RESUMEN
Division and differentiation events by which cell populations with specific functions are generated often take place as part of a developmental programme, which can be represented by a sequence of compartments. A compartment is the set of cells with common characteristics; sharing, for instance, a spatial location or a phenotype. Differentiation events are transitions from one compartment to the next. Cells may also die or divide. We consider three different types of division events: (i) where both daughter cells inherit the mother's phenotype (self-renewal), (ii) where only one of the daughters changes phenotype (asymmetric division), and (iii) where both daughters change phenotype (symmetric division). The self-renewal probability in each compartment determines whether the progeny of a single cell, moving through the sequence of compartments, is finite or grows without bound. We analyse the progeny stochastic dynamics with probability generating functions. In the case of self-renewal, by following one of the daughters after any division event, we may construct lifelines containing only one cell at any time. We analyse the number of divisions along such lines, and the compartment where lines terminate with a death event. Analysis and numerical simulations are applied to a five-compartment model of the gradual differentiation of hematopoietic stem cells and to a model of thymocyte development: from pre-double positive to single positive (SP) cells with a bifurcation to either SP4 or SP8 in the last compartment of the sequence.
Asunto(s)
Diferenciación Celular , División Celular , Procesos Estocásticos , Autorrenovación de las Células , División Celular Asimétrica , Modelos Biológicos , Animales , Humanos , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/fisiologíaRESUMEN
We consider the maintenance of 'product' cell populations from 'progenitor' cells via a sequence of one or more cell types, or compartments, where each cell's fate is chosen stochastically. If there is only one compartment then large amplification, that is, a large ratio of product cells to progenitors comes with disadvantages. The product cell population is dominated by large families (cells descended from the same progenitor) and many generations separate, on average, product cells from progenitors. These disadvantages are avoided using suitably constructed sequences of compartments: the amplification factor of a sequence is the product of the amplification factors of each compartment, while the average number of generations is a sum over contributions from each compartment. Passing through multiple compartments is, in fact, an efficient way to maintain a product cell population from a small flux of progenitors, avoiding excessive clonality and minimizing the number of rounds of division en route. We use division, exit and death rates, estimated from measurements of single-positive thymocytes, to choose illustrative parameter values in the single-compartment case. We also consider a five-compartment model of thymocyte differentiation, from double-negative precursors to single-positive product cells.
Asunto(s)
Células Madre , Humanos , Diferenciación CelularRESUMEN
Deterministic dynamic models for coupled resident and invader populations are considered with the purpose of finding quantities that are effective at predicting when the invasive population will become established asymptotically. A key feature of the models considered is the stage-structure, meaning that the populations are described by vectors of discrete developmental stage- or age-classes. The vector structure permits exotic transient behaviour-phenomena not encountered in scalar models. Analysis using a linear Lyapunov function demonstrates that for the class of population models considered, a large so-called population inertia is indicative of successful invasion. Population inertia is an indicator of transient growth or decline. Furthermore, for the class of models considered, we find that the so-called invasion exponent, an existing index used in models for invasion, is not always a reliable comparative indicator of successful invasion. We highlight these findings through numerical examples and a biological interpretation of why this might be the case is discussed.