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Molecular and Cell Basis of Skin Diseases and Aging

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 49243

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Special Issue Editors

Prof. Dr. Ángele Juarranz

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Guest Editor

Department of Biology, Faculty of Sciences, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Interests: photocarcinogenesis; non-melanoma skin cancer; photodynamic therapy; in vitro and in vivo models
Special Issues, Collections and Topics in MDPI journals

Dr. Elisa Carrasco

E-Mail Website
Guest Editor

Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Centro de Biología Molecular Severo Ochoa (CBMSO, CSIC-UAM), Universidad Autónoma de Madrid (UAM), 28034 Madrid, Spain
Interests: epigenetics; aging; immunometabolism; inflammation; hair follicle; dermal papilla; stem cells

Special Issue Information

Dear Colleagues,

As the major physical barrier of the body, the skin plays an essential role in both stimuli sensing and defense against environmental insults and pathogens. To fulfill these important functions, the skin is a complex organ that harbors a plethora of cell types, as well as different skin appendices such as hair follicles and glands. Keratinocytes, fibroblasts and adipocytes are the major cellular components of the three skin layers: epidermis, dermis and hypodermis, respectively. In addition, several other cell types are present in the skin, for instance melanocytes involved in pigmentation, mechanoreceptors (like Merkel cells) and sensory neurons, or highly specialized dermal cells such as those forming the dermal papilla, a key component of the hair follicle with inductive capacities. Besides, a prominent immune cell compartment that comprises mast cells, macrophages and distinct subtypes of dendritic cells and T lymphocytes is at the crossroad of the complex dialog between skin microbiota and the host, being instrumental to determine the mutualistic or pathogenic character of the interactions. Overall, the relative abundance and structural location of all these components, along with a fine tuning of the intricate signaling network established among them, are determinant for physiological and pathological processes occurring in the skin. With aging, accumulated damage leads to architectural and functional alterations that affect the skin, increasing the susceptibility to develop inflammatory conditions and neoplastic lesions, hindering the repair capacity of the tissue and entailing a decline in cosmetic features that gain importance in the context of social relationships in humans, including pigmentary and hair-related defects. This Special issue is aimed at reviewing the state-of-the-art and presenting groundbreaking research findings that contribute to understand the molecular and cellular cutaneous changes associated with skin pathologies and aging. Increasing the knowledge in this field is key to prevent skin malfunction and to implement novel therapeutic strategies that promote optimal cosmetic and functional patient outcomes.

Prof. Ángeles Juarranz
Dr. Elisa Carrasco
Guest Editors

Manuscript Submission Information

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Keywords

Skin inflammation
Skin disease
Skin aging
Skin rejuvenation
Skin immunity
Hair follicle
Dermal papilla
Hair follicle stem cells
Epidermal stem cells

Published Papers (9 papers)

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Research

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26 pages, 6307 KiB

Open AccessArticle

Phytocannabinoids Stimulate Rejuvenation and Prevent Cellular Senescence in Human Dermal Fibroblasts

by Marta Gerasymchuk, Gregory Ian Robinson, Alyssa Groves, Lucie Haselhorst, Sanjana Nandakumar, Cora Stahl, Olga Kovalchuk and Igor Kovalchuk

