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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.

Mesenchymal stem cells ( MSCs) are an attractive candidate for autologous cell therapy, but their ability to repair damaged myocardium is severely compromised with advanced age. Development of viable autologous cell therapy for treatment of heart failure in the elderly requires the need to address MSC ageing. In this study, MSCs from young (2 months) and aged (24 months) C57 BL/6 mice were characterized for gene expression of IGF-1 , FGF-2 , VEGF , SIRT-1 , AKT , p16INK4a , p21 and p53 along with measurements of population doubling ( PD), superoxide dismutase ( SOD) activity and apoptosis. Aged MSCs displayed senescent features compared with cells isolated from young animals and therefore were pre-conditioned with glucose depletion to enhance age affected function. Pre-conditioning of aged MSCs led to an increase in expression of IGF-1 , AKT and SIRT-1 concomitant with enhanced viability, proliferation and delayed senescence. To determine the myocardial repair capability of pre-conditioned aged MSCs, myocardial infarction ( MI) was induced in 24 months old C57 BL/6 wild type mice and GFP expressing untreated and pre-conditioned aged MSCs were transplanted. Hearts transplanted with pre-conditioned aged MSCs showed increased expression of paracrine factors, such as IGF-1 , FGF-2 , VEGF and SDF-1α. This was associated with significantly improved cardiac performance as measured by d p/d tmax, d p/d tmin, LVEDP and LVDP, declined left ventricle ( LV) fibrosis and apoptosis as measured by Masson's Trichrome and TUNEL assays, respectively, after 30 days of transplantation. In conclusion, pre-conditioning of aged MSCs with glucose depletion can enhance proliferation, delay senescence and restore the ability of aged cells to repair senescent infarcted myocardium. [ABSTRACT FROM AUTHOR]

Background: The essential aetiology of radiation-induced acute myeloid leukaemia (AML) in mice is the downregulation of the transcription factor PU.1. The causative mutation of the PU.1-endocing Sfpi1 gene consists mostly of C:G to T:A transitions at a CpG site and is likely to be of spontaneous origin. To work out a mechanism underlying the association between radiation exposure and the AML induction, we have hypothesised that replicative stress after irradiation accelerates the ageing of haematopoietic stem cells (HSCs), and the ageing-related decline in DNA repair could affect the spontaneous mutation rates.Methods: Mathematical model analysis was conducted to examine whether and to what extent the cell kinetics of HSCs can be modified after irradiation. The haematopoietic differentiation process is expressed as a mathematical model and the cell-kinetics parameters were estimated by fitting the simulation result to the assay data.Results: The analysis revealed that HSCs cycle vigourously for more than a few months after irradiation. The estimated number of cell divisions per surviving HSC in 3 Gy-exposed mice reached as high as ten times that of the unexposed.Interpretation: The mitotic load after 3 Gy irradiation seems to be heavy enough to accelerate the ageing of HSCs and the hypothesis reasonably explains the leukaemogenic process. [ABSTRACT FROM AUTHOR]