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

• Applicant: Dr. Alexander Gerbaulet
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 401355815

The hematopoietic system replenishes vast numbers of mature blood cells each day and can adapt rapidly to situations of even higher demand for mature blood cells e.g. infection or blood loss. While this enormous regenerative capacity is maintained over the entire life span, specific alterations of the system occur at old age that likely are associated with accumulating genome damage. How quiescent subpopulations of hematopoietic stem cells (HSCs) participate in steady state and stress hematopoiesis at young and old age is only partially understood until today. We will address why the hematopoietic systems maintains a substantial number of these quiescent HSCs which hardly contribute to steady state blood cell production. We hypothesize that quiescent HSCs are needed as a functional reserve to prevent exhaustion of the hematopoietic system, to maintain a polyclonal stem cell pool and to counteract accumulation of DNA damage at older age. Our project first aims to track the fate of a quiescent HSC subset within the intact bone marrow under steady state and stress conditions. Mathematical modeling of the experimental data will address how quiescent and proliferative subpopulations of hematopoietic stem and progenitor cells are hierarchically related to each other. In parallel, we will generate new mouse models for in situ (i.e. within the physiological environment without transplantation or ex vivo manipulation) clonal tagging and tracking of the hematopoietic system by the means of CRISPR/Cas9 genome editing. We will then investigate the clonality of stem and progenitor populations and the contribution of single hematopoietic cells in steady-state, upon ageing and after chronic exposure to DNA damaging hazards. As the ageing hematopoietic system frequently shows expansion of discrete hematopoietic clones and progression to pre-leukemic conditions, including myelodysplastic syndrome, we will investigate the effects of oncogenic driver mutations on the clonality of hematopoiesis and the activity and differentiation of stem cell and precursor clones.

• DFG Programme: Research Grants