A single type of progenitor cell maintains normal epidermis

Clayton, Elizabeth; Doupé, David P.; Klein, Allon M.; Winton, Douglas J.; Simons, Benjamin D.; Jones, Philip H.

doi:10.1038/nature05574

Cited by 756 publications

(947 citation statements)

References 28 publications

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“…Future studies will be necessary to determine when, and how, this stem cell heterogeneity is established. On the other hand, the murine interfollicular epidermis, which primarily depends on continuously cycling basal progenitors rather than dormant stem cells 38 for its renewal, shows a much more homogenous clock activity (albeit containing approximately 5% of cells antiphasic with the majority). In this compartment the clock machinery might predominantly establish a correct timing of stem cell activation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .…”

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confidence: 99%

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The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

274

284

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Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.Epidermal stem cells ensure that skin homeostasis is maintained. Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .Bulge stem cells undergo bouts of activation followed by periods of dormancy, to establish hair follicle cycling. Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 . However, the response of bulge stem cells to activating stimuli is a heterogeneous process, as only a subset of them become active during either stage of activation 12,13 . The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 . The core molecular clock is established by a positive limb, composed of heterodimers of the transcription fa...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

274

284

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“…39 At the same time, other studies have argued that the epidermis is maintained by only one type of progenitor cell that stochastically undergoes either symmetric or asymmetric divisions. 40,41 In the HF, molecularly distinct cell sub-populations clearly exist, but whether these lineages differ in their functional ability to contribute to regeneration has remained unclear. While bulge-derived cells have been reported to be lost from the wound over time, again, this may be due to a perceived overall loss of suprabasal cells from the thickened wound epithelium.…”

Section: Discussionmentioning

confidence: 99%

Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration

2015

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Upon wounding, multiple stem cell populations in the hair follicle (HF) and interfollicular epidermis (IFE) converge at the site of injury. Although these cells can contribute permanently to the regenerating epithelium, it remains unclear whether these contributions vary among cells originating from diverse compartments in the skin. By comparing the fates of several keratinocyte lineages, we observed here an initial decrease in both HF-and IFE-derived cells within the transient acanthotic layers of the regenerating epithelium. At the same time, the relative abundance of early-arriving IFE-derived cells specifically in the wound basal layer declined as later-arriving HF-derived cells entered the site of injury. Although laggard bulge-derived cells were typically constrained at the regenerative periphery, these cells persisted in the wound basal layer. Finally, suppressing Notch enabled IFE-derived cells to out-compete HF-derived cells. Taken together, these findings indicate that IFE-, HF-and bulge-derived cells make distinct contributions to regeneration over time. Furthermore, we speculate that extrinsic, non-genetic factors such as spatial constraint, distance from the wound, and basal versus suprabasal position may largely determine whether a cell ultimately persists.

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“…Rather than selecting for β1 integrin-expressing cells, Kaur and colleagues [118] found blast-like α6 bri CD71 dim cells comprising about 2-5% of CK14 + basal cells in human epidermis, that were highly clonogenic and could regenerate a fullthickness epidermis in organotypic culture. Not all agree that mouse skin has both a stem cell and a TAC compartment; from genetic marking of occasional mouse basal cells in the tail and subsequent analysis of clone size, it was deduced that epidermal homeostasis could be maintained by a single population of progenitor cells [119].…”

Section: Stratified Squamous Epitheliamentioning

confidence: 99%

Attributes of adult stem cells

Alison

Islam

2008

The Journal of Pathology

151

115

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While cultured embryonic stem (ES) cells can be harvested in abundance and appear to be the most versatile of cells for regenerative medicine, adult stem cells also hold promise, but the identity and subsequent isolation of these comparatively rare cells remains problematic in most tissues, perhaps with the notable exception of the bone marrow. The ability to continuously self-renew and produce the differentiated progeny of the tissue of their location are their defining properties. Identifying surface molecules (markers) that would aid in stem cell isolation is a major goal. Considerable overlap exists between different putative organspecific stem cells in their repertoire of gene expression, often related to self-renewal, cell survival and cell adhesion. More robust tests of 'stemness' are now being employed, using lineage-specific genetic marking and tracking to show production of long-lived clones and multipotentiality in vivo. Moreover, the characterization of normal stem cells in specific tissues may provide a dividend for the treatment of cancer. The successful treatment of neoplastic disease may well require the specific targeting of neoplastic stem cells, cells that may well have many of the characteristics of their normal counterparts.

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A single type of progenitor cell maintains normal epidermis

Cited by 756 publications

References 28 publications

The circadian molecular clock creates epidermal stem cell heterogeneity

The circadian molecular clock creates epidermal stem cell heterogeneity

Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration

Attributes of adult stem cells

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