental processes such as growth coordinate to achieve the precise patterns of auxin observed experimentally is not well understood. Here we use mathematical modelling to examine the interplay between auxin dynamics and growth and their contribution to formation of patterns in auxin distribution in plant tissues. Mathematical models describing the auxin-related signalling pathway, PIN and AUX1 dynamics, auxin transport, and cell growth in p…
Cell competition is a quality control mechanism in tissues that results in the elimination of less fit cells. Over the past decade, the phenomenon of cell competition has been identified in many physiological and pathological contexts, driven either by biochemical signaling or by mechanical forces within the tissue. In both cases, competition has generally been characterized based on the elimination of loser cells at the population level, but significantly less attention has been focused on determining how single-cell dynamics and interactions regulate population-wide changes. In this review, …
There is increasing interest in the analysis of biological tissue, its organization and its dynamics with the help of mathematical models. In the ideal case emergent properties on the tissue scale can be derived from the cellular scale. However, this has been achieved in rare examples only, in particular, when involving high-speed migration of cells. One major difficulty is the lack of a suitable multiscale simulation platform, which embeds reaction-diffusion of soluble substances, fast cell migration and mechanics, and, being of great importance in several tissue types, cell flow homeostasis.…
We present systematic numerical studies of electrical-wave propagation in two-dimensional (2D) and three-dimensional (3D) mathematical models, for human, ventricular tissue with myocyte cells that are attached (a) regularly and (b) randomly to distributed fibroblasts. In both these cases we show that there is a parameter regime in which single rotating spiral- and scroll-wave states (RS) retain their integrity and do not evolve to a state ST that displays spatiotemporal chaos and turbulence. However, in another range of parameters, we observe a transition from ST to RS states in both 2D or 3D …
Every sixth death in industrialised countries occurs because of cardiac arrhythmias like ventricular tachycardia (VT) and ventricular fibrillation (VF). There is growing consensus that VT is associated with an unbroken spiral wave of electrical activation on cardiac tissue but VF with broken waves, spiral turbulence, spatiotemporal chaos and rapid, irregular activation. Thus spiral-wave activity in cardiac tissue has been studied extensively. Nevertheless many aspects of such spiral dynamics remain elusive because of the intrinsically high-dimensional nature of the cardiac-dynamical system. In…
In preimplantation mammalian embryos, the second cell fate decision introduces spatial patterns of embryonic and extra-embryonic precursor cells. The transcription factors NANOG and GATA6 are the earliest markers for the two cell types and interact between cells via the fibroblast growth factor signaling pathway. Computational models have been used to mimic the patterns and cell type proportions found in experimental studies. However, these models are always phenomenological in nature and lack a proper physical explanation. We derive a cell fate decision model motivated by the ideas of statist…
Local drug delivery has received much recognition in recent years, yet it is still unpredictable how drug efficacy depends on physicochemical properties and delivery kinetics. The purpose of the current study is to provide a useful mathematical model for drug release from a drug delivery device and consecutive drug transport in biological tissue, thereby aiding the development of new therapeutic drug by a systemic approach. In order to study the complete process, a two-layer spatio-temporal model depicting drug transport between the coupled media is presented. Drug release is described by cons…
Morphogenesis, the process by which an adult organism emerges from a single cell, has fascinated humans for a long time. Modelling this process can provide novel insights into development and the principles that orchestrate the developmental processes. This chapter focusses on the mathematical description and numerical simulation of developmental processes. In particular, we discuss the mathematical representation of morphogen and tissue dynamics on static and grow- ing domains, as well as the corresponding tissue mechanics. In addition, we give an overview of numerical methods that are routin…
We consider a continuum mathematical model of biological tissue formation inspired by recent experiments describing thin tissue growth in 3D-printed bioscaffolds. The continuum model involves a partial differential equation describing the density of tissue, $\hat{u}(\hat{\mathbf{x}},\hat{t})$, that is coupled to the concentration of an immobile extracellular substrate, $\hat{s}(\hat{\mathbf{x}},\hat{t})$. Cell migration is modelled with a nonlinear diffusion term, where the diffusive flux is proportional to $\hat{s}$, while a logistic growth term models cell proliferation. The extracellular su…
