Search

Background: Numerous studies have investigated the eyelid margin using confocal laser scanning microscopy (CLSM) and have presented morphological alterations of the examined structures, which were presumed to be Meibomian acini. However, recent data confirm that these structures are the cross-sections of dermal papillae of the dermoepidermal junction. This study aims to present the morphological appearance of Meibomian acini examined by confocal laser scanning microscopy in comparison to dermal papillae, and to reveal the corresponding patterns with specific histological sections., Methods and Material: Twenty healthy patients were examined with a CLSM device in vivo at the marginal edge of the eyelid. Twenty-two samples of full-thickness eyelid wedges from 22 patients treated surgically with ectropion were collected, of which 11 freshly excised samples were imaged on the incision surface with CLSM ex vivo and 11 eyelids underwent conventional histological preparation. The represented structures on CLSM images were compared to Meibomian acini on histological sections in terms of area, longest and shortest diameter, as well as depth and density., Results: On in vivo CLSM images, Meibomian orifices, epidermal cells, and dermal connective tissue could be identified, the latter in a cross-sectional view of the dermal papillae surrounded by basal cells of the epidermis, forming reflective ring-like structures. All morphological parameters of these structures differed from Meibomian acini measured on histological sections. In contrast, the CLSM images of the incision surface showed acinar units with the same morphology as the Meibomian acini seen in the histological images and no statistically significant difference was found between the corresponding parameters., Conclusion: The morphological appearance of Meibomian acini differs from the structures that were previously presumed as Meibomian glands on CLSM images. In vivo imaging of Meibomian glands by commonly used in vivo CLSM cannot be performed., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The skin serves as a complex barrier organ populated by tissue-resident macrophages (TRMs), which play critical roles in defense, homeostasis, and tissue repair. This review examines the functions of dermis resident TRMs in different inflammatory settings, their embryonic origins, and their long-term self-renewal capabilities. We highlight the M2-like phenotype of dermal TRMs and their specialized functions in perivascular and perineuronal niches. Their interactions with type 2 immune cells, autocrine cytokines such as IL-10, and their phagocytic clearance of apoptotic cells have been explored as mechanisms for M2-like dermal TRM self-maintenance and function. In conclusion, we address the need to bridge murine models with human studies, with the possibility of targeting TRMs to promote skin immunity or restrain cutaneous pathology., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Human skin displays extensive spatial heterogeneity and maintains distinct positional identity. However, the impact of disease processes on these site-specific differences remains poorly understood, especially in keloid, a skin disorder characterized by pronounced spatial heterogeneity., Objective: This study aimed to assess whether the spatial heterogeneity and positional identity observed in different anatomic sites persist in keloids., Methods: Transcriptome sequencing was conducted on 139 keloid dermal tissues and 19 keloid fibroblast samples spanning seven distinct anatomic sites to identify the spatial transcriptomic heterogeneity. In addition, single-cell RNA sequencing data were utilized to elucidate the contributions of various cell types to the maintenance of positional identity., Results: Keloid dermal tissues from diverse sites were categorized into three anatomic groupings: trunk and extremity, ear, and mandible regions. Enrichment analysis of differentially expressed genes unveiled that keloids across distinct regions retained unique anatomically-related gene expression profiles, reminiscent of those observed in normal skin. Notably, regional disparities consistently prevailed and surpassed inter-donor variations. Single-cell RNA sequencing further revealed that mesenchymal cells, particularly fibroblasts, made major contributions to positional identity in keloids. Moreover, gene expression profiles in primary keloid fibroblasts demonstrated a remarkable persistence of positional identity, enduring even after prolonged in vitro propagation., Conclusion: Taken together, these findings imply that keloids remain positional identity and developmental imprinting characteristic of normal skin. Fibroblasts predominantly contribute to the spatial heterogeneity observed in keloids., Competing Interests: Declaration of Competing Interest The authors state no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The aim of this study was to evaluate transcriptional changes in the sole epidermis and dermis of bovine claws with septic sole ulceration of the lateral claw. Assessment included changes in transcripts orchestrating epidermal homeostatic processes, including epidermal proliferation, differentiation, inflammation, and cell signaling. Sole epidermis and dermis samples were removed from region 4 of lesion-bearing lateral and lesion-free medial claws of pelvic limbs in multiparous, lactating Holstein cows. Control sole epidermis and dermis samples were obtained from region 4 of lateral claws of normal pelvic limbs. Transcript abundances were evaluated by real-time PCR, and relative expression analyzed by ANOVA. Relative to normal lateral claws, sole epidermis and dermis in ulcer-bearing claws exhibited downregulation of genes associated with growth factors, growth factor receptors, activator protein 1 (AP-1) and proto-oncogene (CMYC) transcription components, cell cycle elements, lateral cell-to-cell signaling elements, and structures of early and late keratinocyte differentiation. These changes were accompanied by upregulation of proinflammatory transcripts interleukin 1 α (IL1A), interleukin1 β (IL1B), interleukin 1 receptor 1 (IL1R1), inducible nitric oxide synthase (NOS2), the inflammasome components NOD-like receptor protein 3 (NLRP3), pyrin and caspase recruitment domain (PYCARD), caspase-1 interleukin converting enzyme (CASPASE), the matrix metalloproteinases (MMP2 and MMP9), and the anti-inflammatory genes interleukin 1 receptor antagonist (IL1RN) and interleukin1 receptor 2 (IL1R2). Transcript abundance varied across epidermis and dermis from the ulcer center, margin, and epidermis and dermis adjacent to the lesion. Sole epidermis and dermis of lesion-free medial claws exhibited changes paralleling those in the adjacent lateral claws in an environment lacking inflammatory transcripts and downregulated IL1A, interleukin 18 (IL18), tumor necrosis factor α (TNFA), and NOS2. These data imply perturbations in signal pathways driving epidermal proliferation and differentiation are associated with, but not inevitably linked to epidermis and dermis inflammation. Further work is warranted to better define the role of crushing tissue injury, sepsis, metalloproteinase activity, and inflammation in sole ulceration., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Pododermatitis aseptica hemorrhagica circumscripta is associated with metalloproteinase 2 weakening of distal phalangeal suspensory structures and sinkage of the distal phalanx in the claw capsule. Pressure from the tuberculum flexorium on the sole epidermis and dermis produces hemorrhagic tissue injury and defective horn production appearing as yellow-red, softened claw horn in region 4 of the sole. A model of the MAPK/ERK signal cascade orchestrating epidermal-dermal homeostasis was employed to determine if sterile inflammatory responses are linked to disturbed signal transduction for epidermal homeostasis in sole epidermis and dermis. The objective was to assess shifts in target genes of inflammation, up- and downstream MAPK/ERK signal elements, and targeted genes supporting epidermal proliferation and differentiation. Sole epidermis and dermis were removed from lateral claws bearing lesions of PAHC, medial claws from the same limb and lateral claws from completely normal limbs of multiparous, lactating Holstein cows. The abundance levels of targeted transcripts were evaluated by real-time PCR. Lesion effects were assessed by ANOVA, and mean comparisons were performed with t-tests to assess variations between mean expression in ulcer-bearing or medial claw dermis and epidermis and completely normal lateral claw dermis and epidermis or between ulcer-bearing dermis and epidermis and medial claw dermis and epidermis. The lesions were sterile and showed losses across multiple growth factors, their receptors, several downstream AP1 transcription components, CMYC, multiple cell-cycle and terminal differentiation elements conducted by MAPK/ERK signals and β 4, α 6, and collagen 17A hemidesmosome components. These losses coincided with increased cytokeratin 6, β 1 integrin, proinflammatory metalloproteinases 2 and 9, IL1B and physiologic inhibitors of IL1B, the decoy receptor, and receptor antagonist. Medial claw epidermis and dermis from limbs with lateral claws bearing PAHC showed reductions in upstream MAPK/ERK signal elements and downstream targets that paralleled those in hemorrhagic lesions. Inhibitors of IL1B increased in the absence of real increases in inflammatory targets in the medial claw dermis and epidermis. Losses across multiple signal path elements and downstream targets were associated with negative effects on targeted transcripts supporting claw horn production and wound repair across lesion-bearing lateral claws and lesion-free medial claw dermis and epidermis. It was unclear if the sterile inflammation was causative or a consequence of these perturbations., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

