Stable contribution of lineage-restricted stem cells to steady-state human haematopoiesis
Multipotent self-renewing haematopoietic stem cells (HSCs), possessing the potential to replenish all mature blood cell lineages, are critical for safe-guarding life-long replenishment of millions of shortlived blood cells every second in steady-state haematopoiesis, as well as in response to haematopoietic challenges. Our knowledge of the functional properties and roles of mammalian HSCs is largely based on studies in mice, due to limitations of available platforms assessing human HSC function. Studies of steady-state replenishment of the different critical blood cell lineages by individual human HSC clones has been hampered by an estimated 50,000-200,000 HSCs actively contributing to adult haematopoiesis. Moreover, while the dynamic contribution of HSC clones to different lineages only can be assessed by lineage-tracing the same individual HSC clones over time, steady-state lineage contribution from individual HSCs has only been investigated at a single time point, in mice as well as in humans. We have used somatically acquired clonal haematopoiesis mutations and non-driver mutations as natural barcodes to identify and fate-map the steady-state lineage contribution of individual HSC clones over time in serial bone marrow samples obtained from healthy old human subjects with normal blood parameters. Our findings establish the existence of distinct human HSC clones with stable multilineage as well as lineage-restricted and -biased contributions to steady-state human haematopoiesis. Regardless of replenishing haematopoiesis in a balanced multilineage or lineage-restricted manner, individual HSCs invariably showed a remarkably stable lineage contribution pattern as well as clonal size through years of observation, and phylogenetic analysis showed that these distinct intrinsic properties are likely to have been programmed decades earlier.
Date: 5 June 2024, 10:30 (Wednesday, 7th week, Trinity 2024)
Venue: MRC Weatherall Institute of Molecular Medicine, Headington OX3 9DS
Speaker: Tetsuichi Yoshizato (Karolinska Institute)
Organising department: MRC Weatherall Institute of Molecular Medicine
Organisers: Fiona Lambert (MRC, Wetherall Institute of Molecular Medicine), Sarah Butler (MRC, Weatherall Institute of Molecular Medic one), Penny Berry (University of Oxford, Department of Oncology, Weatherall Institute of Molecular Medicine), Kevin Clark (University of Oxford, Weatherall Institute of Molecular Medicine), Linda Roberts (University of Oxford, Weatherall Institute of Molecular Medicine), Anne Farmer (University of Oxford, NDM Experimental Medicine, RDM Investigative Medicine Division), Liz Rose (University of Oxford, Weatherall Institute of Molecular Medicine)
Organiser contact email address: fiona.lambert@imm.ox.ac.uk
Part of: WIMM Occasional Seminars
Booking required?: Not required
Audience: Members of the University only
Editor: Fiona Lambert