Cell population modelling describes intrinsic heterogeneity: a case study for hematopoietic stem cells

The control of stem cell properties during in vitro expansion is of paramount importance for their clinical use. According to Food and Drug Administration (FDA) guidelines, phenotypic heterogeneity is a critical aspect influencing therapeutic response. Even if the authors ability to reduce heterogeneity were limited, the sources from which it arises should be well understood for safe clinical applications. The aim of this work was to describe theoretically the intrinsic cell population heterogeneity that is present even when cells are cultured in a perfectly homogeneous environment. A bivariate population balance model is developed to account for the heterogeneity in the number of receptors and receptor-ligand complexes per cell, and is coupled with a ligand conservation equation. As a case study, the model is applied to the hematopoietic stem cell expansion, considering the c-Kit receptor and stem cell factor pair. Results show the dependence of intrinsic heterogeneity from ligand concentration and the kinetics of its administration. By tracking the cell generations within the total population, the authors highlight intra- and an inter-generational contributions to total population heterogeneity. In terms of dimensionless variables, intrinsic heterogeneity is dependent on the ratio of the characteristic time of cell division to that needed by a newborn cell to reach its single-cell steady state. [Includes supplementary material].