There is a need in clinical practice for new wound healing techniques to address full thickness skin injuries, particularly in individuals with diabetes. Herein we investigated whether dermal derived matrix hydrogel (DMH) loaded with curcumin (Cur) could promote healing in diabetic rats. Sixty diabetic rats were randomly assigned into the non-treated group, DMH group, Cur group, and DMH+Cur group. According to the phases of wound healing, sampling was done on days 7, 14, and 21 for further assessments. Our results indicated that the wound contraction rate, new epidermal length and thickness, number of fibroblasts and vascular length, collagen deposition, and strength properties of the healed wounds were meaningfully increased in the treatment groups than in the non-treated group, and these changes were more obvious in the DMH+Cur ones. In addition, the expression of VEGF and IL-10 genes were meaningfully upregulated in all treatment groups compared to the non-treated group and were greater in the DMH+Cur group. This is while the number of neutrophils and expression levels of TNF-α and IL-1β genes decreased more significantly in the DMH+Cur group compared to the other groups. In conclusion, it was found that using both DMH and curcumin has a greater impact on diabetic wound healing., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest associated with this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Rationale: Ultraviolet-B (UVB) light induces dermal inflammation, although it is mostly absorbed in the epidermis. Recent reports suggest extracellular vesicles (EVs) act as a mediator of photodamage signaling. Melatonin is reported to be a protective factor against UV-induced damage. We hypothesized that EVs derived from UVB-irradiated keratinocytes might trigger proinflammatory responses in dermal cells and tested whether melatonin can ameliorate UVB-induced inflammation., Methods: We used UVB-irradiated HaCaT cells, primary keratinocytes and STING knock-out mice to model production of EVs under photodamaging conditions and performed immunoblotting and ELISA to measure their effect on dermal macrophages., Results: UVB-irradiated keratinocytes produce an increased number of EVs that contain higher concentrations of DNA and protein compared with controls. KC-derived EVs (KEVs) induced a STING- and inflammasome-mediated proinflammatory response in macrophages in vitro, and a pronounced inflammatory infiltrate in mouse dermis in vivo. Melatonin ameliorated KEVs inflammatory effect both in vitro and in vivo., Conclusions: This data suggests EVs are mediators in a crosstalk that takes place between keratinocytes and their neighboring cells as a result of photodamage. Further studies exploring EVs induced by damaging doses of UVB, and their impact on other cells will provide insight into photodamage and may help develop targeted therapeutic approaches., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Dermal white adipose tissue (DWAT) is a distinctive adipose depot located within the lower dermis of the skin. Its significance as an ancillary fat in skin homoeostasis has recently received increased attention. New research has revealed that DWAT responses to skin pathology and physiology changes, impacting skin development, hair cycling, defense mechanisms, and fibrotic conditions. In this review, we explore the developmental process of DWAT and the adipose commitment timing of hypodermal. We explore the development process of DWAT and its pivotal role in regulating the hair cycle. We conclude the antibacterial activity and reversible dedifferentiation of dermal adipocytes in response to skin defense. Furthermore, we underscore the potentially crucial yet underestimated anti-fibrotic functions of DWAT-derived adipokines and adipocyte-myofibroblast transition., (© 2024 Federation of American Societies for Experimental Biology.)

The pemphigoid disease epidermolysis bullosa acquisita (EBA) is an autoimmune blistering skin disease characterized by autoantibodies against type VII collagen (COL7), immune cell infiltrates at the dermal-epidermal junction and subepidermal blistering. Proteases, particularly granzyme B (GzmB), have been established as therapeutic targets for the treatment of EBA and other pemphigoid diseases. We investigated the impact of the novel GzmB inhibitor SNT-6935 on anti-COL7 IgG-induced subepidermal blistering in a well-established EBA ex vivo model. Our findings demonstrate that pharmacological targeting of GzmB with its selective inhibitor SNT-6935 significantly reduced autoantibody-induced dermal-epidermal separation in human skin cryosections. Interestingly, treatment of skin cryosections with recombinant human GzmB alone did not cause dermal-epidermal separation, suggesting that additional mechanisms alongside GzmB are required for tissue damage in EBA. In conclusion, our study highlights the significant contribution of GzmB to the pathogenesis of EBA and supports the notion of GzmB as a therapeutic target in EBA and other pemphigoid diseases., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Wound healing is a complex, dynamic process involving the coordinated interaction of diverse cell types, growth factors, cytokines, and extracellular matrix components. Despite emerging evidence highlighting their importance, dermal sheath cells remain a largely overlooked aspect of wound healing research. This review explores the multifunctional roles of dermal sheath cells in various phases of wound healing, including modulating inflammation, aiding in proliferation, and contributing to extracellular matrix remodelling. Special attention is devoted to the paracrine effects of dermal sheath cells and their role in fibrosis, highlighting their potential in improving healing outcomes, especially in differentiating between hairy and non-hairy skin sites. By drawing connections between dermal sheath cells activity and wound healing outcomes, this work proposes new insights into the mechanisms of tissue regeneration and repair, marking a step forward in our understanding of wound healing processes., (© 2024 The Wound Healing Society.)

Scars and stretch marks are extremely common. For scars, evidence of alterations of the dermal and hypodermic layers is known, while for stretch marks, less data are available, and they are considered purely aesthetic conditions. The intra- and inter-subject variability of the skin makes the comparison between these two particularly complex. This study presents the case of a 54-year-old man who had both stretch marks and a surgical scar on his abdomen. We performed ultrasound and elastosonographic investigations for both to analyse the structural alteration of the skin and subcutaneous layers. Their structures were also compared to the structure of intact skin. The two skin conditions appeared substantially morphologically different and different from intact skin. The alterations detected, particularly of the connective structures, allow us to state that both scars and stretch marks are alterations of both the dermis and the hypodermis and stretch marks differ from scars., (© 2024. The Author(s).)

Marfan syndrome (MFS) is a hereditary condition accompanied by disorders in the structural and regulatory properties of connective tissue, including elastic fibers, due to a mutation in the gene encodes for fibrillin-1 protein (FBN1 gene) and the synthesis of abnormal fibrillin-1 glycoprotein. Despite the high potential of mast cells (MCs) to remodel the extracellular matrix (ECM), their pathogenetic significance in MFS has not been considered yet. The group of patients with Marfan syndrome included two mothers and five children (three girls aged 4, 11, and 11 and two boys aged 12 and 13). Normal skin was examined in two children aged 11 and 12. Histochemical, monoplex, and multiplex immunohistochemical techniques; combined protocols of simultaneous histochemical and immunohistochemical staining (the results of staining were assessed using light, epifluorescence, and confocal microscopy); and bioinformatics algorithms for the quantitative analysis of detected targets were used to evaluate mast cells and their relationship with other cells from extracellular structures in the skin dermis. Analysis of the skin MC population in children with Marfan syndrome revealed a considerably increased number of intra-organic populations with the preservation of the specific Tryptase + Chymase + CPA3 + protease profile typical of the skin. The features of the MC histotopography phenotype in MFS consisted of closer colocalization with elastic fibers, smooth muscle cells, and fibroblasts. MCs formed many intradermal clusters that synchronized the activity of cell functions in the stromal landscape of the tissue microenvironment with the help of spatial architectonics, including the formation of cell chains and the creation of fibrous niches. In MCs, the expression of specific proteases, TGF-β, and heparin increased, with targeted secretion of biologically active substances relative to the dermal elastic fibers, which had specific structural features in MFS, including abnormal variability in thickness along their entire length, alternating thickened and thinned areas, and uneven surface topography. This paper discusses the potential role of MCs in strain analysis (tensometry) of the tissue microenvironment in MFS. Thus, the quantitative and qualitative rearrangements of the skin MC population in MFS are aimed at altering the stromal landscape of the connective tissue. The results obtained should be taken into account when managing clinical signs of MFS manifested in other pathogenetically critical structures of internal organs, including the aorta, tendons, cartilage, and parenchymal organs.

