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Unravelling stem cell dynamics by lineage tracing

Nature Reviews Molecular Cell Biology volume 14, pages 489–502 (2013)Cite this article

Subjects

Key Points

  • The rules governing cell fate choice are key to understanding the mechanisms that regulate stem cell behaviour in development and homeostasis and to identifying the factors leading to their dysregulation in disease.

  • Lineage-tracing approaches are essential to obtain information on the long-term self-renewal potential and fate choice of stem and progenitor cell populations.

  • Population-based methods involving the incorporation of thymidine analogues, such as 5-bromodeoxyuridine (BrdU), or the dilution of histone 2B (H2B)–GFP, provide quantitative information on proliferation kinetics and fate specification of cell populations.

  • Lineage-tracing methods based on the use of transgenic animal models provide access to quantitative information on the activity, potency and fate choice of individual stem cells and their progeny.

  • The quantitative analysis of lineage-tracing data following inducible genetic labelling has contributed to the understanding of the proliferative hierarchy and fate behaviour of stem and progenitor cell populations in the mouse interfollicular epidermis and the intestinal epithelium in homeostasis.

  • Lineage-tracing methods can also be used to study the renewal and lineage potential of precursors in adult tissue, as well as during embryonic and postnatal development.

  • Lineage-tracing assays in animal models provide new quantitative insights into the fate behaviour and tumour-maintaining potential of cells within solid tumours.

Abstract

During embryonic and postnatal development, the different cells types that form adult tissues must be generated and specified in a precise temporal manner. During adult life, most tissues undergo constant renewal to maintain homeostasis. Lineage-tracing and genetic labelling technologies are beginning to shed light on the mechanisms and dynamics of stem and progenitor cell fate determination during development, tissue maintenance and repair, as well as their dysregulation in tumour formation. Statistical approaches, based on proliferation assays and clonal fate analyses, provide quantitative insights into cell kinetics and fate behaviour. These are powerful techniques to address new questions and paradigms in transgenic mouse models and other model systems.

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Figure 1: Lineage tracing as a quantitative tool.
Figure 2: Lineage tracing of the intestinal epithelium.
Figure 3: Clonal dynamics of the skin epidermis.
Figure 4: Lineage tracing during epithelial development.
Figure 5: Clonal dynamics of tumour cells.

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Acknowledgements

B.D.S. thanks A. Klein for important discussions and contributions, and he gratefully acknowledges the financial support of the Wellcome Trust (grant number 098357/Z/12/Z). C.B. is an investigator of Walloon Excellence in Life Science and Biotechnology (WELBIO), and he is supported by the Belgian Fund for Scientific Research (FNRS) and the European Research Council (ERC).

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Authors and Affiliations

  1. Université Libre de Bruxelles, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), 808 route de Lennik, Brussels, B-1070, Belgium

    Cédric Blanpain

  2. Walloon Excellence in Life Science and Biotechnology (WELBIO), Université Libre de Bruxelles, 808 route de Lennik, Brussels, B-1070, Belgium

    Cédric Blanpain

  3. Department of Physics, Cavendish Laboratory, University of Cambridge, J. J. Thomson Avenue, Cambridge, CB3 0HE, UK

    Benjamin D. Simons

  4. Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK

    Benjamin D. Simons

  5. Wellcome Trust Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK

    Benjamin D. Simons

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Glossary

Equipotent precursor cells

A group of progenitor cells that present the same intrinsic capacity to renew and differentiate. The term equipotency does not imply that all cells will give rise to identical daughter cells, as the cell cycle time may be different between equipotent progenitors, and the choice between renewal and differentiation may be stochastically defined.

Terminal divisions

Cell divisions that lead to the generation of two terminally differentiated cells that will not divide anymore.

Stem cell niche

The particular microenvironment in which stem cells reside. The stem cell niche is thought to regulate stem cell activity and influence fate decisions through the release of extrinsic signals (for example, growth factors, morphogens, nutriments and oxygen).

Pulse-chase

A method that involves the administration of nucleotide analogues for a certain period (pulse), followed by a period during which no nucleotide analogues is administrated (chase). During the chase period, cells that divide will dilute the label equally between the two daughter cells. After a few rounds of cell division (3–4 divisions), the label typically becomes undetectable. By contrast, in non-dividing cells the label remains detectable, and these cells are thus termed label-retaining.

Clonal density

The density of labelled cells that allows the fate of single labelled cells to be resolved and followed over time.

Genetic labelling

A method of cell labelling that uses a genetic system (such as a fluorescent reporter gene). The advantage of genetic labelling is its irreversibility, leading to a permanent expression of the reporter gene in the cells initially labelled and all their progeny. Non-genetic labelling, based on, for example, the incorporation of fluorescent dyes in some cells, eventually becomes undetectable as the dyes are diluted.

Scaling behaviour

Behaviour that does not vary under a change of scale. For example, for a population defined by a statistical size distribution, while the average size may change over time, if the chance of finding a member of the population with a size greater than some multiple of the average remains constant over time, the distribution is said to scale.

Neutral drift

A term that was initially used to define the statistical distribution of gene mutations (drift) with no selective advantage (neutral) in a human population. This term can be used to describe a similar phenomenology in other contexts such as the time evolution of the statistical distribution of clone sizes in a lineage-tracing assay.

Rete ridges

Defines the bottom of the undulation present in the human skin epidermis, which was thought to contain human epidermal stem cells in certain parts of the body.

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Blanpain, C., Simons, B. Unravelling stem cell dynamics by lineage tracing. Nat Rev Mol Cell Biol 14, 489–502 (2013). https://doi.org/10.1038/nrm3625

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