Epigenetic regulation and signalling pathways in Merkel cell development

Oss-Ronen, Liat; Cohen, Idan

doi:10.1111/exd.14415

Cited by 8 publications

(6 citation statements)

References 228 publications

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“…Molecular control of MC development has primarily been studied in rodent hairy skin (reviewed by Oss-Ronen and Cohen, 2021 ). While this system has been useful for understanding many aspects of MC development and function, the rodent system also has several significant limitations that warrant additional models to improve the understanding of MCs.…”

Section: Introductionmentioning

confidence: 99%

Dermal appendage-dependent patterning of zebrafish atoh1a+ Merkel cells

Brown

Horton

Craig

et al. 2023

eLife

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Touch system function requires precise interactions between specialized skin cells and somatosensory axons, as exemplified by the vertebrate mechanosensory Merkel cell-neurite complex. Development and patterning of Merkel cells and associated neurites during skin organogenesis remains poorly understood, partly due to the in utero development of mammalian embryos. Here, we discover Merkel cells in the zebrafish epidermis and identify Atonal homolog 1a (Atoh1a) as a marker of zebrafish Merkel cells. We show that zebrafish Merkel cells derive from basal keratinocytes, express neurosecretory and mechanosensory machinery, extend actin-rich microvilli, and complex with somatosensory axons, all hallmarks of mammalian Merkel cells. Merkel cells populate all major adult skin compartments, with region-specific densities and distribution patterns. In vivo photoconversion reveals that Merkel cells undergo steady loss and replenishment during skin homeostasis. Merkel cells develop concomitant with dermal appendages along the trunk and loss of Ectodysplasin signaling, which prevents dermal appendage formation, reduces Merkel cell density by affecting cell differentiation. By contrast, altering dermal appendage morphology changes the distribution, but not density, of Merkel cells. Overall, our studies provide insights into touch system maturation during skin organogenesis and establish zebrafish as an experimentally accessible in vivo model for the study of Merkel cell biology.

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Section: Introductionmentioning

confidence: 99%

Dermal appendage-dependent patterning of zebrafish atoh1a+ Merkel cells

Brown

Horton

Craig

et al. 2023

eLife

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“…They are primarily localized in the basal cell layer of the epidermis, where they are in close contact with Aβ sensory neurons forming special Merkel cell-neurite complexes. Indeed, Merkel cells can be found in touch-sensitive areas of the skin, including lips, fingertips, as well as in touch domes of hairy skin ( Oss-Ronen and Cohen, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Human fetal skin derived merkel cells display distinctive characteristics in vitro and in bio-engineered skin substitutes in vivo

Michalak‐Micka

Rütsche

Mazzone

et al. 2022

Front. Bioeng. Biotechnol.

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Human skin contains specialized neuroendocrine Merkel cells responsible for fine touch sensation. In the present study, we performed in-depth analysis of Merkel cells in human fetal back skin. We revealed that these Merkel cells expressed cytokeratin 20 (CK20), were positive for the neuroendocrine markers synaptophysin and chromogranin A, and the mechanosensitive ion channel Piezo2. Further, we demonstrated that Merkel cells were present in freshly isolated human fetal epidermal cells in vitro, and in tissue-engineered human dermo-epidermal skin substitutes 4 weeks after transplantation on immune-compromised rats. Merkel cells retained the expression of CK20, synaptophysin, chromogranin A, and Piezo2 after isolation and in culture, and in the skin substitutes after transplantation. Interestingly, we observed that in fetal skin and in skin substitutes, only Merkel cells were positive for CK8, while in culture, also non-Merkel cells showed positivity for CK8. In summary, human fetal Merkel cells showed phenotypical features confirming their cell identity. This findings are of pivotal importance for the future application of fetal tissue-engineered skin in clinics.

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“…Merkel cells (MCs) are found in the skin of most vertebrates, making up less than 5% of the total epidermal cells. 1 These cells of epithelial origin 2,3 form chemical synapses with sensory neurons, with which they communicate through action potentials and by releasing neuromodulators. 1,[4][5][6][7] Initially described as important for the mechanotransduction of light-touch sensory stimuli, 5,6,[8][9][10][11] and initiation of mechanical itch, 12 human MCs are now proven to also be thermosensitive, as they express functional cold-sensitive TRPM8 channels, whose activation triggers intracellular calcium mobilization in vitro.…”

Section: Backg Rou N Dmentioning

confidence: 99%

Preliminary evidence that Merkel cells exert chemosensory functions in human epidermis

Piccini,

Chéret,

Tsutsumi

et al. 2023

Experimental Dermatology

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The mechanotransduction of light‐touch sensory stimuli is considered to be the main physiological function of epidermal Merkel cells (MCs). Recently, however, MCs have been demonstrated to be also thermo‐sensitive, suggesting that their role in skin physiologically extends well beyond mechanosensation. Here, we demonstrate that in healthy human skin epidermal MCs express functional olfactory receptors, namely OR2AT4, just like neighbouring keratinocytes. Selective stimulation of OR2AT4 by topical application of the synthetic odorant, Sandalore®, significantly increased Piccolo protein expression in MCs, as assessed by quantitative immunohistomorphometry, indicating increased vesicle trafficking and recycling, and significantly reduced nerve growth factor (NGF) immunoreactivity within MCs, possibly indicating increased neurotrophin release upon OR2AT4 activation. Live‐cell imaging showed that Sandalore® rapidly induces a loss of FFN206‐dependent fluorescence in MCs, suggesting OR2AT4‐dependent MC depolarization and subsequent vesicle secretion. Yet, in contrast to keratinocytes, OR2AT4 stimulation by Sandalore® altered neither the number nor the proliferation status of MCs. These preliminary ex vivo findings demonstrate that epidermal MCs also exert OR‐dependent chemosensory functions in human skin, and invite one to explore whether these newly identified properties are dysregulated in selected skin disorders, for example, in pruritic dermatoses, and if these novel MC functions can be therapeutically targeted to maintain/promote skin health.

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Epigenetic regulation and signalling pathways in Merkel cell development

Cited by 8 publications

References 228 publications

Dermal appendage-dependent patterning of zebrafish atoh1a+ Merkel cells

Dermal appendage-dependent patterning of zebrafish atoh1a+ Merkel cells

Human fetal skin derived merkel cells display distinctive characteristics in vitro and in bio-engineered skin substitutes in vivo

Preliminary evidence that Merkel cells exert chemosensory functions in human epidermis

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