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Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer

Nature Reviews Genetics volume 19, pages 311–325 (2018)Cite this article

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Abstract

Stem cells (SCs) govern tissue homeostasis and wound repair. They reside within niches, the special microenvironments within tissues that control SC lineage outputs. Upon injury or stress, new signals emanating from damaged tissue can divert nearby cells into adopting behaviours that are not part of their homeostatic repertoire. This behaviour, known as SC plasticity, typically resolves as wounds heal. However, in cancer, it can endure. Recent studies have yielded insights into the orchestrators of maintenance and lineage commitment for SCs belonging to three mammalian tissues: the haematopoietic system, the skin epithelium and the intestinal epithelium. We delineate the multifactorial determinants and general principles underlying the remarkable facets of SC plasticity, which lend promise for regenerative medicine and cancer therapeutics.

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Figure 1: Stem cell heterogeneity in space and in time.
Figure 2: Stem cell plasticity under stress.
Figure 3: Stem cell plasticity in cancer.

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Acknowledgements

The authors thank R. C. Adam, M. Laurin and S. Ellis for discussions and critical feedback of the manuscript. This work was supported by grants from the National Institutes of Health (AR05042). Y.G. is an awardee of Robertson Therapeutic Development Fund. E.F. is an investigator of the Howard Hughes Medical Institute.

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  1. Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA

    Yejing Ge & Elaine Fuchs

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  1. Yejing Ge
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  2. Elaine Fuchs
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The authors contributed equally to all aspects of the article.

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Correspondence to Elaine Fuchs.

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Glossary

Totipotency

The ability of a zygote to give rise to all the lineages of the embryo and extra-embryonic tissues. It differs from the ability of embryonic stem cells to generate all lineages of the embryo (pluripotency) and the ability of adult stem cells to reconstitute multiple (multipotency), a few selective (oligopotency) or a single lineage (unipotency) of a tissue.

Plasticity

In this Review, any process that is distinct from homeostasis. For example, the increased differentiation of haematopoietic stem cells (HSCs) into cells of all blood lineages upon injury is in sharp contrast to their homeostatic behaviour, where HSCs contribute minimally; therefore, we consider such behaviour to be plastic. Plasticity is not restricted to stem cells, although this Review focuses primarily on stem cell plasticity.

Stemness

The unique ability of stem cells to undergo long-term self-renewal and multilineage differentiation.

Engraftment

A procedure in which transplantation of a stem cell of interest is grafted into a host recipient animal to test for the ability of the cell to contribute to host tissue regeneration.

Epicentres

DNA regulatory elements of about 1 kb in length that sit within broad chromatin domains marked by histone 3 lysine 27 acetylation, so-called super-enhancers or stretch-enhancers and are bound by clustered cell identity and/or stress-specific transcription factors.

Lineage infidelity

A term initially used in blood malignancies to describe the presence of multiple differentiation markers specific to distinct lineages in the same cell. In epithelial wounding, lineage infidelity was observed for skin stem cells, which were found to co-express markers of otherwise confined lineages and functionally rely upon them to cope with stress and mediate repair. Lineage infidelity occurs transiently during wound repair but is hijacked by squamous cell carcinoma where it becomes sustained and is essential for malignancy.

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Ge, Y., Fuchs, E. Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer. Nat Rev Genet 19, 311–325 (2018). https://doi.org/10.1038/nrg.2018.9

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