Cells 2022, 11(23), 3939; https://doi.org/10.3390/cells11233939 - 06 Dec 2022

Cited by 10 | Viewed by 22117

Abstract

In light of the increased popularity of phytocannabinoids (pCBs) and their appearance in beauty products without rigorous research on their rejuvenation efficacy, we decided to investigate the potential role of pCBs in skin rejuvenation. Utilizing healthy and stress-induced premature senescent (SIPS) CCD-1064Sk skin fibroblasts, the effects of pCBs on cellular viability, functional activity, metabolic function, and nuclear architecture were tested. Both delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) within the range of 0.5 µM to 2.0 µM increased cell growth in a dose-dependent manner while significantly decreasing senescence as measured by beta-galactosidase activity. Utilizing a scratch assay, both THC and CBD (2.0 µM) significantly improved wound healing in both healthy and SIPS fibroblasts. THC and CBD altered nuclear architecture and mRNA levels of cell cycle regulators and genes involved in ECM production. Subsequently, we found ELN, Cyclin D1, PCNA, and BID protein levels altered by SIPS but ameliorated after pCBs exposure in human dermal fibroblasts. Lastly, we compared the efficacy of THC and CBD with common anti-aging nutrient signaling regulators in replicative senescent adult human dermal fibroblasts, CCD-1135Sk. Both THC and CBD were found to improve wound healing better than metformin, rapamycin, and triacetylresveratrol in replicative senescent CCD-1135Sk fibroblasts. Therefore, pCBs can be a valuable source of biologically active substances used in cosmetics, and more studies using clinical trials should be performed to confirm the efficacy of phytocannabinoids. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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16 pages, 2797 KiB

Open AccessArticle

Aldosterone Increases Vascular Permeability in Rat Skin

by Michal Aleksiejczuk, Anna Gromotowicz-Poplawska, Natalia Marcinczyk, Joanna Stelmaszewska, Janusz Dzieciol and Ewa Chabielska

Cells 2022, 11(17), 2707; https://doi.org/10.3390/cells11172707 - 30 Aug 2022

Cited by 2 | Viewed by 1310

Abstract

The aim of this study was to evaluate the effect of acute aldosterone (ALDO) administration on the vascular permeability of skin. ALDO was injected intradermally into rats, and vascular permeability was measured. Eplerenone (EPL), a selective mineralocorticoid receptor (MR) antagonist, was used. Skin biopsies were carried out for immunohistochemical (IHC) staining, and polymerase chain reactions were performed to analyze the expression of MR, 11β-hydroxysteroid dehydrogenase type 2, von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), and zonula occludens 1. Our study showed the presence of MR in the rat skin vasculature for the first time. It was found that ALDO injection resulted in a more than 30% increase in vascular permeability and enhanced the endothelial exocytosis of vWF. The effect of ALDO diminished after EPL administration. An accumulation of vWF and a reduction in VEGF IHC staining were observed following chronic EPL administration. No effect of ALDO or EPL on the mRNA expression of the studied genes or skin structure was observed. The results suggest that ALDO increases vascular permeability in the skin via an MR-dependent mechanism. This effect of ALDO on skin microcirculation may have important therapeutic implications for diseases characterized by increased levels of ALDO and coexisting skin microangiopathy. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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16 pages, 4117 KiB

Open AccessFeature PaperArticle

Maintenance of Chronological Aging Features in Culture of Normal Human Dermal Fibroblasts from Old Donors

by Julie Rorteau, Fabien P. Chevalier, Sébastien Bonnet, Théo Barthélemy, Amandine Lopez-Gaydon, Lisa S. Martin, Nicolas Bechetoille and Jérôme Lamartine

Cells 2022, 11(5), 858; https://doi.org/10.3390/cells11050858 - 02 Mar 2022

Cited by 11 | Viewed by 3411

Abstract

Chronological aging is defined as a time-dependent decline of tissue homeostasis which severely impacts skin. Understanding the mechanisms of skin aging is an active research area limited by the lack of relevant in vitro models. Being a component of aging, replicative or stress-induced senescence is repeatedly used to mimic skin aging in vitro, thus presenting only a partial view of the complexity of aging. Herein, we aimed to clarify whether primary normal human dermal fibroblasts retained age-related characteristics when cultured in 2D monolayer, and could be used as a relevant model for aging research. We compared three groups of fibroblasts isolated from different aged donors. We observed strongly decreased population doubling capacities, a reduced clonogenic ability, an impairment in extracellular matrix production together with modifications of respiratory metabolism with an increase in age. These disruptions were particularly marked when comparing fibroblasts isolated from old individuals (over 70 years old) to those isolated from young individuals (18–37 years old), while cells from middle-aged donors exhibited an intermediate profile. These alterations of cell features can be related to the signs of dermis aging, thus showing that cultured primary cells indeed retain some characteristics of the original tissue from which they were extracted. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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15 pages, 4122 KiB

