‘Hints’ in the horn: diagnostic clues in the stratum corneum

Cardoso, José Carlos; Veraitch, Ophelia; Gianotti, Raffaele; Ferrara, Gerardo; Tomasini, Carlo Francesco; Singh, Mohan B.; Zalaudek, Iris; Stefanato, Catherine M.

doi:10.1111/cup.12839

Cited by 20 publications

(23 citation statements)

References 95 publications

(205 reference statements)

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“…Parakeratosis results from abnormal keratinocyte maturation and is defined by the persistence of nucleated cells in the stratum corneum. It is one of the most common stratum corneum abnormalities found in many pathological processes including seborrheic dermatitis, pityriasis rosea and psoriasis . In this study, we saw evidence of parakeratosis in a number of dandruff lesional samples.…”

Section: Discussionsupporting

confidence: 59%

Changes in epidermal morphology associated with dandruff

Pople

Bhogal

Moore

et al. 2019

Intern J of Cosmetic Sci

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Objective Dandruff is a very common scalp condition characterized by flaking and pruritus usually with no visible signs of inflammation, such as redness and erythema. Dandruff is considered a multifactorial condition with both microbial colonization and host factors such as sebum production thought to play a role. There is evidence of changes in epidermal morphology in the scalp skin of dandruff sufferers, with reports of an increase in mean thickness and more nucleated cell layers. The underlying mechanisms driving these morphological changes are currently unclear. The objective of this study was to fully characterize epidermal morphology in dandruff compared to healthy scalp skin and to evaluate potential mechanisms underlying any changes observed. Methods Scalp skin biopsies were taken from 22 healthy female subjects and 21 dandruff sufferers, from both lesional and non‐lesional sites. Samples were processed, sectioned and stained using haematoxylin and eosin (H&E). To fully characterize epidermal morphology, measurements were taken of epidermal thickness, the convolution of the dermal‐epidermal junction and the depth of epidermal rete ridges. To analyse changes in epidermal proliferation immunohistochemical staining was performed using Ki67, a well‐established marker of cell proliferation, and quantified using image analysis. Results Histochemical analysis of skin sections revealed that in dandruff lesional samples, the epidermis was thicker, had a more convoluted dermal epidermal junction and the rete ridges were elongated, compared to healthy scalp skin. Similar directional changes in epidermal morphology, were observed in non‐lesional dandruff samples, albeit to a lesser extent. Image analysis of Ki67 expression in the epidermis revealed dandruff lesional skin contained significantly more Ki67‐positive proliferating keratinocytes than healthy controls samples. This suggests dandruff scalp skin epidermal keratinocytes are in a hyper‐proliferative state. Conclusion There were significant changes in epidermal morphology in dandruff lesional skin compared to healthy scalp skin including increased epidermal thickness, a more convoluted dermal‐epidermal junction and elongation of rete ridges. Interestingly, we found there was evidence of an increase in the percentage of epidermal Ki67‐positive cells, which has not been reported previously, and demonstrates dandruff is a condition displaying epidermal hyper‐proliferation.

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Section: Discussionsupporting

confidence: 59%

Changes in epidermal morphology associated with dandruff

Pople

Bhogal

Moore

et al. 2019

Intern J of Cosmetic Sci

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“…The disruption of nuclear degradation leading to retention of nuclei in the cornified layer, known as parakeratosis, is a frequent observation in many skin diseases (Song and Shea 2010;Cardoso et al 2017); however, the mechanisms by which keratinocytes remove their nuclei are not well defined (Rogerson, Bergamaschi, and O'Shaughnessy 2018;Eckhart et al 2013). Nuclear removal is dependent on the Akt1 kinase.…”

Section: Introductionmentioning

confidence: 99%

Akt1-associated actomyosin remodelling is required for nuclear lamina dispersal and nuclear shrinkage in epidermal terminal differentiation

