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

The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.

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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Crossref · 10.1038/nature14242

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Metadata

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
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
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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