Open AccessArticle

Anti-Aging Effects of a Serum Based on Coconut Oil Combined with Deer Antler Stem Cell Extract on a Mouse Model of Skin Aging

by Truc Le-Buu Pham, Thuy Truong Thi, Huyen Thi-Thuong Nguyen, Thuan Duc Lao, Nguyen Trong Binh and Quan Dang Nguyen

Cells 2022, 11(4), 597; https://doi.org/10.3390/cells11040597 - 09 Feb 2022

Cited by 12 | Viewed by 5020

Abstract

Anti-aging is one of the top goals in the field of health care and aesthetics. Anti-aging cosmetics derived from nature are oriented to long-term development, bringing safety to users and being environmentally friendly. The aim of this study was to develop an anti-aging cosmetic formulation process based on coconut oil in combination with deer antler stem cell extract. The results show that the presence of deer antler stem cell extract added to the foundation made the serum product highly stable and helped improve skin aging significantly after 2 weeks of use. The skin site where the serum product was applied showed a smooth and elastic skin surface, with very few fine lines and shallow wrinkles. Serum reduced the number of wrinkles (48.09% compared to commercial serum (ME) and 60.31% compared to positive control (PC)), reduced skin recovery time (39.31% compared to ME and 67.1% of PC) after two weeks of use. After 2 weeks of use, collagen density increased 10.18% compared to ME and 63.76% compared to control. Epidermal thickness increased by 106.1% compared to PC and 121.7% compared to ME. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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15 pages, 2087 KiB

Open AccessArticle

Evaluation of Immunomodulatory Responses and Changed Wound Healing in Type 2 Diabetes—A Study Exploiting Dermal Fibroblasts from Diabetic and Non-Diabetic Human Donors

by Kimberly Nickel, Ursula Wensorra, Horst Wenck, Nils Peters and Harald Genth

Cells 2021, 10(11), 2931; https://doi.org/10.3390/cells10112931 - 28 Oct 2021

Cited by 7 | Viewed by 2626

Abstract

The dermis is the connective layer between the epidermis and subcutis and harbours nerve endings, glands, blood vessels, and hair follicles. The most abundant cell type is the fibroblast. Dermal fibroblasts have a versatile portfolio of functions within the dermis that correspond with different types of cells by either direct contact or by autocrine and paracrine signalling. Diabetic skin is characterized by itching, numbness, ulcers, eczema, and other pathophysiological changes. These pathogenic phenotypes have been associated with the effects of the reactive glucose metabolite methylglyoxal (MGO) on dermal cells. In this study, dermal fibroblasts were isolated from diabetic and non-diabetic human donors. Cultured dermal fibroblasts from diabetic donors exhibited reduced insulin-induced glucose uptake and reduced expression of the insulin receptor. This diabetic phenotype persists under cell culture conditions. Secretion of IL-6 was increased in fibroblasts from diabetic donors. Increased secretion of IL-6 and MIF was also observed upon the treatment of dermal fibroblasts with MGO, suggesting that MGO is sufficient for triggering these immunomodulatory responses. Remarkably, MIF treatment resulted in decreased activity of MGO-detoxifying glyoxalase-1. Given that reduced glyoxalase activity results in increased MGO levels, these findings suggested a positive-feedback loop for MGO generation, in which MIF, evoked by MGO, in turn blocks MGO-degrading glyoxalase activity. Finally, secretion of procollagen Type I C-Peptide (PICP), a marker of collagen production, was reduced in fibroblast from diabetic donors. Remarkably, treatment of fibroblasts with either MGO or MIF was sufficient for inducing reduced PICP levels. The observations of this study unravel a signalling network in human dermal fibroblasts with the metabolite MGO being sufficient for inflammation and delayed wound healing, hallmarks of T2D. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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26 pages, 12213 KiB

