Cell biology

Dormant and restless skin stem cells

It has been unclear whether a uniform group of stem cells gives rise to most cells in the epidermis. A study reveals the presence of at least two stem-cell populations that have different proliferative abilities. See Article p.257

All renewing tissues, such as blood and skin, are sustained and repaired by a small population of resident stem cells. These cells have the ability to self-renew and to generate committed progenitor cells that differentiate into the cell lineages of the tissue of origin. However, the nature and the specific activities of stem and progenitor cells at different body sites are a matter of debate. For example, several theories have been proposed regarding the epidermis, the outer covering of the skin (Fig. 1). On page 257 of this issue, Mascré et al.1 provide compelling evidence for the existence of two cell populations that differ in their proliferative dynamics, their gene-expression profile and their ability to repair the epidermis after injury.

Figure 1: Models for self-renewal of the epidermis.
figure1

a, One model2 of epidermal renewal relies on quiescent stem cells that generate transient actively dividing (amplifying) cells, which in turn generate non-dividing, differentiated cells. Curly arrows indicate self-renewing cells. b, A second model3,4 posits the existence of a single population of actively cycling, committed progenitor cells that directly generate differentiated cells. c, Mascré and colleagues' results1 suggest that epidermal renewal is sustained by slowly dividing stem cells that persist during the lifetime of the animal and contribute to both repair and long-term regeneration of the epidermis. These cells give rise to actively cycling, self-renewing stem cells (or committed progenitors) that persist for various periods of time, replenish differentiated cells and make only a short-term contribution to wound healing. d, We suggest that slowly dividing stem cells generate activated stem cells that give rise to transient amplifying progenitors, which eventually produce differentiated cells. A similar model has previously been proposed for other tissues5,6,7,8,9,10.

To investigate the origin, location, proliferation and fate of stem cells in mouse-tail epidermis, the authors used genetic lineage tracing — a technique that allows in vivo fluorescent marking of specific cell types and their progeny — as well as elegant studies of individual clones (cells derived from a single initial cell). The specificity of the marking depends on the nature of the promoters (regulatory DNA sequences) that are employed to trigger permanent expression of a fluorescent protein. This is useful because different promoters are active in different cell types.

Mascré et al. used two distinct promoters (K14 and Inv) and unambiguously identified two cell populations. One of these populations consisted of slowly dividing cells, which represented the stem-cell reservoir and contributed to wound repair. These stem cells gave rise to a second population that comprised actively dividing committed progenitors, which eventually generated differentiated cells. The K14 promoter targeted both stem cells and committed progenitors, whereas the Inv promoter targeted only progenitors.

The results confirm the notion that the epidermis contains long-lived quiescent stem cells as well as cells endowed with differing proliferative abilities2, and argues against the model proposing that a single progenitor-cell pool sustains self-renewal and regeneration of the mouse epidermis3,4 (Fig. 1a–c). Moreover, the authors' study provides an explanation for previous findings that seemed to suggest a single-progenitor model3,4. These earlier studies had used a promoter (Ach) that targets just one group of actively cycling cells that make only a short-term contribution to epidermal repair — in other words, the Ach-marked cells behaved in a similar way to Mascré and colleagues' Inv-targeted progenitor cells.

Interestingly, the two cell populations described by the authors both possess a fundamental stem-cell property, namely, self-renewal. However, the slowly cycling stem cells persist throughout the animal's lifetime and contribute to the repair and long-term regeneration of the epidermis, whereas the actively dividing progenitors endure for shorter periods (up to several months) and make only a short-term contribution to wound healing. Therefore, these actively dividing progenitors are not the canonical 'transient amplifying cells' proposed by a previous model (Fig. 1a).

How can we define the K14- and Inv-labelled cells from a functional point of view? To try to answer this question, it may be useful to discuss what happens in other tissues. It has been shown5 that the bone marrow contains a pool of quiescent haematopoietic (blood-forming) stem cells that generate a population of rapidly cycling stem cells. K14-marked stem cells are functionally similar to quiescent haematopoietic stem cells, whereas Inv-marked progenitors mirror actively cycling, self-renewing haematopoietic stem cells. A similar situation has been described for tissues such as hair follicles and the small intestine6,7. In all of these tissues, stem cells can switch between quiescence and activation depending on the functional status of the tissue; that is, normal self-renewal or acute wound healing. In our opinion, Mascré and colleagues' data support a model envisaging the coexistence of quiescent and activated stem cells as a general strategy for tissue renewal (Fig. 1c).

The notion that the mammalian epidermis contains cells endowed with different proliferative dynamics raises interesting questions that need further investigation. What factors specify the fate of these two cell populations? What are the molecular pathways that regulate stem-cell quiescence and activation in the epidermis, especially upon injury? And is the switch from quiescence to activation a cell-autonomous process, or is it controlled by environmental cues?

The study also highlights the limitations of genetic lineage tracing. Results obtained with this technique are influenced by the dynamics of the stem-cell populations in the tissues analysed, as well as by the types of promoter used and by how the promoters are activated. For instance, the authors did not detect transient amplifying progenitors, but it is not clear whether such cells are genuinely absent from the mouse epidermis or whether they were not detected owing to the lack of an appropriate promoter (Fig. 1d).

Mascré and colleagues' work sheds light on the heterogeneity of the proliferative cell populations in mouse epidermis, and has increased our understanding of stem-cell biology. But does this knowledge apply to human tissues? Caution is required when inferring aspects of human tissue physiology from animal data. For instance, clonal analyses of several human squamous epithelia (tissues such as the epidermis, cornea and conjunctiva) have unambiguously shown the existence of self-renewing cells endowed with stem-cell properties, as well as non-self-renewing cells with differing capacities for multiplication, including canonical transient amplifying cells8,9. Both cell types participate in the regeneration of these epithelia in the clinic10.

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Correspondence to Michele De Luca.

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De Rosa, L., De Luca, M. Dormant and restless skin stem cells. Nature 489, 215–217 (2012) doi:10.1038/489215a

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