Mathematical Modeling and Analysis of Aging Alteration of Hematopoietic Stem Cell Symmetric and Asymmetric Division

Hematopoietic stem cells (HSCs) self-renew and differentiate into all blood lineages throughout life. In order to maintain homeostasis, three modes of HSC divisions, stem cell-stem cell (S-S) divisions, stem cell-progenitor cell (S-P) divisions, and progenitor cell-progenitor cell (P-P) divisions, are tightly regulated during the development and regeneration. With aging, both quantitative and qualitative changes in the HSC population occur. Previous studies have reported that the number of HSC increases with age in both mice and humans whereas they gradually lose their function with age. However, little is known about in vivo quantitative dynamics of HSCs during aging. It has either remained unclear whether the distribution of symmetric and asymmetric division is changed depending on age. Our recent study found that murine HSCs could be efficiently expanded in polyvinyl alcohol (PVA)-containing culture medium. This culture system allows for long-term culture of HSCs, indicating that it can reproduce the in vivo environment better than before. Here we describe the age-associated quantitative changes of HSCs and the distribution of symmetric and asymmetric division in the murine HSCs combining mathematical modeling with the experimental data using the novel HSCs expansion cultures containing PVA. Noting that the EPCR surface marker, also known as CD201, is a good marker for identifying HSCs after a period of culture in a PVA-based medium, we investigated age-related differences of the three division modes through experiments in which single cells from mice of various week-olds were cultured in PVA medium. Our experimental data demonstrate several important and novel findings; first, S-S divisions are predominant throughout life, which expands the HSC pool, but the proportion gradually decreases with aging, and the proportion of the P-P division increases instead. Second, the S-P divisions were subordinate throughout life. Third, the size of the HSC population monotonically increases with near linear kinetics as mice age.

On the other hand, progenitor cells demonstrated unique and non-linear kinetics. Through mathematical modeling, we describe the age-related serial alteration of three types of division modes, which have been shown by either sampling of limited time-points in previous studies. Thereby we could explain how it contributes to the age-associated linear expansion of the HSC pool size. These approaches provide a further understanding of hematopoiesis and highlight the complexity of hematopoietic differentiation. These are remarkable findings because they have the potential to clarify various issues about hematopoiesis, such as the mechanisms of clonal hematopoiesis.

No relevant conflicts of interest to declare.