The Epidermis Comprises Autonomous Compartments Maintained by Distinct Stem Cell Populations

Page, Mahalia E.; Lombard, Patrick; Ng, Felicia S.L.; Göttgens, Berthold; Jensen, Kim B.

doi:10.1016/j.stem.2013.07.010

Cited by 291 publications

(378 citation statements)

References 51 publications

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“…10 Indeed, once we focused our analyses on the wound basal layer, we observed that HF-derived cells, including bulge-derived cells, actually increased in the wound over time. Altogether, these findings suggest that cellular position within the wound epithelium-basal vs. suprabasal-may affect whether a cell persists.…”

Section: Discussionmentioning

confidence: 98%

“…Consistent with these findings, previous studies have indicated that mobilized bulge cells can be retained in the HF infundibulum, 15,36 and that HF isthmus-derived cells appear to migrate farther into the wound than do lower bulgederived cells. 10 It is important to note that these observations might also be explained if bulge-derived cells exhibit innate differences in proliferation or migration rates that delay their entry into the site of injury. Nonetheless, the relative absence of bulgederived cells in the middle of the wound might provide an extrinsic explanation for why these cells reportedly do not contribute to HF neogenesis, which occurs only at the wound center.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Consequently, stem cells that do not ordinarily encounter one another during homeostasis, such as those of the HF bulge and the basal layer of the IFE, are suddenly brought into contact when they converge at the wounded area. 8 Although multiple reports have documented the overall persistence of different HF stem cell-derived sub-populations following wound healing, [9][10][11][12][13][14][15][16] few have quantitated the specific ability of these cells to populate the permanent, basal layer of the regenerating epithelium over time. This layer is likely to be significant, since IFE stem cells are found exclusively in the basal layer, whereas their differentiated progeny stratify into the overlying suprabasal layers of the skin and are eventually sloughed off.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2015

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“…Lineage tracing studies using transgenic mouse models have revealed a surprising degree of compartmentalization, with the turnover of hair follicle, sebaceous gland, and interfollicular epidermis (IFE) maintained by independent stem-cell populations (24). In IFE, proliferation is confined to…”

Section: Deep Sequencing As a Clonal Marker In Human Epidermismentioning

confidence: 99%

Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

Simons

2015

Proc. Natl. Acad. Sci. U.S.A.

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Using deep sequencing technology, methods based on the sporadic acquisition of somatic DNA mutations in human tissues have been used to trace the clonal evolution of progenitor cells in diseased states. However, the potential of these approaches to explore cell fate behavior of normal tissues and the initiation of preneoplasia remain underexploited. Focusing on the results of a recent deep sequencing study of eyelid epidermis, we show that the quantitative analysis of mutant clone size provides a general method to resolve the pattern of normal stem cell fate and to detect and characterize the mutational signature of rare field transformations in human tissues, with implications for the early detection of preneoplasia.stem cells | DNA sequencing | epidermis | cancer A dvances in genetic lineage tracing in transgenic animal models have provided important insights into the proliferative potential and fate behavior of stem and progenitor cell populations in normal tissues (1, 2). As well as providing constraints on the mechanisms that regulate stem cell self-renewal, these approaches have established a quantitative framework to address tumor initiation and progression (3-6). However, studies based on the clonal activation of oncogenes in animal models can fail to recapitulate the natural processes that lead to neoplasia in human tissues. In recent years, there has been increasing emphasis on the characterization of cancer genomes in human tissues and their potential to elucidate the pathways involved in tumor progression (7)(8)(9)(10)(11)(12)(13)(14). Although these studies have revealed a range of cancer genes (15), the heterogeneity and evolutionary diversity of the tumor environment make the separation of driver and passenger mutations challenging.Against the trend to focus on human tumor samples, a recent study has used ultradeep exome sequencing to determine the mutational profile of normal human eyelid epidermis (16). In the course of DNA replication, all dividing cells are subject to random SNPs. If the mutation rate is sufficiently low that their acquisition at a given locus in a cell subpopulation is typically associated with a single event, they confer a potentially unique hereditary label on cells, allowing the fate of their progeny to be traced over time. By resolving the mutant allele fraction in a biopsy using deep sequencing, the relative size of mutant clones can be inferred. A similar approach based on the spontaneous acquisition of mitochondrial DNA mutation has been used to address progenitor cell fate in human airways and intestinal epithelia (17,18). To assess the selective growth advantage of different mutations in normal epidermis, Martincorena et al. (16) compared the dN/dS ratio and average size of clones derived from mutations in genes associated with cancer drivers with those associated with synonymous mutations in nondriver genes. Their analysis showed a significant increase in the abundance and average size of clones that bear mutations in NOTCH1 and tumor protein p53 (TP53) compared wit...

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“…stem cell | perineural niche | touch dome | Merkel cell | Hedgehog T he skin is one of several tissues in which the epithelium is organized into specialized regions, and each compartment is maintained by lineage-specific stem cells (1). Epithelial-mesenchymal interactions are classically regarded as critical signals in establishing and maintaining epidermal lineage compartments (2).…”

mentioning

confidence: 99%

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

Xiao

Thoresen

Williams

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

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The Epidermis Comprises Autonomous Compartments Maintained by Distinct Stem Cell Populations

Cited by 291 publications

References 51 publications

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

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

Deep sequencing as a probe of normal stem cell fate and preneoplasia in human epidermis

Neural Hedgehog signaling maintains stem cell renewal in the sensory touch dome epithelium

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