Bullous pemphigoid (BP) is an autoantibody-mediated blistering skin disease characterized by local inflammation and dermal-epidermal separation, with no approved targeted therapy. The Syk tyrosine kinase is critical for various functions of the immune response. Second-generation Syk inhibitors such as entospletinib are currently being tested for hematological malignancies. Our aim was to test the effect of entospletinib in a fully human model system of BP. Incubating BP serum-treated human frozen skin sections with normal human granulocytes and fresh plasma triggered dermal-epidermal separation that was dependent on complement, NADPH oxidase, and protease activity. Entospletinib dramatically reduced dermal-epidermal separation with a half-maximal inhibitory concentration of ≈16 nM. Entospletinib also reduced ROS production, granule release, and spreading of human granulocytes plated on immobilized immune complexes consisting either of a generic antigen-antibody pair or of recombinant collagen type XVII (BPAg2) and BP serum components (supposedly autoantibodies). However, entospletinib did not affect the chemotactic migration of human granulocytes or their responses to nonphysiological stimulation by phorbol esters. Entospletinib had no effect on the survival of granulocytes either. Taken together, entospletinib abrogates dermal-epidermal separation, likely through inhibition of granulocyte responsiveness to deposited immune complexes. Entospletinib or other Syk inhibitors may provide therapeutic benefits in BP., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Microdermabrasion is a cosmetic procedure that has gained popularity for skin rejuvenation by causing repetitive intraepidermal injury to stimulate the proliferation of fibroblasts and collagen production. Various clinical studies have demonstrated microdermabrasion's effectiveness in skin rejuvenation; however, most of these studies rely on clinical observation and scoring by observers rather than histologic or microscopic analysis. In our single-center prospective study, we used line-field confocal optical coherence tomography (LC-OCT), to non-invasively visualize the early effects of one microdermabrasion treatment on the facial epidermal and dermal structure., Aim: Using LC-OCT, this study aims to elucidate the microscopic and histological effects of microdermabrasion on epidermal and dermal structures, including epidermal thickness, as well as collagen and vascular patterns., Patients/methods: Eight volunteers (Fitzpatrick skin types II-V) underwent one treatment of microdermabrasion. LC-OCT and VISIA imaging were performed before and 10 min after microdermabrasion, and at 48-h follow-up. Subjective evaluations of skin texture and adverse reactions were assessed 1 week posttreatment via a telephone call., Results: Compared to LC-OCT images before treatment, images captured after one treatment of microdermabrasion showed a decrease in thickness and number of undulations in the stratum corneum. In the superficial dermis, enhancement in fibrillar collagen, as demonstrated by an increased prominence of crisscrossing hyper-refractile strands, was visualized. This was consistent with subjective and objective improvement in facial rhytids calculated by VISIA skin analysis., Conclusions: Treatment monitoring with LC-OCT demonstrated consistent histopathological changes with clinical visual improvement. Therefore, LC-OCT, has the potential to enable long-term histopathological monitoring of microdermabrasion and other cosmetic procedures without biopsy., (© 2024 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Wound healing is a complex process that is still not fully understood despite extensive research. To address this, we aimed to design and characterize a standardized porcine model for the evaluation of wound healing, dressings, cell therapies, and pharmaceutical agents. Using a standardized approach, we examined the wound healing process in 1.2 mm-deep dermatome wounds at defined positions in 11 female pigs. Unlike previous studies that have only described/analyzed selected punch biopsies, we performed and described histological analyses along the complete wound length using quantitative morphometric methods. All animals remained fully healthy following surgery and showed no signs of infection. Our histopathological evaluation using a predetermined grading score and quantitative manual morphometry demonstrated the impact of different tissue sampling methods, sampling sites, and residual dermis thickness on wound healing. Our study presents a reproducible model for wound healing evaluation and demonstrates the usefulness of porcine models for assessing dermal and epidermal wound healing. The use of histological analyses over the complete wound length provides advantages over previous studies, leading to the possibility of a deeper understanding of the wound healing process. This model could potentially facilitate future research on novel wound dressings and local wound healing therapies.

Background: The negative effects of skin aging are primarily related to the destruction of dermal architectural structure. More specifically, this includes changes in the spatial arrangement of collagen, elastin fibers, mucopolysaccharides, proteoglycans, and ground substances., Aims: The purpose of this study is to investigate the histologic effects of dermal and subdermal tissue after a controlled single treatment with radiofrequency (RF) macroneedling. This therapy provides a controlled, localized, thermal effect on the dermis whereby triggering the body's own healing processes of extracellular matrix remodeling. Clinically benefits include skin tightening., Methods: Biopsies were obtained for histologic evaluation from four patients (n = 4), 4 weeks after completing a single RF macroneedling facial treatment., Results: Age-related changes of the dermal and subdermal architecture were observed at baseline. After treatment, all biopsies demonstrated an increase in epidermal cells, collagen, elastin, fibroblasts, vasculature, and a decrease in inflammatory cells., Conclusions: The results of this histologic study confirm a significant "subsurfacing" thermal effect from the noncoagulative ascendant thermal injury. The obtained results characterize RF macroneedling therapy as an effective method for correcting age-related changes in facial skin., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Collagen VII forms anchoring fibrils that are essential for the stability of the skin and other epithelial organs. In addition to such structural functions, it is emerging that collagen VII fills instructive functions. Collagen VII is synthesized by both epithelial cells and fibroblasts. Genetic loss of collagen VII causes dystrophic epidermolysis bullosa, which manifests with chronic skin fragility and fibrosis. Significant progress has been made in developing therapies for dystrophic epidermolysis bullosa; however, such work has also raised questions on the importance of the cellular source of collagen VII for maintenance of tissue integrity and homeostasis. Toward this end, we engineered mice that kept the physiological expression of collagen VII only in epithelial cells or in fibroblasts. Our study revealed that production of collagen VII either by keratinocytes or fibroblasts alone is sufficient for creation of mechanically robust skin. Importantly, we also show tissue-diverse dependence on epithelial and mesenchymal production of collagen VII and provide support for limited amounts of collagen VII being sufficient for tissue protection. Furthermore, a disconnect between collagen VII abundance and anchoring fibril numbers supports the concept that restoration of fully physiological collagen VII levels may not be needed to achieve complete mechanical protection of dystrophic epidermolysis bullosa skin., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Pseudoxanthoma elasticum (PXE) is a rare disease characterized by ectopic calcification, however, despite the widely spread effect of pro/anti-calcifying systemic factors associated with this genetic metabolic condition, it is not known why elastic fibers in the same patient are mainly fragmented or highly mineralized in clinically unaffected (CUS) and affected (CAS) skin, respectively. Cellular morphology and secretome are investigated in vitro in CUS and CAS fibroblasts. Here we show that, compared to CUS, CAS fibroblasts exhibit: a) differently distributed and organized focal adhesions and stress fibers; b) modified cell-matrix interactions (i.e., collagen gel retraction); c) imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases; d) differentially expressed pro- and anti-calcifying proteoglycans and elastic-fibers associated glycoproteins. These data emphasize that in the development of pathologic mineral deposition fibroblasts play an active role altering the stability of elastic fibers and of the extracellular matrix milieu creating a local microenvironment guiding the level of matrix remodeling at an extent that may lead to degradation (in CUS) or to degradation and calcification (in CAS) of the elastic component. In conclusion, this study contributes to a better understanding of the mechanisms of the mineral deposition that can be also associated with several inherited or age-related diseases (e.g., diabetes, atherosclerosis, chronic kidney diseases)., (© 2024. The Author(s).)