We propose an uncertainty propagation study and a sensitivity analysis with the Ocular Mathematical Virtual Simulator, a computational and mathematical model that predicts the hemodynamics and biomechanics within the human eye. In this contribution, we focus on the effect of intraocular pressure, retrolaminar tissue pressure and systemic blood pressure on the ocular posterior tissue vasculature. The combination of a physically-based model with experiments-based stochastic input allows us to gain a better understanding of the physiological system, accounting both for the driving mechanisms and …
A mathematical model for fluid and solute transport in peritoneal dialysis is constructed. The model is based on a three-component nonlinear system of two-dimensional partial differential equations for fluid, glucose and albumin transport with the relevant boundary and initial conditions. Its aim is to model ultrafiltration of water combined with inflow of glucose to the tissue and removal of albumin from the body during dialysis, and it does this by finding the spatial distributions of glucose and albumin concentrations and hydrostatic pressure. The model is developed in one spatial dimension…
The majority of solid tumours arise in epithelia and therefore much research effort has gone into investigating the growth, renewal and regulation of these tissues. Here we review different mathematical and computational approaches that have been used to model epithelia. We compare different models and describe future challenges that need to be overcome in order to fully exploit new data which present, for the first time, the real possibility for detailed model validation and comparison.
The growth of several biological tissues is known to be controlled in part by local geometrical features, such as the curvature of the tissue interface. This control leads to changes in tissue shape that in turn can affect the tissue's evolution. Understanding the cellular basis of this control is highly significant for bioscaffold tissue engineering, the evolution of bone microarchitecture, wound healing, and tumour growth. While previous models have proposed geometrical relationships between tissue growth and curvature, the role of cell density and cell vigor remains poorly understood. We pr…
Simple ideas, endowed from the mathematical theory of control, are used in order to analyze in general grounds the human immune system. The general principles are minimization of the pathogen load and economy of resources. They should constrain the parameters describing the immune system. In the simplest linear model, for example, where the response is proportional to the load, the annihilation rate of pathogens in any tissue should be greater than the pathogen's average rate of growth. When nonlinearities are added, a reference value for the number of pathogens is set, and a stability conditi…
Cell-based, mathematical modeling of collective cell behavior has become a prominent tool in developmental biology. Cell-based models represent individual cells as single particles or as sets of interconnected particles, and predict the collective cell behavior that follows from a set of interaction rules. In particular, vertex-based models are a popular tool for studying the mechanics of confluent, epithelial cell layers. They represent the junctions between three (or sometimes more) cells in confluent tissues as point particles, connected using structural elements that represent the cell bou…
Heterogeneity within tumour cell populations is associated with an increase in malignancy and appears to play an important role during cancer metastasis. Using in silico experiments, we study the interplay between collective behaviours and cell motility heterogeneities in a model system. Working with tumour spheroids that contain two non-proliferating cell populations of different motile properties, we explore the conditions required for maximal invasion into surrounding tissues. We show emerging spatial patterns of cellular organisation and invasion which are consistent with in vitro and in v…
Abnormal electrical activity from the boundaries of ischemic cardiac tissue is recognized as one of the major causes in generation of ischemia-reperfusion arrhythmias. Here we present theoretical analysis of the waves of electrical activity that can rise on the boundary of cardiac cell network upon its recovery from ischaemia-like conditions. The main factors included in our analysis are macroscopic gradients of the cell-to-cell coupling and cell excitability and microscopic heterogeneity of individual cells. The interplay between these factors allows one to explain how spirals form, drift tog…
