Abstract
BackgroundIn vitro cultivated stem cell populations are in general heterogeneous with respect to their expression of differentiation markers. In hematopoietic progenitor populations, this heterogeneity has been shown to regenerate within days from isolated subpopulations defined by high or low marker expression. This kind of plasticity has been suggested to be a fundamental feature of mesenchymal stem cells (MSCs) as well. Here, we study MSC plasticity on the level of individual cells applying a multi-scale computer model that is based on the concept of noise-driven stem cell differentiation.ResultsBy simulation studies, we provide detailed insight into the kinetics of MSC organisation. Monitoring the fates of individual cells in high and low oxygen culture, we calculated the average transition times of individual cells into stem cell and differentiated states. We predict that at low oxygen the heterogeneity of a MSC population with respect to differentiation regenerates from any selected subpopulation in about two days. At high oxygen, regeneration becomes substantially slowed down. Simulation results on the composition of the functional stem cell pool of MSC populations suggest that most of the cells that constitute this pool originate from more differentiated cells.ConclusionsIndividual cell-based models are well-suited to provide quantitative predictions on essential features of the spatio-temporal organisation of MSC in vitro. Our predictions on MSC plasticity and its dependence on the environment motivate a number of in vitro experiments for validation. They may contribute to a better understanding of MSC organisation in vitro, including features of clonal expansion, environmental adaptation and stem cell ageing.
Highlights
In vitro cultivated stem cell populations are in general heterogeneous with respect to their expression of differentiation markers
Mesenchymal stem cells (MSCs) are multi-potent cells that persist in adult life in some tissue types, such as bone-marrow stroma, fat, skeletal muscle, and synovium without loosing their capacity to proliferate and differentiate [9,10]
Plasticity has been suggested to represent a fundamental feature of mesenchymal stem cells (MSCs) [13]
Summary
Monitoring individual cell fates Using the IBM the fates of individual cells in growing populations can be monitored. We simulated this population regeneration experiment as follows: Starting from a population that was grown at low density, i.e. which shows no signs of contact inhibition of growth, we selected 200 stem cells and 200 differentiated cells and followed their development over 5 days in secondary cultures. If regeneration started from differentiated cells at high oxygen, most of the cells remained quiescent throughout the observation time (137 out of 200 in Figure 4c) and only a few cells started to proliferate and formed large clones. These simulation results implicate that if regeneration refers to the growth of a few large clones, as in the case of differentiated cells at high oxygen, the effect of contact inhibition becomes more relevant for population regeneration. All progenitor states contribute to this pool, while at high oxygen tension most cells originate from progenitor states with a high α value between 0.7 and 0.8
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