While histological diagnosis of Paget disease of vulva is mostly straightforward, identifying and confirming invasion can be challenging. Often invasion is accompanied by epidermal hyperplasia, marked inflammatory response and desmoplastic reaction. Diagnosis of invasion in Paget disease portends a poor outcome. We report findings from a recurrent primary vulvar Paget disease where overall histomorphology of possible invasive disease is unusual and raises a possibility of displacement of Paget cells in the dermis. We compare histology of the index case with known invasive vulvar Paget disease cases retrieved from our pathology archives. Unique histomorphology in the index case suggests a possibility of previous excision related dermal displacement of Paget cells., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Keloid are a fibroproliferative disorder caused by abnormal healing of skin, specifically reticular dermis, when subjected to pathological or inflammatory scars demonstrating redness, elevation above the skin surface, extension beyond the original wound margins and resulting in an unappealing cosmetic appearance. The severity of keloids and risk of developing keloids scars are subjected to elevation by other contributing factors such as systemic diseases, general health conditions, genetic disorders, lifestyle and natural environment. In particular, recently, daily physical work interpreted into mechanical force as well as the interplay between mechanical factors such as stress, strain and stiffness have been reported to strongly modulate the cellular behaviour of keloid formation, affect their location and shape in keloids. Herein, we review the extensive literature on the effects of these factors on keloids and the contributing predisposing mechanisms. Early understanding of these participating factors and their effects in developing keloids may raise the patient awareness in preventing keloids incidence and controlling its severity. Moreover, further studies into their association with keloids as well as considering strategies to control such factors may help clinicians to prevent keloids and widen the therapeutic options., (© 2024 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Scleromyxedema or generalized diffuse lichen myxoedematosus is a rare mucinosis that is associated with monoclonal gammopathy and which frequently affects multiple extracutaneous organ systems. The pathogenesis of scleromyxedema has not been fully elucidated, but includes stimulation of glycosaminoglycan synthesis. The clinical course of scleromyxedema is chronic and often progressive, leading to severe morbidity and even death. The characteristic skin findings encompass multiple waxy papules often on indurated plaques, while thickening of skin leads to conspicuous folds on glabella and dorsal aspects of finger joints. Microscopical manifestations are dermal deposits of glycosaminoglycans between collagen bundles in reticular dermis, increased numbers of fibroblasts and fibrosis as well as loss of elastic fibers. Progressive skin involvement results in decreased mobility of the mouth and joints and even contractures. Extracutaneous manifestations occur in the musculoskeletal or cardiovascular system, in the gastrointestinal or respiratory tract, in the kidneys or in the central and peripheral nervous system. There are no in-label or evidence-based treatments available for scleromyxedema, but by expert consensus high-dose immunoglobulins are considered as treatment of choice, followed in case of insufficient efficacy by systemic glucocorticosteroids and then lenalidomide or thalidomide. In severe and refractory cases, autologous hematopoietic stem cell transplantation has been performed. Long-term maintenance treatment is usually required to prevent recurrences. Close interdisciplinary follow-up is recommended., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Lichen planus is a chronic inflammatory disorder. Transcriptional coactivator with PDZ-binding motif (TAZ/WWTR1) is an important downstream effector of the Hippo pathway which regulates organ size and tissue homeostasis. But little is known about the role of TAZ in lichen planus so far., Objective: To explore the expression of TAZ in lichen planus and normal skin, and to discover the relationship between TAZ expression and the clinical characteristics of lichen planus patients., Methods: The method of immunohistochemistry was performed to quantify the expression of TAZ in 262 patients with lichen planus and 90 control tissues. Western blot and quantitative real-time reverse transcriptase-PCR (qRT-PCR) analysis were performed to examine and compare TAZ expression in 4 cases of fresh lichen planus lesions and normal skin tissues., Results: TAZ was weakly expressed in the basal layers of the epidermis in normal skin tissues with a positive rate of 52.22% (47/90). But in lichen planus, TAZ was strongly expressed in almost the entire epidermis with a positive rate of 81.30% (213/262), and the difference between the two groups was statistically significant (p<0.05). Additionally, TAZ expression was significantly related to the location of the lichen planus, clinical phenotype, smoking, and alcohol preference (p<0.05). Western blot and qRT-PCR showed that the expression of TAZ in protein and mRNA levels in four cases of lichen planus lesions was significantly higher than that in normal skin tissues., Conclusion: TAZ may play a regulatory role in the occurrence and development of lichen planus, which might provide a new perspective for studying pathogenesis and theoretical treatment targets., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Exosomes are small membrane-derived vesicles that transmit DNA constituents, mRNAs, microRNAs, and proteins from donor cells to a receiver cell. Various cells comprising of mesenchymal, immune, and cancer cells discharge exosomes. Cancer cell exosomes form the entry and reprogramming of essentials connected to a tumor environment. Melanoma-derived exosomes transport diverse proteins such as c-MET and RAB27a, which leave a melanoma mark. Increased mesenchymal epithelial transition (MET) expressions in serum exosomes have been considered an indicator of disease progression. Meanwhile, RAB27a has been identified as being involved in exosome discharge and trafficking. Decreased expressions of RAB27a in human melanoma cells have shown to diminish exosome release.We examined the effects of the downregulation and upregulation of RAB27a and c-MET in human dermal fibroblasts by utilizing the isolated exosomes of malignant melanoma cell lines. Melanoma exosomes derived from cancer cells conveyed information to healthy dermal fibroblasts and stem cells while inducing phenotypic change. In this chapter, we show optimized protocols that were used by our group for in vitro analysis with melanoma exosomes., (© 2024. Springer Science+Business Media, LLC.)

We present a 57-year-old woman with cutaneous lupus erythematosus (CLE), initially treated as acne. She noted blemishes, including nodules and facial swelling for nine months associated with discrete itching of the ears. Examination showed multiple malar nodules, comedones, pustules, atrophic scars, and hyperpigmentation. A biopsy was performed and revealed atrophic epidermis, discrete hyperkeratosis, vacuolar degeneration of basal layer, basal membrane zone with upper dermal lymphohistiocytic inflammatory infiltrate and deep perivascular and peri-adenexal lymphocytes, vascular ectasia, and mucin deposits. The acneiform presentation of CLE is commonly underdiagnosed due to the similarity with inflammatory acne. Histopathologic diagnostic in acneiform lupus is of extreme importance. This case emphasizes the relevance of knowing the notable variety of presentations of CLE and considering this diagnosis.