Open AccessArticle

PI3Kδ Sustains Keratinocyte Hyperproliferation and Epithelial Inflammation: Implications for a Topically Druggable Target in Psoriasis

by Laura Mercurio, Martina Morelli, Claudia Scarponi, Giovanni Luca Scaglione, Sabatino Pallotta, Cristina Albanesi and Stefania Madonna

Cells 2021, 10(10), 2636; https://doi.org/10.3390/cells10102636 - 02 Oct 2021

Cited by 5 | Viewed by 2505

Abstract

The phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathway is aberrantly activated in psoriatic lesions and contributes to disease pathogenesis. Among PI3Ks enzymes, PI3Kα, β, and δ isoforms are known to bind the p85 regulatory subunit and mediate activation of AKT and other downstream effectors. In this study, we deepened our understanding of the expression and function of PI3Kδ in skin lesions of patients affected by psoriasis. For the first time, we found that PI3Kδ is overexpressed in psoriatic plaques, and its expression is not only confined to infiltrating immune cells but also accumulates in proliferating keratinocytes of the epidermal basal layer. We investigated the function of PI3Kδ in psoriatic skin by evaluating the impact of seletalisib, a newly developed selective PI3Kδ inhibitor, in both in vitro and in vivo experimental models of psoriasis. Of note, we found that PI3Kδ sustains keratinocyte hyperproliferation and impaired terminal differentiation induced by IL-22, as well as induces epithelial inflammation and resistance to apoptosis mediated by TNF-α in human keratinocytes. Mechanistically, PI3Kδ promotes PDK1 phosphorylation and signals through AKT-dependent or -independent pathways. It is worth mentioning that PI3Kδ inhibition by seletalisib attenuates the severity of psoriasiform phenotype induced in the Imiquimod-induced mouse model of psoriasis by restoring the physiological proliferation and differentiation programs in epidermal keratinocytes and contrasting the cutaneous inflammatory responses. Therefore, we suggest PI3Kδ as a potential topically druggable target in psoriasis and skin diseases characterized by epidermal hyperproliferation and skin inflammation. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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18 pages, 3130 KiB

Open AccessArticle

Raloxifene and n-Acetylcysteine Ameliorate TGF-Signalling in Fibroblasts from Patients with Recessive Dominant Epidermolysis Bullosa

by Tania Aguado, Marta García, Adela García, Gemma Ferrer-Mayorga, Lucía Martínez-Santamaría, Marcela del Río, Luisa-María Botella and José-María Sánchez-Puelles

Cells 2020, 9(9), 2108; https://doi.org/10.3390/cells9092108 - 16 Sep 2020

Cited by 6 | Viewed by 3481

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by mutation of the COL7A1 gene. RDEB is associated with high levels of TGF-β1, which is likely to be involved in the fibrosis that develops in this disease. Endoglin (CD105) is a type III coreceptor for TGF-β1 and its overexpression in fibroblasts deregulates physiological Smad/Alk1/Alk5 signalling, repressing the synthesis of TGF-β1 and extracellular matrix (ECM) proteins. Raloxifene is a specific estrogen receptor modulator designated as an orphan drug for hereditary hemorrhagic telangiectasia, a rare vascular disease. Raloxifene stimulates endoglin synthesis, which could attenuate fibrosis. By contrast, the antioxidant N-acetylcysteine may have therapeutic value to rectify inflammation, fibrosis and endothelial dysfunction. Thus, we present here a repurposing strategy based on the molecular and functional screening of fibroblasts from RDEB patients with these drugs, leading us to propose the repositioning of these two well-known drugs currently in clinical use, raloxifene and N-acetylcysteine, to counteract fibrosis and inflammation in RDEB. Both compounds modulate the profibrotic events that may ultimately be responsible for the clinical manifestations in RDEB, suggesting that these findings may also be relevant for other diseases in which fibrosis is an important pathophysiological event. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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Review