Rogerson

Wotherspoon

O'Shaughnessy

2019

Preprint

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Keratinocyte cornification and epidermal barrier formation are tightly controlled processes, which require complete degradation of intracellular organelles, including removal of keratinocyte nuclei. Keratinocyte nuclear destruction requires Akt1-dependent phosphorylation and degradation of the nuclear lamina protein, Lamin A/C, essential for nuclear integrity. However, the molecular mechanisms that result in complete nuclear removal and their regulation are not well defined. Post-confluent cultures of rat epidermal keratinocytes (REKs) undergo spontaneous and complete differentiation, allowing visualisation and perturbation of the differentiation process in vitro. We demonstrate that there is dispersal of phosphorylated Lamin A/C to structures throughout the cytoplasm in differentiating keratinocytes. We show that the dispersal of phosphorylated Lamin A/C is Akt1-dependent and these structures are specific for the removal of Lamin A/C from the nuclear lamina; nuclear contents and Lamin B were not present in these structures.Immunoprecipitation identified a group of functionally related Akt1 target proteins involved in Lamin A/C dispersal, including actin, which forms cytoskeletal microfilaments, Arp3, required for actin filament nucleation, and Myh9, a component of myosin IIa, a molecular motor that can translocate along actin filaments. Disruption of actin filament polymerisation, nucleation or myosin IIa activity prevented formation and dispersal of cytoplasmic Lamin A/C structures. Live imaging of keratinocytes expressing fluorescently tagged nuclear proteins showed a nuclear volume reduction step taking less than 40 minutes precedes final nuclear destruction. Preventing Akt1-dependent Lamin A/C phosphorylation and disrupting cytoskeletal Akt1associated proteins prevented nuclear volume reduction. Single cell RNA sequencing of differentiating keratinocytes identified gene changes correlated with lamin dispersal, which we propose are due to changes in lamina-associated domains upon Lamin A/C dispersal. We propose keratinocyte nuclear destruction and differentiation requires myosin II activity and the actin cytoskeleton for two intermediate processes: Lamin A/C dispersal and rapid nuclear volume reduction.

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“…The nucleus is degraded during normal cornification resulting in corneocytes that are homogeneously filled with keratin (orthokeratosis). However, in lesions of psoriasis, atopic dermatitis, and other skin diseases the nucleus is retained in corneocytes (parakeratosis) 3, 4 . In mice and human in vitro skin models, various treatments and gene modifications disturb terminal differentiation of keratinocytes and manifest in parakeratosis, but mechanistic insights into the development of parakeratosis have remained scarce 5–9 .…”

Section: Introductionmentioning

confidence: 99%

Inactivation of DNase1L2 and DNase2 in keratinocytes suppresses DNA degradation during epidermal cornification and results in constitutive parakeratosis

Fischer

Buchberger

Napirei

et al. 2017

Sci Rep

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The stratum corneum of the epidermis constitutes the mammalian skin barrier to the environment. It is formed by cornification of keratinocytes, a process which involves the removal of nuclear DNA. Here, we investigated the mechanism of cornification-associated DNA degradation by generating mouse models deficient of candidate DNA-degrading enzymes and characterizing their epidermal phenotypes. In contrast to Dnase1l2 −/− mice and keratinocyte-specific DNase2 knockout mice (Dnase2 Δep), Dnase1l2 −/− Dnase2 Δep mice aberrantly retained nuclear DNA in the stratum corneum, a phenomenon commonly referred to as parakeratosis. The DNA within DNase1L2/DNase2-deficient corneocytes was partially degraded in a DNase1-independent manner. Isolation of corneocytes, i.e. the cornified cell components of the stratum corneum, and labelling of DNA demonstrated that corneocytes of Dnase1l2 −/− Dnase2 Δep mice contained DNA in a nucleus-shaped compartment that also contained nucleosomal histones but lacked the nuclear intermediate filament protein lamin A/C. Parakeratosis was not associated with altered corneocyte resistance to mechanical stress, changes in transepidermal water loss, or inflammatory infiltrates in Dnase1l2 −/− Dnase2 Δep mice. The results of this study suggest that cornification of epidermal keratinocytes depends on the cooperation of DNase1L2 and DNase2 and indicate that parakeratosis per se does not suffice to cause skin pathologies.

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‘Hints’ in the horn: diagnostic clues in the stratum corneum

Cited by 20 publications

References 95 publications

Changes in epidermal morphology associated with dandruff

Changes in epidermal morphology associated with dandruff

Akt1-associated actomyosin remodelling is required for nuclear lamina dispersal and nuclear shrinkage in epidermal terminal differentiation

Inactivation of DNase1L2 and DNase2 in keratinocytes suppresses DNA degradation during epidermal cornification and results in constitutive parakeratosis

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