Known as one of the hallmarks of cancer [30], cancer cell invasion of human body tissue is a complicated spatio-temporal multiscale process which enables a localised solid tumour to transform into a systemic, metastatic and fatal disease. This process explores and takes advantage of the reciprocal relation that solid tumours establish with the extracellular matrix (ECM) components and other multiple distinct cell types from the surrounding microenvironment. Through the secretion of various proteolytic enzymes such as matrix metalloproteinases (MMP) or the urokinase plasminogen activator (uPA),…
A new mathematical model and numerical approach are proposed for the simulation of fluid and chemical exchanges between a growing capillary network and the surrounding tissue, in the context of tumor-induced angiogenesis. Thanks to proper modeling assumptions the capillaries are reduced to their centerline: a well posed mathematical model is hence worked out, based on the coupling between a three-dimensional and a one-dimensional equation (3D-1D coupled problem). Also the application of a PDE-constrained optimization formulation is here proposed for the first time for angiogenesis simulations.…
In order to describe two-dimensionally packed cells in epithelial tissues both mathematically and physically, there have been developed several sorts of geometrical models, such as the vertex model, the finite element model, the cell-centered model, the cellular Potts model. So far, in any case, pressures have not neatly been dealt with and curvatures of the cell boundaries have been even omitted through their approximations. We focus on these quantities and formulate them on the vertex model. Thus, a model with the curvatures is constructed and its algorithm is given for simulation. Its possi…
Colorectal cancers are the third most common type of cancer. They originate from intestinal crypts, glands that descend from the intestinal lumen into the underlying connective tissue. Normal crypts are thought to exist in a dynamic equilibrium where the rate of cell production at the base of a crypt is matched by that of loss at the top. Understanding how genetic alterations accumulate and proceed to disrupt this dynamic equilibrium is fundamental to understanding the origins of colorectal cancer. Colorectal cancer emerges from the interaction of biological processes that span several spatial…
To maintain renewing epithelial tissues in a healthy, homeostatic state, (stem) cell divisions and differentiation need to be tightly regulated. Mechanisms of homeostatic control often rely on crowding control: cells are able to sense the cell density in their environment (via various molecular and mechanosensing pathways) and respond by adjusting division, differentiation, and cell state transitions appropriately. Here we determine, via a mathematically rigorous framework, which general conditions for the crowding feedback regulation (i) must be minimally met, and (ii) are sufficient, to allo…
Although tissues are usually studied in isolation, this situation rarely occurs in biology, as cells, tissues, and organs, coexist and interact across scales to determine both shape and function. Here, we take a quantitative approach combining data from recent experiments, mathematical modelling, and Bayesian parameter inference, to describe the self-assembly of multiple epithelial sheets by growth and collision. We use two simple and well-studied continuum models, where cells move either randomly or following population pressure gradients. After suitable calibration, both models prove to be p…
Background: Radiotherapy outcomes are usually predicted using the Linear Quadratic model. However, this model does not integrate complex features of tumor growth, in particular cell cycle regulation. Methods: In this paper, we propose a multiscale model of cancer growth based on the genetic and molecular features of the evolution of colorectal cancer. The model includes key genes, cellular kinetics, tissue dynamics, macroscopic tumor evolution and radiosensitivity dependence on the cell cycle phase. We investigate the role of gene-dependent cell cycle regulation in the response of tumors to th…
The analytical theory of our earlier study (Mortensen et al. (2021), Mathematical Medicine and Biology, 38(1), pp. 106-131) is extended to address the outstanding cases of fibroblast barrier distribution and myocyte strait distribution. In particular, closed-form approximations to the resting membrane potential and to the critical parameter values for propagation are derived for these two non-uniform fibroblast distributions and are in good agreement with numerical estimates.
We show that when cells communicate by contact-mediated interactions, heterogeneity in cell shapes and sizes leads to qualitatively distinct collective behavior in the tissue. For inter-cellular coupling that implements lateral inhibition, such disorder-driven transitions can substantially alter the asymptotic pattern of differentiated cells by modulating their fate choice through changes in the neighborhood geometry. In addition, when contact-induced signals influence inherent cellular oscillations, disorder leads to the emergence of functionally relevant partially-ordered dynamical states.
