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Do haematopoietic stem cells age?

Nature Reviews Immunology volume 20, pages 196–202 (2020)Cite this article

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Abstract

Genetic defects that accumulate in haematopoietic stem cells (HSCs) are thought to be responsible for age-related changes in haematopoiesis that include a decline in lymphopoiesis and skewing towards the myeloid lineage. This HSC-centric view is based largely on studies showing that HSCs from aged mice exhibit these lineage biases following transplantation into irradiated young recipient mice. In this Opinion article, we make the case that the reliance on this approach has led to inaccurate conclusions regarding the effects of ageing on blood-forming stem cells; we suggest instead that changes in the environment contribute to haematopoietic system ageing. We propose that a complete understanding of how ageing affects haematopoiesis depends on the analysis of blood cell production in unperturbed mice. We describe how this can be achieved using in situ fate mapping. This approach indicates that changes in downstream progenitors, in addition to any HSC defects, may explain the reduced lymphopoiesis and sustained myelopoiesis that occur during ageing.

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Fig. 1: Recipient conditioning and the composition of the haematopoietic stem cell compartment affect reconstitution.
Fig. 2: Haematopoietic stem cell and progenitor output in situ can be measured by fate mapping.

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Acknowledgements

The authors’ research presented here was supported by grants to K.D. from the US National Institutes of Health (AG056480), Deutsche Forschungsgemeinschaft DFG-SFB 873-B11 to T.H. and H.-R.R., and European Research Council Advanced Grant 742883 and DFG Leibniz program to H.-R.R.

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  1. Peter D. Pioli

    Present address: Present address: Center for Immunobiology, Homer Stryker M.D. School of Medicine, Western Michigan University, Kalamazoo, MI, USA

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Kenneth Dorshkind, Encarnacion Montecino-Rodriguez & Peter D. Pioli

  2. Division of Theoretical Systems Biology, German Cancer Research Center, Heidelberg, Germany

    Thomas Höfer

  3. Division of Cellular Immunology, German Cancer Research Center, Heidelberg, Germany

    Hans-Reimer Rodewald

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Glossary

Barcoding

Genetic tagging of cells with large numbers of distinct, and ideally unique, labels. Originally this was achieved by analyses of highly diverse integration sites of viral DNA in the genomes of cells infected in vitro, followed by cell transplantation and tracking of barcodes in progeny. More recently, endogenous barcoding has been developed, in which cells can be tagged in whole organisms without the need for cell manipulations in vitro. Examples of endogenous techniques include CRISPR–Cas9-based methods, transposon integration site analysis and Cre-dependent Polylox barcoding. When the probability of induction of a given barcode is smaller than the target population, it becomes highly likely that single cells are being labelled. Hence, endogenous barcoding can reveal precursor–product relationships emerging from single stem cells and can provide insights into lineage relationships.

Conditioning

The treatment of recipients before transplantation in order to create space in the bone marrow to allow for donor bone marrow cells to engraft. Conditioning regimens include drugs, such as 1,4-butanediol dimethanesulfonate (busulfan), and/or ionizing irradiation that kills endogenous stem and progenitor cells.

Fate-mapping approaches

Experimental approaches in which a single genetic switch, usually lineage-specific or stage-specific and sometimes inducible, is used to turn on a heritable marker in stem or progenitor cells. All progeny that arise from labelled cells can be tracked, which yields information on precursor–product relationships and on the flow of differentiation. Combined with mathematical analysis and modelling, fate mapping can reveal in situ frequencies of differentiating stem cells and progenitors and differentiation rates, independent of the vagaries of cell transplantation. The inducible Cre systems referred to in this article include Tie2–MerCreMer mice, Pdzk1ip1–CreER mice and Fgd5–CreERT2 mice.

Irradiation

Process in which a subject is exposed to radiation. Ionizing radiation can be delivered from caesium137 or cobalt60 γ-irradiators or X-ray devices. Both γ radiation and X-rays are highly penetrating and can travel into tissue, and as a result these forms of radiation are frequently used to deplete haematopoietic cells from the bone marrow before transplantation.

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Dorshkind, K., Höfer, T., Montecino-Rodriguez, E. et al. Do haematopoietic stem cells age?. Nat Rev Immunol 20, 196–202 (2020). https://doi.org/10.1038/s41577-019-0236-2

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