Cell division is a process that involves many biochemical steps and complex biophysical mechanisms. To simplify the understanding of what triggers cell division, three basic models that subsume more microscopic cellular processes associated with cell division have been proposed. Cells can divide based on the time elapsed since their birth, their size, and/or the volume added since their birth -- the timer, sizer, and adder models, respectively. Here, we propose unified adder-sizer models and investigate some of the properties of different adder processes arising in cellular proliferation. Although the adder-sizer model provides a direct way to model cell population structure, we illustrate how it is mathematically related to the well-known model in which cell division depends on age and size. Existence and uniqueness of weak solutions to our 2+1-dimensional PDE model are proved, leading to the convergence of the discretized numerical solutions and allowing us to numerically compute the dynamics of cell population densities. We then generalize our PDE model to incorporate recent experimental findings of a system exhibiting mother-daughter correlations in cellular growth rates. Numerical experiments illustrating possible average cell volume blowup and the dynamical behavior of cell populations with mother-daughter correlated growth rates are carried out. Finally, motivated by new experimental findings, we extend our adder model cases where the controlling variable is the added size between DNA replication initiation points in the cell cycle.
We analyse the asymptotic behaviour of a nonlinear mathematical model of cellular proliferation which describes the production of blood cells in the bone marrow. This model takes the form of a system of two maturity structured partial differential equations, with a retardation of the maturation variable and a time delay depending on this maturity. We show that the stability of this system depends strongly on the behaviour of the immature cells population. We obtain conditions for the global stability and the instability of the trivial solution.
Cells of the human body have nearly identical genome but exhibit very different phenotypes that allow them to carry out specific functions and react to changes in their surrounding environment. This division of labour is achieved by cellular division and cellular differentiation, events which lead to a population of cells with unique characteristics. In this paper, we model the dynamics of cells over time across a sequence of compartments. Cells within a compartment may represent being at the same spatial location or sharing the same phenotype. In this sequence of compartments, cells can eithe…
For various species of biological cells, experimental observations indicate the existence of universal distributions of the cellular size, scaling relations between the cell-size moments and simple rules for the cell-size control. We address a class of models for the control of cell division, and present the steady state distributions. By introducing concepts such as effective force and potential, we are able to address the appearance of scaling collapse of different distributions and the connection between various moments of the cell-size. Our approach allows us to derive strict bounds which …
We propose a modelling framework to analyse the stochastic behaviour of heterogeneous, multi-scale cellular populations. We illustrate our methodology with a particular example in which we study a population with an oxygen-regulated proliferation rate. Our formulation is based on an age-dependent stochastic process. Cells within the population are characterised by their age. The age-dependent (oxygen-regulated) birth rate is given by a stochastic model of oxygen-dependent cell cycle progression. We then formulate an age-dependent birth-and-death process, which dictates the time evolution of th…
We present a novel mathematical model of heterogeneous cell proliferation where the total population consists of a subpopulation of slow-proliferating cells and a subpopulation of fast-proliferating cells. The model incorporates two cellular processes, asymmetric cell division and induced switching between proliferative states, which are important determinants for the heterogeneity of a cell population. As motivation for our model we provide experimental data that illustrate the induced-switching process. Our model consists of a system of two coupled delay differential equations with distribut…
Cancer cells exhibit increased motility and proliferation, which are instrumental in the formation of tumours and metastases. These pathological changes can be traced back to malfunctions of cellular signalling pathways, and calcium signalling plays a prominent role in these. We formulate a new model for cancer cell movement which for the first time explicitly accounts for the dependence of cell proliferation and cell-cell adhesion on calcium. At the heart of our work is a non-linear, integro-differential (non-local) equation for cancer cell movement, accounting for cell diffusion, advection a…
Incorporating stochastic gene expression, signaling-mediated intercellular interactions, and regulated cell proliferation in models of coordinated tissue development
Tissue culture environment liberates cells from ordinary laws of multi-cellular organisms. This liberation enables cells several behaviors, such as proliferation, dedifferentiation, acquisition of pluripotency, immortalization, and reprogramming. Recently, the quantitative value of cellular dedifferentiation and differentiation was defined as liberality, which is measurable as Shannon entropy of numerical transcriptome data and Lempel-Zip complexity of nucleotide sequence transcriptome data. The increasing liberality induced by the culture environment had first been observed in animal cells an…
