Emerging interactions between skin stem cells and their niches

Hsu, Ya‐Chieh; Li, Lishi; Fuchs, Elaine

doi:10.1038/nm.3643

Cited by 472 publications

(458 citation statements)

References 137 publications

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“…In mammals, skin is composed of a multilayered sheet of keratinocytes interspersed with hair follicles, sebaceous glands, and sweat glands (23). 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).…”

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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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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“…S tem and progenitor cells are crucial for tissue homeostasis, repair, and regeneration. In response to injury, they proliferate and differentiate to replace damaged or dysfunctional cells (1,2). In the skin, epidermal basal cells differentiate to form distinct epidermal layers: the stratum basale (SB), stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC) (3).…”

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confidence: 99%

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Velarde

Demaria

Melov

et al. 2015

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

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Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1) 20Efu/J × Sod2 tm1Smel , that generates mitochondrial oxidative stress in keratin 14-expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure.

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“…Indeed, keratinocytes compose 4 major layers, characterized by cells in stages of progressive differentiation, thanks to a temporal and spatial gene regulation. 2 Stem cells (SCs) and transient amplifying (TA)-cells are localized in the basal layer and are the only proliferative cells. Owing to their self-renewal properties, SCs maintain tissue homeostasis and repair.…”

Section: Introductionmentioning

confidence: 99%

“…They are cells endowed with a high proliferative capacity and able to generate a differentiated progeny. 2,3 Whenever SCs are activated, they enter into a transient state of rapid proliferation, giving rise to TAcells, the largest group of dividing cells. After several divisions, these cells withdraw from cell cycle and generate post-mitotic keratinocytes, which migrate upwards and form suprabasal layers executing their terminal differentiation program.…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

Dellambra¹

2016

Small GTPases

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The human epidermal clonal evolution, i.e. the transition from stem cells (SCs) to transient amplifying (TA)-cells and post-mitotic cells, is a continuous and tightly regulated process that ensures physiologic tissue homeostasis. The Ras family of small GTPases has a key role in skin homeostasis and tumorigenesis. Indeed, activating mutations in Ras genes have been found in human cutaneous squamous cell carcinomas (cSCCs) and in experimentally-induced murine cSCCs. In mouse models, the Ras signaling might lead to hyperproliferative phenotypes, including the development of cSCCs, depending on the nature of the founding cells. Tumor-initiating cells or Cancer Stem Cells (CSCs) have been demonstrated in murine and human cSCCs even if the mechanism of their development from normal SCs or TA-cells is not completely elucidated. Here, the relation between the Ras expression outcome and the clonogenic potential of the target keratinocyte is discussed.

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Emerging interactions between skin stem cells and their niches

Cited by 472 publications

References 137 publications

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

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

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

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