Replicative cellular age distributions in compartmentalised tissues

Abstract

The cellular age distribution of hierarchically organized tissues can reveal important insights into the dynamics of cell differentiation and self-renewal and associated cancer risks. Here, we examine theoretically the effect of progenitor compartments with varying differentiation and self-renewal capacities on the resulting observable distributions of replicative cellular ages. We find that strongly amplifying progenitor compartments, i.e. compartments with high self-renewal capacities, substantially broaden the age distributions which become skewed towards younger cells with a long tail of few old cells. However, since mutations predominantly accumulate during cell division, a few old cells may considerably increase cancer risk. In contrast, if tissues are organised into many downstream compartments with low self-renewal capacity, the shape of the replicative cell distributions in more differentiated compartments are dominated by stem cell dynamics with little added variation. In the limiting case of a strict binary differentiation tree without self-renewal, the shape of the output distribution becomes indistinguishable from the shape of the input distribution. Our results suggest that a comparison of cellular age distributions between healthy and cancerous tissues may inform about dynamical changes within the hierarchical tissue structure, i.e. an acquired increased self-renewal capacity in certain tumours.