Cellular aging leads to functional heterogeneity of hematopoietic stem cells: a modeling perspective

Abstract

SummaryHematopoietic stem cells (HSCs) are the source for the lifelong supply of functional cells in peripheral blood while they simultaneously maintain their own reserve pool. However, there is accumulating evidence that HSCs are themselves subject to quantitative and qualitative exhaustion. Although several processes linked to mitotic activity can potentially account for the observed aging phenomena (e.g., DNA damage, telomere shortening, epigenetic modification), a precise understanding of HSC exhaustion is still missing. It is particularly unclear how individual aging processes on the single-cell level translate on the phenotypic level of the overall tissue and whether there is a functional implication of an age-structured HSC population. We address these issues by applying a novel mathematical model of HSC organization in which division-specific, cumulative alterations of stem cell quality determine the phenotypic and functional appearance of the overall cell population. Adapting the model to a number of basic experimental findings, we quantify the level of additional heterogeneity that is introduced by a population of individually aging cells. Based on this model, we are able to conclude that division-dependent processes of cellular aging explain a wide range of phenomena on HSC exhaustion and that HSC aging needs to be considered as a highly heterogeneous process. We furthermore report that functional heterogeneity between young and old HSCs appears closely similar to the phenomena described for long-and short-term repopulating cells. We speculate whether differential, division-coupled stem cell aging introduces an intra-animal variability that also accounts for heterogeneity with respect to the repopulation ability of HSCs.

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis

“…We chose the ABM for HSC introduced by Roeder and Loeffler [26] to replace the stem cell compartment of our ODE for two reasons: it represents the stem cell population in a highly structured way (two niches, affinity, cell cycle) and has been proven successful in a broad range of scenarios relevant for clinical applications such as Imatinib-treatment of chronic myeloid leukemia in humans [30,32]. Replacement is performed on the basis of a difference equations formulation of the ABM proposed by Kim et al [34].…”

“…In one of these two GE, which can be interpreted as a stem cell niche [24], the stem cells are quiescent and regenerate their ability to remain in the niche, while in the other GE they proliferate and lose this niche affinity. The broad range of successful applications of this modeling concept includes modeling of clonal competition [27,28], age-dependent repopulation potential after irradiation [29] and treatment of chronic myeloid leukemia with Imatinib and interferon-α [30-32]. …”

The Mechanobiology of Aging

“…However, this study brings up an interesting premise that warrants further investigation: cellular heterogeneity. Cellular heterogeneity plays an important part in dictating cell function—that is, how cells process information and respond to perturbations (76, 77). Although often neglected in aging studies, heterogeneity can be dictated by many factors, in vitro and in vivo, from both cell-intrinsic and cell-extrinsic factors, such as stochasticity in cellular morphogenesis, the cell-cycle state, cell–cell and cell–matrix interactions, genetic predispositions, lifestyle (factors such as nutrition or diet, and exercise), and environmental factors and exposures.…”

Not so benign haematology: anaemia of the elderly

“…Transplantation is thought accelerate replicative senescence by requiring transplanted cells to rapidly proliferate to repopulate the recipient host. Mathematical models have suggested that this type of HSC exhaustion would take several life-times under homeostatic conditions and would not be relevant to normal ageing, but could contribute to anaemia in subset of patients who experienced extensive haematopoietic demands over a lifetime (Glauche, et al 2011). …”