Cited by 769Hematopoietic Stem Cell TransplantationMesenchymal stem cell researchBlood disorders and treatments

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Fundamental properties of unperturbed haematopoiesis from stem cells in vivo

Busch, Katrin, Klapproth, Kay, Barile, Melania, Flossdorf, Michael, Holland-Letz, Tim, Schlenner, Susan M., Reth, Michael, Höfer, Thomas, Rodewald, Hans-Reimer·2015·Nature

DOI 10.1038/nature14242

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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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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
ORCID: Barile, Melania
Schlenner, Susan M.
Reth, Michael
Höfer, Thomas
Rodewald, Hans-Reimer
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-02-11
Volume: 518
Issue: 7540
Pages: 542-546
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature14242
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
FWCI: 71.55
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
Health Sciences › Medicine › Hematology › 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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Fundamental properties of unperturbed haematopoiesis from stem cells in vivo

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