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Effects of ageing and DNA damage on activity and clonality of the hematopoietic stem cell pool

Subject Area Hematology, Oncology
Immunology
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 401355815
 
Final Report Year 2022

Final Report Abstract

Hematopoietic stem cells (HSCs) reside atop the hematopoietic hierarchy and are the ultimate source of all blood cell lineages. While the potential and heterogeneity of HSC subpopulations has been well established by perturbative transplantation assays, there is little and partially contradictory knowledge about HSC behavior under native conditions. For example, a study performed long-term mitotic tracking of HSCs in mice and concluded that HSCs initially undergo four divisions to then abruptly entering permanent quiescence. However, fate mapping experiments in mice employing labeled HSCs revealed continuous differentiation of HSCs throughout life. These fate mapping studies also sparked a controversy on the contribution of HSCs to native steady-state hematopoiesis. In this project, we employed fate mapping and proliferation tracking mouse models to investigate native HSC behavior. We re-evalutated histone 2B-fluorescent protein (H2B-FB) data and found that in addition to cell division, inevitable leaky background expression and division-independent degradation of H2B-FPs must be considered in the analysis of label dilution data. In order to account for these factors, we developed a mathematical model, which allows for the quantitative interpretation of H2B-FP decay dynamics. Moreover, our analysis revealed continuous mitotic activity of adult HSCs, but we did not find evidence for HSCs counting and remembering four discrete cell divisions to then enter permanent quiescence. By integrating HSC proliferation tracking and fate mapping data through means of mathematical modelling, we identified the hitherto elusive tip HSC population, which was demarcated by high expression of the surface markers CD201 and Sca-1. We found that this HSC subpopulation contributed very little but continuously to steady state hematopoiesis. We also show that the level of Sca-1 expression can predict lymphoid or myeloid fate already in HSC populations. In addition, we discovered two complementary subpopulations of megakaryocyte progenitors (MkPs). While MkPs with low CD48 expression differentiate directly from HSCs, their CD48 high expressing counterparts are generated via multipotent progenitors. Both pathways contribute equally to steady-state thrombopoiesis, while enhanced thrombopoietin stimulation as well as ageing increased the short pathway via CD48-/lo MkPs. In a further set of experiments, we investigated how HSCs respond in situ to hematopoietic stressor like infections or blood cell loss. While artificial stressors like the chemotherapeutic agent 5-fluorouracil or sublethal ionizing radiation strongly activate HSCs to regenerate hematopoiesis after myeloablation, perturbations mimicking bacterial or viral infections did not induce robust HSC proliferation or differentiation. Finally, we started to investigate how loss of the epigenetic regulator Tet2, which favors development of clonal hematopoiesis and preleukemia, affected proliferation and differentiation of HSCs. In sum, this project investigated the native fate and mitotic activity of HSC at steady state or under stress conditions including infections, ageing or oncogenic driver mutation.

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