Skin is composed of different layers, including the stratum corneum, epidermal living layer and papillary and reticular dermis. Each has specific optical properties due to differences in their biological components. Alterations in the skin's cutaneous biological components resulting from photoaging caused by chronic exposure to UV light affect the deterioration of appearance associated with the skin's optical properties. Various methods for analysing cutaneous optical properties have been previously proposed, including mathematical models and computer simulations. However, these were insufficient to elucidate changes in each skin layer and comprehensively understand the skin's integrated optical properties. We focused on UV-induced yellowing of the facial skin. We evaluated site-specific optical absorption of human skin tissue sections to investigate the yellowish discoloration, which is suggested to be related to the photodamage process. The method includes our original technique of separating the transmitted and scattered light using high-frequency illumination microscopy, leading to microscopic analysis of the tissue's optical absorption in the regions of interest. In analysing the sun-exposed facial skin tissue sections, we successfully showed that dermal regions of aged skin have increased absorption at 450 nm, where yellowish colours are complemented. Furthermore, we confirmed that elastic fibres with observable histological disorder resulting from photodamage are a prominent source of high optical absorption. We detected changes in the skin's optical absorption associated with dermal degeneration resulting from photodamage using a novel optical microscopy technique. The results provide a base for the evaluation of optical property changes for both yellowing discoloration and other tissue disorders., (© 2023 Shiseido Co., LTD/Global Innovation Center and The Authors. Experimental Dermatology published by Australasian Hair and Wool Research Society (AHWRS) and European Immunodermatology Society.)

Vitiligo is a common depigmentation disorder characterized by the selective loss of melanocytes. In our daily clinic experience, we noticed that the skin tightness of hypopigmented lesions would be more evident in comparison to that of uninvolved perilesional skin in vitiligo patients. Therefore, we hypothesized that collagen homeostasis might be maintained in vitiligo lesions, irrespective of the substantial excessive oxidative stress that occurs in association with the disease. We found that the expression levels of collagen-related genes and anti-oxidative enzymes were upregulated in vitiligo-derived fibroblasts. Abundant collagenous fibers were observed in the papillary dermis of vitiligo lesions in comparison to uninvolved perilesional skin by electron microscopy. The production of matrix metalloproteinases that degraded collagen fibers was suppressed. The deposition of acrolein adduct protein, which is a product of oxidative stress, was significantly reduced in vitiligo dermis and fibroblasts. As part of the mechanism, we found upregulation of the NRF2 signaling pathway activity, which is an important defense system against oxidative stress. Taken together, we demonstrated that the anti-oxidative action and collagen production were upregulated and that the collagen degeneration was attenuated in vitiligo dermis. These new findings may provide important clues for the maintenance of antioxidant ability in vitiligo lesions., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The prevalence of fibrotic diseases and the lack of pharmacologic modalities to effectively treat them impart particular importance to the discovery of novel antifibrotic therapies. The repurposing of drugs with existing mechanisms of action and/or clinical data is a promising approach for the treatment of fibrotic diseases. One paradigm that pervades all fibrotic diseases is the pathological myofibroblast, a collagen-secreting, contractile mesenchymal cell that is responsible for the deposition of fibrotic tissue. In this study, we use a gene expression paradigm characteristic of activated myofibroblasts in combination with the Connectivity Map to select compounds that are predicted to reverse the pathological gene expression signature associated with the myofibroblast and thus contain the potential for use as antifibrotic compounds. We tested a small list of these compounds in a first-pass screen, applying them to fibroblasts, and identified the retinoic acid receptor agonist Ch55 as a potential hit. Further investigation exhibited and elucidated the antifibrotic effects of Ch55 in vitro as well as showing antiscarring activity upon intradermal application in a preclinical rabbit ear hypertrophic scar model. We hope that similar predictions to uncover antiscarring compounds may yield further preclinical and ultimately clinical success., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives : For many years, fully ablative laser treatments, particularly those performed with a carbon dioxide (CO 2 ) laser, were regarded as the gold standard for resurfacing. This study's goal is to assess the depth that can be reached by a new CO 2 scanner system, through a skin model with greater dermal thickness, to use in the treatment of deep scarring. Materials and Methods : Male human skin tissue was laser-treated using a CO 2 fractional laser and a new scanning system, and all samples were fixed in 10% neutral buffered formalin, dehydrated using a series of crescent alcohol, embedded in paraffin, sectioned in series (4-5 µm thick), stained with haematoxylin and eosin (H&E), and then analysed under an optical microscope. Results : From the epidermis through the underlying papillary and reticular dermis to various depths of the dermis, microablation columns of damage and coagulated microcolumns of collagen were observed. The reticular dermis was fully penetrated up to 6 mm at higher energy levels (210 mJ/DOT), resulting in deeper tissue injury. Although the laser might penetrate further, the skin stops there, leaving just the fat and muscular tissue. Conclusions : The deep layers of the dermis can be penetrated by the CO 2 laser system throughout the entire dermal thickness when using the new scanning system, suggesting that this laser's potential impact, at the selected settings, covers all skin targets required to perform superficial or deep treatments on any dermatological issue. Finally, patients who have problems, such as morbid scar-deep complications, which affect their quality of life, are more likely to profit from this innovative technique.

Pathological hair loss (also known as alopecia) and shortage of hair follicle (HF) donors have posed an urgent requirement for HF regeneration. With the revelation of mechanisms in tissue engineering, the proliferation of HFs in vitro has achieved more promising trust for the treatments of alopecia and other skin impairments. Theoretically, HF organoids have great potential to develop into native HFs and attachments such as sweat glands after transplantation. However, since the rich extracellular matrix (ECM) deficiency, the induction characteristics of skin-derived cells gradually fade away along with their trichogenic capacity after continuous cell passaging in vitro. Therefore, ECM-mimicking support is an essential prelude before HF transplantation is implemented. This review summarizes the status of providing various epidermal and dermal cells with a three-dimensional (3D) scaffold to support the cell homeostasis and better mimic in vivo environments for the sake of HF regeneration. HF-relevant cells including dermal papilla cells (DPCs), hair follicle stem cells (HFSCs), and mesenchymal stem cells (MSCs) are able to be induced to form HF organoids in the vitro culture system. The niche microenvironment simulated by different forms of biomaterial scaffold can offer the cells a network of ordered growth environment to alleviate inductivity loss and promote the expression of functional proteins. The scaffolds often play the role of ECM substrates and bring about epithelial-mesenchymal interaction (EMI) through coculture to ensure the functional preservation of HF cells during in vitro passage. Functional HF organoids can be formed either before or after transplantation into the dermis layer. Here, we review and emphasize the importance of 3D culture in HF regeneration in vitro. Finally, the latest progress in treatment trials and critical analysis of the properties and benefits of different emerging biomaterials for HF regeneration along with the main challenges and prospects of HF regenerative approaches are discussed.

Background: Wrinkles appear with aging, producing an aged impression, but the mechanism of wrinkle formation has not yet been fully elucidated. We recently reported that subcutaneous fat infiltrates into the dermal layer with aging and impairs skin elasticity, but the contribution of this process to wrinkle formation is still unclear., Purpose: We aimed to clarify the contribution of dermal fat infiltration to wrinkle formation by analyzing the relationship between them in the forehead of female volunteers., Methods: We measured the severity of fat infiltration in the forehead of 29 middle-aged female volunteers by means of ultrasonography. Fixed wrinkles present when the eyes were closed and wrinkles transiently formed when the eyes were open were evaluated using a photograph-based 6-grade evaluation system for each type of wrinkle., Results: Fat infiltration at the forehead area was observed similarly to that in the cheek area as we reported previously. We found that opening the eyes induced the formation of stable transient wrinkles, the grade of which was significantly related to fat infiltration severity. Furthermore, fat infiltration was also significantly related to the severity of fixed wrinkles. Moreover, the severity of transient wrinkles was significantly related to that of fixed wrinkles., Conclusions: Our results suggest that fat infiltration into the dermal layer enhances transient wrinkle formation during facial expression by impairing the ability of the skin to resist deformation, thereby promoting fixed wrinkle formation. Therefore, fat infiltration is a critical cause of wrinkle formation., (© 2023 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

A 59-year-old man presented with a growing tumor on the glans penis, which we excised. Histologically, there was an acanthotic epidermis under which the papillary dermis was filled with foamy macrophages, best seen in a CD 68 stain. Verruciform xanthoma was diagnosed. Knowledge of this benign diagnosis may prevent an overly hasty, aggressive approach, since the differential diagnosis of penile carcinoma requires much more radical therapy, and mutilating penile surgery is associated with considerable psychosexual distress for patients., (© 2022. The Author(s).)