Diffusion models are important in tissue engineering as they enable an understanding of molecular delivery to cells in tissue constructs. As three-dimensional (3D) tissue constructs become larger, more intricate, and more clinically applicable, it will be essential to understand internal dynamics and signaling molecule concentrations throughout the tissue. Diffusion characteristics present a significant limitation in many engineered tissues, particularly for avascular tissues and for cells whose viability, differentiation, or function are affected by concentrations of oxygen and nutrients. Thi…
This paper concerns multiphase models of tumor growth in interaction with a surrounding tissue, taking into account also the interplay with diffusible nutrients feeding the cells. Models specialize in nonlinear systems of possibly degenerate parabolic equations, which include phenomenological terms related to specific cell functions. The paper discusses general modeling guidelines for such terms, as well as for initial and boundary conditions, aiming at both biological consistency and mathematical robustness of the resulting problems. Particularly, it addresses some qualitative properties such…
Incorporating stochastic gene expression, signaling-mediated intercellular interactions, and regulated cell proliferation in models of coordinated tissue development
Most biological tissues grow by the synthesis of new material close to the tissue's interface, where spatial interactions can exert strong geometric influences on the local rate of growth. These geometric influences may be mechanistic, or cell behavioural in nature. The control of geometry on tissue growth has been evidenced in many in-vivo and in-vitro experiments, including bone remodelling, wound healing, and tissue engineering scaffolds. In this paper, we propose a generalisation of a mathematical model that captures the mechanistic influence of curvature on the joint evolution of cell den…
The initial reaction of the body to pathogenic microbial infection or severe tissue trauma is an acute inflammatory response. The magnitude of such a response is of critical importance, since an uncontrolled response can cause further tissue damage, sepsis, and ultimately death, while an insufficient response can result in inadequate clearance of pathogens. A normal inflammatory response helps to annihilate threats posed by microbial pathogenic ligands, such as endotoxins, and thus, restore the body to a healthy state. Using a personalized mathematical model, comprehension and a detailed descr…
Cell proliferation, apoptosis, and myosin-dependent contraction can generate elastic stress and strain in living tissues, which may be dissipated by internal rearrangement through cell topological transition and cytoskeletal reorganization. Moreover, cells and tissues can change their sizes in response to mechanical cues. The present work demonstrates the role of tissue compressibility and internal rearranging activities on its size and mechanics regulation in the context of differential growth induced by a field of growth-promoting chemical factors. We develop a mathematical model based on fi…
One of the key characteristics of multicellular organisms is the ability to establish and maintain shapes, or morphologies, under a variety of physical and chemical perturbations. A quantitative description of the underlying morphological dynamics is a critical step to fully understand the self-organising properties of multicellular systems. Although many powerful mathematical tools have been developed to analyse stochastic dynamics, rarely these are applied to experimental developmental biology. Here, we take root tip regeneration in the plant model system Arabidopsis thaliana as an example o…
A contemporary procedure to grow artificial tissue is to seed cells onto a porous biomaterial scaffold and culture it within a perfusion bioreactor to facilitate the transport of nutrients to growing cells. Typical models of cell growth for tissue engineering applications make use of spatially homogeneous or spatially continuous equations to model cell growth, flow of culture medium, nutrient transport, and their interactions. The network structure of the physical porous scaffold is often incorporated through parameters in these models, either phenomenologically or through techniques like math…
Single-species reaction-diffusion equations, such as the Fisher-KPP and Porous-Fisher equations, support travelling wave solutions that are often interpreted as simple mathematical models of biological invasion. Such travelling wave solutions are thought to play a role in various applications including development, wound healing and malignant invasion. One criticism of these single-species equations is that they do not explicitly describe interactions between the invading population and the surrounding environment. In this work we study a reaction-diffusion equation that describes malignant in…