Experimental evidence indicates that human brain cancer cells proliferate or migrate, yet do not display both phenotypes at the same time. Here, we present a novel computational model simulating this cellular decision-process leading up to either phenotype based on a molecular interaction network of genes and proteins. The model's regulatory network consists of the epidermal growth factor receptor (EGFR), its ligand transforming growth factor-a (TGFa), the downstream enzyme phospholipaseC-gamma (PLCg) and a mitosis-associated response pathway. This network is activated by autocrine TGFa secret…
Angiogenesis, the development of new vasculature, is a critical process in the growth of new tumors. Driven by a goal to understand this aspect of cancer proliferation, I develop a discrete computationally optimized mathematical model of angiogenesis that specializes in intercellular interactions. I model vascular endothelial growth factor spread and dynamics of endothelial cell movement in a competitive environment, with parameters specific to our model calculated through Dependent Variable Sensitivity Analysis (DVSA) and experimentally observed data. Through simulation testing, we find the c…
We study the asymptotic behaviors of stochastic cell fate decision between proliferation and differentiation. We propose a model of a self-replicating Langevin system, where cells choose their fate (i.e. proliferation or differentiation) depending on local cell density. Based on this model, we propose a scenario for multi-cellular organisms to maintain the density of cells (i.e., homeostasis) through finite-ranged cell-cell interactions. Furthermore, we numerically show that the distribution of the number of descendant cells changes over time, thus unifying the previously proposed two models r…
The importance of collective cellular migration during embryogenesis and tissue repair asks for a sound understanding of underlying principles and mechanisms. Here, we address recent in vitro experiments on cell monolayers which show that the advancement of the leading edge relies on cell proliferation and protrusive activity at the tissue margin. Within a simple viscoelastic mechanical model amenable to detailed analysis, we identify a key parameter responsible for tissue expansion, and we determine the dependence of the monolayer velocity as a function of measurable rheological parameters. O…
Bacterial physiology is a branch of biology that aims to understand overarching principles of cellular reproduction. Many important issues in bacterial physiology are inherently quantitative, and major contributors to the field have often brought together tools and ways of thinking from multiple disciplines. This article presents a comprehensive overview of major ideas and approaches developed since the early 20th century for anyone who is interested in the fundamental problems in bacterial physiology. This article is divided into two parts. In the first part (Sections 1 to 3), we review the f…
A ubiquitous feature of living cells is their growth over time followed by division into daughter cells. How isogenic cell populations maintain size homeostasis, i.e., a narrow distribution of cell size, is an intriguing fundamental problem. We model cell size using a stochastic hybrid system, where a cell grows exponentially in size (volume) over time and probabilistic division events are triggered at discrete time intervals. Moreover, whenever division events occur, size is randomly partitioned among daughter cells. We first consider a scenario, where a timer (i.e., cell-cycle clock) that me…
Feedback loops are essential for regulating cell proliferation and maintaining the delicate balance between cell division and cell death. Thanks to the exact solution of a few simple models of cell growth it is by now clear that stochastic fluctuations play a central role in this process and that cell growth (and in particular the robustness and stability of homeostasis) can be properly addressed only as a stochastic process. Using epidermal homeostasis as a prototypical example, we show that it is possible to discriminate among different feedback strategies which turn out to be characterized …
Continuum models for the spatial dynamics of growing cell populations have been widely used to investigate the mechanisms underpinning tissue development and tumour invasion. These models consist of nonlinear partial differential equations that describe the evolution of cellular densities in response to pressure gradients generated by population growth. Little prior work has explored the relation between such continuum models and related single-cell-based models. We present here a simple stochastic individual-based model for the spatial dynamics of multicellular systems whereby cells undergo p…
Predictive modeling of the evolutionary dynamics of cancer is a challenge issue in computational cancer biology. In this paper, we propose a general mathematical model framework for the evolutionary dynamics of cancer with plasticity and heterogeneity in cancer cells. Cancer is a group of diseases involving abnormal cell growth, during which abnormal regulations in stem cell regeneration are essential for the dynamics of cancer development. In general, the dynamics of stem cell regeneration can be simplified as a $\mathrm{G_0}$ phase cell cycle model, which lead to a delay differentiation equa…
