Different types of stem cell maintain the skin's epidermis and contribute to its healing after damage. The identity of a stem-cell type that gives rise to different epidermal-cell lineages has just been revealed.
Skin acts as an essential barrier, protecting organisms from their environment. It is composed of two parts: the epidermis, the cells of which form the barrier; and the dermis, which provides support and nutrition to the epidermis. The epidermis also produces appendages, including sweat glands, and hair follicles and their associated sebaceous glands. The different epidermal compartments undergo constant cellular turnover to replace the dead or damaged cells. This homeostatic process is thought to involve several types of stem cell, each located in a specific epidermal region and contributing to the maintenance of a discrete compartment of the skin1 (Fig. 1a). In a paper published in Science, Snippert et al.2 identify the Lgr6 protein as the marker of progenitors that can differentiate into different cell lineages of the skin epidermis.
The first evidence that skin stem cells can differentiate into interfollicular epidermis, sebaceous gland and hair follicle lineages came from transplantation of bulge stem cells3,4 — a cell population located at the base of hair follicles. Further experiments revealed that, during both embryonic development and normal adult skin homeostasis, bulge stem cells and their progeny contribute to hair-follicle regeneration but not to the maintenance of the interfollicular epidermis4,5,6. In conditions such as wounding, however, bulge stem cells rapidly migrate towards the interfollicular epidermis to help with the rapid regeneration of the wounded skin5,7,8.
Later findings also showed that sebaceous-gland cells are maintained by progenitors located above the bulge, which express the Blimp1 protein during morphogenesis9. Maintenance of the interfollicular epidermis, meanwhile, involves many small units of proliferation scattered throughout this skin layer, called epidermal proliferative units10,11. The infundibulum — the upper part of the hair follicle, which interfaces with the interfollicular epidermis — is thought to be maintained by progenitors located in a hair-follicle region known as the isthmus; these cells, which express the marker proteins MTS24 and Lrig1 (refs 12, 13, 14), can differentiate into all epidermal cell lineages after transplantation13,14.
Snippert et al.2 set out to identify the 'mother' of these epidermal stem cells. They find that, during skin formation in mice, the transmembrane receptor Lgr6 is expressed in both the hair follicle and the interfollicular epidermis. In adult animals, however, Lgr6 expression becomes restricted to the isthmus, where about one-third of Lgr6-marked cells also express MTS24 and a few co-express Blimp1.
To more precisely define the differentiation potential of Lgr6-expressing cells, the authors used genetic wizardry to permanently label Lgr6-expressing cells and their progeny. As expected from the first set of results2, as well as previous data6,8, Lgr6-expressing cells gave rise to cells of both the hair follicle and the sebaceous gland during embryonic development. Moreover, some cells of the interfollicular epidermis were derived from Lgr6-expressing cells (Fig. 1b).
The authors' lineage tracing of adult skin shows that Lgr6 labelling was initially restricted mainly to the cells of the isthmus region, with some labelling of cells in the interfollicular epidermis and other parts of the hair follicles, albeit at lower frequency. Two months later, Lgr6 progeny were found mainly in the isthmus and sebaceous gland, with some in the interfollicular epidermis, and more rarely elsewhere in the hair follicle. These findings suggest that Lgr6-expressing cells contribute mostly to the homeostasis of the isthmus region and the sebaceous gland, whereas a few may have the potential to differentiate into other epidermal lineages. It remains unclear whether a single subpopulation within the Lgr6-marked cells regenerates both the isthmus and sebaceous gland or whether Lgr6 is expressed in both the previously identified12,13,14 isthmus progenitors expressing Lrig1 and MTS24, and the Blimp1-expressing sebaceous-gland progenitors9.
Snippert et al. also find that, like isthmus stem cells13,14, Lgr6-expressing cells transplanted into immunodeficient mice give rise to all epidermal cell lineages. Moreover, like bulge stem cells, Lgr6-expressing stem cells are activated by wounding and migrate towards the epidermis to aid wound repair (Fig. 1b). These intriguing observations suggest that at least two different hair-follicle stem-cell populations can actively contribute to the repair of the damaged epidermis.
The presence of Lgr6-derived cells in the interfollicular epidermis during tissue homeostasis is more puzzling. According to previous cell-lineage tracing of embryonic skin6,8, all cells of the mature hair follicle, including those of the isthmus region, are derived from cells expressing two other progenitor markers, Shh and Sox9. By contrast, the interfollicular epidermis is not labelled with these markers unless wounded, suggesting little or no contribution of hair-follicle cells to the maintenance of the interfollicular epidermis6,8.
Three scenarios could explain Snippert and colleagues' observation that Lgr6-derived cells are present in the interfollicular epidermis. First, some rare Lgr6-expressing isthmus cells might originate from a pool of hair-follicle progenitors different from those expressing Shh and Sox9, and these would then migrate to the interfollicular epidermis to contribute to its maintenance. Second, Lgr6 might be more broadly expressed than Shh or Sox9, thus marking a population of progenitors that resides in the interfollicular epidermis, and contributing locally to the development and homeostasis of cells there. Finally, micro-wounding or stress to the epidermis might cause migration of cells from the follicle into the interfollicular epidermis.
This study2 adds yet another piece to the complex puzzle of skin homeostasis, clearly demonstrating that Lgr6-expressing progenitors actively cycle to ensure the renewal of the isthmus region and the sebaceous gland under physiological conditions. During wounding, both bulge stem cells5,7,8 and Lgr6-expressing stem cells2 are actively recruited to repair the interfollicular epidermis. For most skin stem cells, the natural turnover of cells serves several purposes: to replace the dead cells that are shed from the skin surface (interfollicular epidermal stem cells), to fuel hair growth (bulge stem cells) or to make oil cells (sebaceous-gland stem cells). But Lgr6-expressing cells are constantly cycling and are not known to die frequently. So where are their progeny going?
One possibility is that the proliferation of Lgr6-marked isthmus cells essentially serves to fuel the high turnover of sebaceous-gland cells. It would be interesting to determine the intrinsic and extrinsic signals that dictate the fate of different skin epidermal progenitors during development, and to define factors that control their regionalization during both development and homeostasis. Moreover, deciphering the mechanisms that allow the migration of isthmus and bulge stem cells across these boundaries during wound healing will be essential.
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