Abstract
Stem cells are important to generate all specialized tissues at an early life stage, and in some systems, they also have repair functions to replenish the adult tissues. Repeated cell divisions lead to the accumulation of molecular damage in stem cells, which are commonly recognized as drivers of ageing. In this paper, a novel model is proposed to integrate stem cell proliferation and differentiation with damage accumulation in the stem cell ageing process. A system of two structured PDEs is used to model the population densities of stem cells (including all multiple progenitors) and terminally differentiated (TD) cells. In this system, cell cycle progression and damage accumulation are modelled by continuous dynamics, and damage segregation between daughter cells is considered at each division. Analysis and numerical simulations are conducted to study the steady-state populations and stem cell damage distributions under different damage segregation strategies. Our simulations suggest that equal distribution of the damaging substance between stem cells in a symmetric renewal and less damage retention in stem cells in the asymmetric division are favourable strategies, which reduce the death rate of the stem cells and increase the TD cell populations. Moreover, asymmetric damage segregation in stem cells leads to less concentrated damage distribution in the stem cell population, which may be more robust to the stochastic changes in the damage. The feedback regulation from stem cells can reduce oscillations and population overshoot in the process, and improve the fitness of stem cells by increasing the percentage of cells with less damage in the stem cell population.
Highlights
Stem cells are characterized by their ability to give rise to a variety of cell types through self-renewal and differentiation [1]
Asymmetric damage segregation in stem cells leads to less concentrated damage distribution in stem cells population, which may be more robust to the stochastic change in damage
Cell cycle progression and damage accumulation are continuous while division is discrete, and the damage segregation takes place at each division
Summary
Stem cells are characterized by their ability to give rise to a variety of cell types through self-renewal and differentiation [1]. Assuming that cell proliferation is negatively affected by telomere shortening, an agent-based stochastic model [23] was proposed to study telomere-dependent stem cell replicative ageing. This model provides a good approximation of the qualitative growth of cultured human mesenchymal stem cells. In [41], the authors applied the mean-field approach to approximate an agent-based model for studying heterogeneity within the haematopoietic stem cell population Their proposed PDE model can capture the key structure of the model including the ‘age’-structure of stem cells and improve the efficiency of the numerical algorithms.
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