Physicians occasionally come across with patients with locally advanced breast cancer (LABC) bringing about distress, due to tumor growth, invasion to the skin, bleeding or an ill smell. Physicians often experience much difficulty in selecting and administering therapeutic option. The clinical courses of patient who had been treated with total resection of LABC and an attachment of artificial dermis (TERUDERMIS) were mentioned. Elimination of the symptoms derived from the tumors could be successfully accomplished for all of the patients. Except for one patients who initially had bone metastasis and died 13 months after operation, the other patients have been alive under preferable condition without any signs for tumor recurrence. The surgical resection and an attachment of artificial dermis is quite reliable and helpful for both patients and physicians in palliating symptoms and reducing care for infections and hemorrhage due to LABC.

To investigate if donor and recipient site morbidity (healing time and cosmesis) could be reduced by a novel, modified split-thickness skin grafting (STSG) technique using a dermal component in the STSG procedure (DG). The STSG technique has been used for 150 years in surgery with limited improvements. Its drawbacks are well known and relate to donor site morbidity and recipient site cosmetic shortcomings (especially mesh patterns, wound contracture, and scarring). The Dermal graft technique (DG) has emerged as an interesting alternative, which reduces donor site morbidity, increases graft yield, and has the potential to avoid the mesh procedure in the STSG procedure due to its elastic properties. A prospective, dual-centre, intra-individual controlled comparison study. Twenty-one patients received both an unmeshed dermis graft and a regular 1:1.5 meshed STSG. Aesthetic and scar assessments were done using The Patient and Observer Scar Assessment Scale (POSAS) and a Cutometer Dual MPA 580 on both donor and recipient sites. These were also examined histologically for remodelling and scar formation. Dermal graft donor sites and the STSG donor sites healed in 8 and 14 days, respectively (p < 0.005). Patient-reported POSAS showed better values for colour for all three measurements, i.e., 3, 6, and 12 months, and the observers rated both vascularity and pigmentation better on these occasions (p < 0.01). At the recipient site, (n = 21) the mesh patterns were avoided as the DG covered the donor site due to its elastic properties and rendered the meshing procedure unnecessary. Scar formation was seen at the dermal donor and recipient sites after 6 months as in the standard scar healing process. The dermis graft technique, besides potentially rendering a larger graft yield, reduced donor site morbidity, as it healed faster than the standard STSG. Due to its elastic properties, the DG procedure eliminated the meshing requirement (when compared to a 1:1.5 meshed STSG). This promising outcome presented for the DG technique needs to be further explored, especially regarding the elasticity of the dermal graft and its ability to reduce mesh patterns.Trial registration: ClinicalTrials.gov Identifier (NCT05189743) 12/01/2022., (© 2022. The Author(s).)

Objective: To explore the effect of deep dermal tissue dislocation injury on skin fibrosis in pig, in order to provide some theoretical basis for burn scar treatment. Methods: The experimental research method was applied. Six 2-month-old female Duroc pigs were taken. Fifteen operative areas on the right dorsum of pigs on which medium-thick skin grafts and deep dermal tissue slices were cut and re-implanted were included into dermal in situ reimplantation group, and fifteen operative areas on the left dorsum of pigs on which medium-thick skin grafts and deep dermal tissue slices were cut and the deep dermal tissue slice was placed under the fat layer were included into the dermal dislocation group. The hair growth in the operative areas on post-injury day (PID) 7, 14, and 21 and the cross-sectional structure on PID 14 were observed in the two groups. On PID 7, 14, and 21, the skin thickness (the distance from the epidermis to the upper edge of the fat), the dermal thickness (the distance from the lower edge of the epidermis to the upper edge of the fat, excluding the fibrotic tissue thickness between the dermis and the fat), and the fibrosis tissue thickness of the dermis-fat interface (from the lower edge of the deep dermis to the upper edge of the fat in dermal in situ reimplantation group and from the lower edge of the superficial dermis to the upper edge of the fat in dermal dislocation group) in the operative areas were measured and compared between the two groups; the fibrotic tissue thickness at the dermal cutting interface (from the lower edge of the superficial dermis to the upper edge of the deep dermis) in the operative areas in dermal in situ reimplantation group was measured and compared with the fibrotic tissue thickness at the dermal-fat interface. Sirius red staining was performed to observe and compare the type Ⅰ and Ⅲ collagen content in the dermal-fat interface in the operative areas between the 2 groups and between the dermal cutting interface and dermal-fat interface in the operative areas in dermal in situ reimplantation group. Immunohistochemical staining was performed to observe the positive expressions of proliferating cell nuclear antigen (PCNA), transforming growth factor β 1 (TGF-β 1 ), fibroblast growth factor 2 (FGF-2), and hepatocyte growth factor (HGF) in the operative areas in the two groups. The sample number was 6. Data were statistically analyzed with independent sample t test. Results: On PID 7, 14, and 21, the hairs in the operative areas in dermal in situ reimplantation group were denser than those in dermal dislocation group. On PID 14, the skin cross section in the operative areas in dermal dislocation group showed a "sandwich"-like structure, while the skin cross section in the operative areas in dermal in situ reimplantation group had normal structure. On PID 7, 14, and 21, the skin thickness in the operative areas in dermal dislocation group was (4 234±186), (4 688±360), and (4 548±360) μm, respectively, which was close to (4 425±156), (4 714±141), and (4 310±473) μm in dermal in situ reimplantation group ( P >0.05); the dermal thickness in the operative areas in dermal dislocation group was significantly thinner than that in dermal in situ reimplantation group (with t values of -9.73, -15.85, and -15.41, respectively, P <0.01); the fibrotic tissue thickness at the dermal-fat interface in the operative areas in dermal dislocation group was significantly thicker than that in dermal in situ reimplantation group (with t values of 14.48, 20.58, and 15.67, respectively, P <0.01); there was no statistically significant difference between the fibrotic tissue thickness at the dermal-fat interface and the dermal cutting interface in the operative areas in dermal in situ reimplantation group ( P >0.05). On PID 7, 14, 21, the type Ⅲ collagen content in the dermal-fat interface in the operative areas in dermal dislocation group was increased significantly compared with that in dermal in situ replantation group (with t values of 2.65, 0.61, and 7.39, respectively, P <0.05 or P <0.01), whereas there were no statistically significant differences in the type Ⅰ collagen content at the dermal-fat interface in the operative areas between the 2 groups ( P >0.05) and the type Ⅰ and Ⅲ collagen content between the dermal-fat interface and the dermal cutting interface in the operative areas in dermal in situ reimplantation group ( P >0.05). On PID 7, 14, and 21, PCNA, TGF-β 1 , FGF-2, and HGF were positively expressed in the superficial dermis and adipose tissue in the operative areas in dermal dislocation group, while PCNA, TGF-β 1 , FGF-2, and HGF were positively expressed in the superficial dermis, deep dermis, and adipose tissue in the operative areas in dermal in situ reimplantation group. Conclusions: Inadequate intrinsic thickness of dermal tissue is the key factor causing fibrosis, and the biological purpose of fibrosis is to "compensate" the intrinsic thickness of the skin. Besides, adipose tissue may also be an important component of fibrotic skin repair.