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11 pages, 279 KiB

Open AccessReview

Squamous Cell Carcinoma in Patients with Inherited Epidermolysis Bullosa: Review of Current Literature

by Domenico Bonamonte, Angela Filoni, Aurora De Marco, Lucia Lospalluti, Eleonora Nacchiero, Valentina Ronghi, Anna Colagrande, Giuseppe Giudice and Gerardo Cazzato

Cells 2022, 11(8), 1365; https://doi.org/10.3390/cells11081365 - 17 Apr 2022

Cited by 8 | Viewed by 2554

Abstract

Epidermolysis bullosa (EB) is a group of rare congenital diseases caused by mutations in structural proteins of the dermal/epidermal junction that are characterized by extreme epithelial fragility, which determines the formation of bullae and erosions either spontaneously or after local mechanical traumas. In EB patients, skin fragility leads to many possible complications and comorbidities. One of the most feared complications is the development of cutaneous squamous cell carcinomas (SCCs) that particularly in the dystrophic recessive EB subtype can be extremely aggressive and often metastatic. SCCs in EB patients generally arise more often in the extremities, where chronic blisters and scars are generally located. SCCs represent a big therapeutic challenge in the EB population. No standard of care exists for the treatment of SCC in these patients, and therapy is based on small case studies. Moreover, the pathogenesis of cSCC in EB patients is still unclear. Many theories have been indeed postulated in order to explain why cSCC behaves so much more aggressively in EB patients compared to the general population. cSCC in EB seems to be the result of many complex interactions among cancer cells, skin microenvironment, susceptibility to DNA mutations and host immune response. In this review, we analyze the different pathogenetic mechanisms of cSCC in EB patients, as well as new therapies for this condition. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

7 pages, 389 KiB

Open AccessReview

GLUT1, GLUT3 Expression and 18FDG-PET/CT in Human Malignant Melanoma: What Relationship Exists? New Insights and Perspectives

by Gerardo Cazzato, Anna Colagrande, Antonietta Cimmino, Caterina Abbatepaolo, Emilio Bellitti, Paolo Romita, Lucia Lospalluti, Caterina Foti, Francesca Arezzo, Vera Loizzi, Teresa Lettini, Sara Sablone, Leonardo Resta, Gennaro Cormio, Giuseppe Ingravallo and Roberta Rossi

Cells 2021, 10(11), 3090; https://doi.org/10.3390/cells10113090 - 09 Nov 2021

Cited by 6 | Viewed by 4413

Abstract

Background: Malignant melanoma is the most aggressive of skin cancers and the 19th most common cancer worldwide, with an estimated age-standardized incidence rate of 2.8–3.1 per 100,000; although there have been clear advances in therapeutic treatment, the prognosis of MM patients with Breslow thickness greater than 1 mm is still quite poor today. The study of how melanoma cells manage to survive and proliferate by consuming glucose has been partially addressed in the literature, but some rather interesting results are starting to be present. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a search of PubMed and Web of Sciences (WoS) databases was performed until 27 September 2021 using the terms: glucose transporter 1 and 3 and GLUT1/3 in combination with each of the following: melanoma, neoplasm and immunohistochemistry. Results: In total, 46 records were initially identified in the literature search, of which six were duplicates. After screening for eligibility and inclusion criteria, 16 publications were ultimately included. Conclusions: the results discussed regarding the role and expression of GLUT are still far from definitive, but further steps toward understanding and stopping this mechanism have, at least in part, been taken. New studies and new discoveries should lead to further clarification of some aspects since the various mechanisms of glucose uptake by neoplastic cells are not limited to the transporters of the GLUT family alone. Full article

(This article belongs to the Special Issue Molecular and Cell Basis of Skin Diseases and Aging)

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