Fundamental properties of unperturbed haematopoiesis from stem cells in vivo
Abstract
Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or ∼5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.
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Barcodes produced through Cre-lox recombination in different hematopoietic cells confirmed a major replicative role of MPPs, while also demonstrating a consistent contribution of HSCs.
“However, barcodes produced through Cre-lox recombination in different hematopoietic cells confirmed a major replicative role of MPPs, while also demonstrating a consistent contribution of HSCs (Busch et al., 2015).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Busch et al., 2015
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- Authors
- Busch, K., Klapproth, K., Barile, M., Flossdorf, M., Holland-Letz, T., Schlenner, S. M., Reth, M., Höfer, T., & Rodewald, H.-R.
- Affiliations
- German Cancer Research Center (DE)
- KU Leuven (BE)
- University of Freiburg (DE)
- Corresponding author
- Höfer, Thomas
- Rodewald, Hans-Reimer
- Venue
- Nature
- Published
- 2015-02-11
- Volume
- 518
- Issue
- 7540
- Pages
- 542-546
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2142043313
- Cited by
- 769
- References
- 34
- Citations by year
- 2026: 31 · 2025: 48 · 2024: 72 · 2023: 72 · 2022: 71 · 2021: 69 · 2020: 75 · 2019: 56 · 2018: 88 · 2017: 80 · 2016: 79 · 2015: 26 · 2014: 1
- FWCI
- 71.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Deutsches Krebsforschungszentrum
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, self-renewal, long-term HSCs, progenitor cells, limiting dilution analysis
- MeSH terms
- Aging, Animals, Animals, Newborn, Female, Fetus, Fluorouracil, Hematopoiesis, Hematopoietic Stem Cells, Male, Stem Cells, Bone Marrow Transplantation, Cell Lineage, Receptor, TIE-2, Cell Proliferation, Mice, Cell Tracking
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