The golden hamster (Mesocricetus auratus) is commonly used as a promising model for Leishmania braziliensis infection developing skin-ulcerated lesions. However, different protocols using high concentration of parasites inoculated in the footpad result in severe clinical disease. Here, we further investigate the outcome of the site of infection and concentration of L. braziliensis parasites inoculated on the immunopathogenesis and clinical evolution. Initially, hamsters were infected in the ear dermis or hind footpad with a concentration of 1 × 10 5 parasites. Animals infected in the ear dermis developed a disease, with an increased parasite load that more closely resembled human cutaneous leishmaniasis lesions comparing to the group infected in the footpad. Next, we evaluated if different parasite concentrations (10 4 , 10 5 and 10 6 ) inoculated in the ear dermis would impact the course and clinical aspects of infection. Hamsters infected with 10 4 and 10 5 parasites developed mild lesions compared to the group infected with 10 6 that presented severe and persistent lesions. The parasite load varied between the different parasite concentrations. The inflammatory response was more intense when infection was initiated with 10 6 parasites accompanied by an increased initial expression of IL-4, IL-10 and arginase in the lymph node followed by expression of both pro-and anti-inflammatory cytokines comparing to groups infected with 10 4 and 10 5 parasites. In conclusion, the number of parasites inoculated, and the initial site of infection could influence the inflammatory response, and clinical presentation. Our results suggest that the ear dermis infection model induces a chronic disease that relates to immunopathological aspects of CL natural infection., (© 2022 John Wiley & Sons Ltd.)

Up to a certain developmental stage, a fetus can completely regenerate wounds in the skin. To clarify the mechanism of fetal skin regeneration, identifying when the skin switches from fetal-type wound regeneration to adult-type wound repair is necessary. We hypothesized that this switch occurs at several time points and that complete skin regeneration requires epidermal-dermal interactions and the formation of actin cables. We compared normal skin and wound morphology at each developmental stage. We examined two parameters: epidermal texture and dermal structure. We found that the three-dimensional structure of the skin was completely regenerated in full-thickness skin incisions made before embryonic day (E) 13. However, the skin texture did not regenerate in wounds made after E14. We also found that the dermal structure regenerates up to E16, but wounds created after E17 heal as scars with dermal fibrosis. By controlling the activity of AMP-activated protein kinase and altering actin cable formation, we could regulate scar formation in utero. These findings may contribute to therapies that allow complete skin regeneration without scarring., (© 2022. The Author(s).)

Scar formation and chronic ulcers can develop following a skin injury. They are the result of the over- or underproduction of collagen. It is very important to evaluate the quality and quantity of the collagen that is produced during wound healing, especially with respect to its structure, as these factors are very important to a complicated outcome. However, there is no standard way to quantitatively analyse dermal collagen. As prior work characterised some potentially fractal properties of collagen, it was hypothesised that collagen structure could be evaluated with fractal dimension analysis. Small-angle X-ray scattering technology (SAXS) was used to evaluate the dermis of rats exposed to graft harvest, burn, and diabetic pathologic states. It was found that almost all collagen structures could be quantitatively measured with fractal dimension analysis. Further, there were significant differences in the three-dimensional (3-D) structure of normal collagen versus that measured in pathologic tissues. There was a significant difference in the 3-D structure of collagen at different stages of healing. The findings of this work suggest that fractal analysis is a good tool for wound healing analysis, and that quantitative collagen analysis is very useful for assessing the structure of dermal collagen., (© 2021 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Background: Fibrotic scars are common in both human and mouse skin wounds. However, wound-induced hair neogenesis in the murine wounding models often results in regenerative repair response. Herein, we aimed to uncover cellular functional heterogeneity in dermis between fibrotic and regenerative wound healing fates., Methods: The expression matrix of single-cell RNA sequencing (scRNA-seq) data of fibrotic and regenerative wound dermal cells was filtered, normalized, and scaled; underwent principal components analysis; and further analyzed by Uniform Manifold Approximation and Projection (UMAP) for dimension reduction with the Seurat package. Cell types were annotated, and cell-cell communications were analyzed. The core cell population myofibroblast was identified and the biological functions of ligand and receptor genes between myofibroblast and macrophage were evaluated. Specific genes between fibrotic and regenerative myofibroblast and macrophage were identified. Temporal dynamics of myofibroblast and macrophage were reconstructed with the Monocle tool., Results: Across dermal cells, there were six cell types, namely, EN1-negative myofibroblasts, EN1-positive myofibroblasts, hematopoietic cells, macrophages, pericytes, and endothelial cells. Ligand and receptor genes between myofibroblasts and macrophages mainly modulated cell proliferation and migration, tube development, and the TGF-β pathway. Specific genes that were differentially expressed in fibrotic compared to regenerative myofibroblasts or macrophages were separately identified. Specific genes between fibrotic and regenerative myofibroblasts were involved in the mRNA metabolic process and organelle organization. Specific genes between fibrotic and regenerative macrophages participated in regulating immunity and phagocytosis. We then observed the underlying evolution of myofibroblasts or macrophages., Conclusion: Collectively, our findings reveal that myofibroblasts and macrophages may alter the skin wound healing fate through modulating critical signaling pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Kajita, Takaya, Aramaki-Hattori, Sakai, Asou and Kishi.)

Introduction: Plasma IQ™, the first FDA-cleared hand-held plasma energy device, is indicated for removal and destruction of skin lesions and coagulation of tissue. Treatment involves use of an electrostatic plasma spark to heat the skin and create discrete microthermal wounds., Methods: Microthermal wounds on pre-auricular and upper eyelid skin from two individual subjects were created using multiple treatment parameters to assess the impacts of power, pulse duration and needle electrode type on wound depth, width and thermal spread, and analyzed using histology to characterize treatment effects., Results: Device power had a statistically significant impact on upper eyelid skin microthermal wound depth and width (2-sided t-test p < 0.0001 for both) but not on thermal spread (p = 0.1171). No meaningful differences in wound width, depth, or thermal spread were observed based on pulse duration or electrode type. All microthermal wounds demonstrated dual zones of tissue injury and extended to the superficial reticular dermis., Conclusion: Treatment with the Plasma IQ™ device creates focal microthermal wounds of reproducible depth and width that are comprised of dual thermal injury zones similar to other plasma energy skin rejuvenation devices. Device power is the most important factor determining microthermal wound depth and width., (© 2022 Wiley Periodicals LLC.)

Currently, there is a lack of models representing the skin dermal heterogeneity for relevant research and skin engineering applications. This is the first study reporting production of dermal equivalents reproducing features of papillary and reticular dermal compartments. Inspired from our current knowledge on the architecture and composition differences between the papillary and reticular dermis, we evaluated different collagen-based porous materials to serve as scaffolds for the three-dimensional expansion of freshly isolated papillary and/or reticular fibroblasts. The scaffolds, composed of either collagen I or collagen I and III mixtures, were prepared by lyophilization. Pore size and hydrolytic stability were controlled by crosslinking with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) or EDC/NHS with covalently bound heparin. The evaluation of the resultant "papillary" and "reticular" dermal equivalents was based on the analysis of characteristic features of each dermal compartment, such as cell density and deposition of newly synthetized extracellular matrix components in histological sections. Crosslinking supported cell growth during dermal tissue formation independent on the fibroblast subpopulation. The presence of collagen III seemed to have some positive but non-specific effect only on the maintenance of the mechanical strength of the scaffolds during dermal formation. Histological analyses demonstrated a significant and specific effect of heparin on generating dermal equivalents reproducing the respective higher papillary than reticular cell densities and supporting distinct extracellular matrix components deposition (three to five times more carbohydrate material deposited by papillary fibroblasts in all scaffolds containing heparin, while higher collagen production was observed only in the presence of heparin)., (© 2021 Wiley Periodicals LLC.)

