A dynamic model of ex vivo granulopoiesis: Effects of oxygen tension, pH, and IL-3

Evaluating kinetics in hematopoietic cultures is complicated by the distribution of cells over various stages of differentiation and by the presence of cells from different lineages. Growth factors and other parameters can greatly affect the lineage and maturation stage of a culture. In order to resolve the kinetics and more clearly define the differential effects of O2 tension (pO2), pH, and IL-3 on granulopoiesis, a mathematical model-based approach was undertaken. Granulocytic differentiation is described within a continuous, deterministic framework in which cells develop from primitive granulocytic progenitors to mature neutrophils. The model predicts distributed cell populations by incorporating independent rates of growth, death, differentiation, and transition between quiescence and active cycling. The response of these four model processes to changes in the culture environment was examined. Model simulations of experimental data revealed that (i) pO2 effects are exerted only on the growth rate, (ii) pH effects between pH 7.25 and 7.4 on growth and differentiation are coupled; however, with increasing pH values, especially at pH 7.6, the death rate for cells in the early stages of differentiation becomes increasingly significant, and (iii) the absence of IL-3 markedly enhances the rate of differentiation through the myeloblast window in the differentiation pathway. The combined effects of these environmental factors can be predicted based on changes in the model parameters derived from the individual effects. Integrating experimental data with mathematical modeling can be used to elucidate the mechanisms underlying the regulation of granulopoiesis by pO2, pH, IL-3, and other conditions, and to improve culture strategies.