Abstract: Primary dermal melanoma (PDM) is defined as a primary melanoma tumor confined to the dermis, subcutis, or both, without epidermal involvement. The significant overlap of histopathological features in PDM and cutaneous metastatic melanoma makes diagnostic accuracy of PDM challenging. We present a case of a 48-year-old man with a nontender 1.5 × 1.5 cm subcutaneous nodule on the left leg, which had been present for years. Biopsy revealed a dermal tumor with melanocytic differentiation noted to be positive for SOX-10. Additional pathology findings included a high Ki-67 proliferation index and a loss of p16 expression. Pathology reports were consistent with primary tumor stage 4a, and the patient was referred to surgical oncology where examination and workup demonstrated no evidence of the residual lesion representing a metastasis from a primary site. As PDM is histologically indistinguishable from melanoma metastasis to the skin, clues including a history of an evolving subepidermal nodule and exclusion of previous or concurrent melanomas can assist in its accurate diagnosis. Currently, a consensus on the criteria, staging, and management of PDM does not exist. Poorly defined diagnostic criteria and general lack of awareness of PDM result in high rates of incorrect and late-stage diagnoses. This case report highlights the importance of physician familiarity with PDM to ensure accurate recognition, evidence-based management, and improved patient outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The elasticity of the dermal layer decreases with aging, leading to ulcer formation and wrinkling, but the mechanism of this change is not fully understood, because it is difficult to access the complex three-dimensional (3D) internal structure of the dermis., Objective: To clarify age-dependent changes in the overall 3D structure of the dermal layer by means of 3D analysis technology., Methods: We observed sun-protected human skin by means of X-ray micro CT, identified the layers of the skin, and reconstructed the 3D structure on computer. Age-dependent structural changes of the dermal layer were evaluated by statistical comparison of young and aged skin., Results: Histological observations suggested the presence of two types of ectopic fat deposits, namely infiltrated subcutaneous fat and isolated fat, in the lower region of the reticular dermal layer in aged skin. To elucidate their nature, we observed skin specimens by X-ray microCT. The epidermis, dermal layer, and subcutaneous adipose layer were well differentiated on CT images, and 3D skin was digitally reconstructed on computer. This method clearly showed that the isolated fat observed histologically was in fact connected to the subcutaneous fat, namely all ectopic fat is connected to the subcutaneous adipose layer. Statistical analysis showed that the severity of fat infiltration into dermal layer is significantly increased in aged skin compared with young skin., Conclusion: Our findings indicate that subcutaneous fat infiltrates into the dermal layer of aged skin. Our 3D analysis approach is advantageous to understand changes of complex internal skin structures with aging., (© 2022 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Scleroderma, characterized by extensive fibrosis and vascular alterations, involves excessive fibroblast activation, uncontrolled inflammation, and abnormal collagen deposition. Previous studies showed that administrations of either 1,25(OH) 2 D 3 or vitamin D analog effectively decreased or reversed skin fibrosis by regulating the extracellular matrix homeostasis. The actions of 1,25(OH) 2 D 3 are mediated by the vitamin D receptor (VDR), a transcription regulator crucial for skin homeostasis. Although evidence suggests that keratinocyte-fibroblast interaction influences the development of scleroderma, the role of keratinocytes in scleroderma remains unknown. Here, we demonstrated that the ablation of VDR in keratinocytes greatly exacerbated dermal fibrosis in HOCl-induced scleroderma in mice. The deficiency of VDR in the epidermis marked increased dermal thickness, inflammatory cell infiltration, and severe collagen deposition in comparison to the control group in HOCl-treated skin. Moreover, significant elevations in expression levels of mRNA for collagen overproduction (Col1A1, Col1A2, Col3A1, α-SMA, MMP9, TGF-β1) and proinflammatory cytokines (IL-1β, IL-6, CXCL1, CXCL2) were observed in VDR conditional KO versus control mice following HOCl treatment. Collectively, these results suggest that VDR in keratinocytes plays a pivotal role in scleroderma progression, and the interplay between keratinocytes and fibroblasts deserves more attention regarding the exploration of the pathogenesis and treatment for scleroderma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Laminitis is one of the most important and intractable diseases in dairy cows, which can lead to enormous economic losses. Although many scholars have conducted a large number of studies on laminitis, the therapeutic test of medicinal plants in vitro is really rare. Licochalcone A is proved to possess anti-inflammatory and anti-oxidant properties. But the effect of licochalcone A on LPS-induced inflammatory claw dermal cells has not been discovered yet. In this study, the primary dairy cow claw dermal cells were treated with gradient concentrations of licochalcone A (1, 5, 10 µg/mL) in the presence of 10 µg/mL lipopolysaccharides (LPS). The results indicated that licochalcone A reduced the concentrations of inflammation mediators (TNF-α, IL-1β and IL-6), increased the activity of SOD, reduced the levels of MDA and ROS, downregulated the mRNA expressions of TLR4 and MyD88, suppressed the protein levels of p-IκBα and p-p65, and upregulated the protein expression of PPARγ. In summary, licochalcone A protected dairy cow claw dermal cells against LPS-induced inflammatory response and oxidative stress through the regulation of TLR4/MyD88/NF-κB and PPARγ signaling pathways., (© 2022. The Author(s).)

This review focuses on recent advances in understanding the mechanisms involved in itch signaling in the skin and how these new findings fit into the wider picture of the expression of itch mediators and their receptors in the dermal layer. Because at present studies mostly concentrate on single cellular compartments (e.g., neural alone), we suggest that they may miss important interactions with other compartments. Therefore, to fully appreciate pruritus, we propose that studies should consider (e.g., using transcriptomic information) signal transmission within the entire neuro‒immune‒stromal triad., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We previously demonstrated that the non-calcemic pregnacalciferol (pD) analog 17,20S (OH) 2 pD suppressed TGF-β1-induced type I collagen production in cultured normal human dermal fibroblasts. In the present studies, we examined fibroblasts cultured from the lesional skin of patients with systemic sclerosis (scleroderma (SSc)) and assessed the effects of 17,20S(OH) 2 pD on fibrosis-related mediators. Dermal fibroblast lines were established from skin biopsies from patients with SSc and healthy controls. Fibroblasts were cultured with either 17,20S(OH) 2 pD or 1,25(OH) 2 D 3 (positive control) with/without TGF-β1 stimulation and extracted for protein and/or mRNA for collagen synthesis and mediators of fibrosis (MMP-1, TIMP-1, PAI-1, BMP-7, PGES, GLI1, and GLI2). 1 7,20S(OH) 2 pD (similar to 1,25(OH) 2 D 3 ) significantly suppressed net total collagen production in TGF-β1-stimulated normal donor fibroblast cultures and in cultures of SSc dermal fibroblasts. 17,20S(OH) 2 pD (similar to 1,25(OH) 2 D 3 ) also increased MMP-1, BMP-7, and PGES and decreased TIMP-1 and PAI1 expression in SSc fibroblasts. Although 17,20S(OH) 2 pD had no effect on Gli1 or Gli2 in SSc fibroblasts, it increased Gli2 expression when cultured with TGF-β1 in normal fibroblasts. These studies demonstrated that 17,20S(OH) 2 pD modulates mediators of fibrosis to favor the reduction of fibrosis and may offer new noncalcemic secosteroidal therapeutic approaches for treating SSc and fibrosis.