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Biology
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An Overview on Keratinocyte Fate: Physiological and Pathological Aspects
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An Overview on Keratinocyte Fate: Physiological and Pathological Aspects

A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (1 July 2022) | Viewed by 18365

Special Issue Editors

Dr. Giorgia Cardinali

E-Mail Website
Guest Editor
San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
Interests: bioactive modulators of cutaneous homeostasis
Special Issues, Collections and Topics in MDPI journals
Dr. Daniela Kovacs

E-Mail Website
Guest Editor
San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy
Interests: dermal-epidermal cross-talk in skin diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The skin, the interface with the external environment, represents the first line of protection against physical (wounding, UV radiation), chemical, and biological insults. Moreover, it provides a water-impermeable barrier that prevents dehydration. Skin regeneration is guaranteed by the proliferation of basal keratinocytes having stem cell properties. When proliferating keratinocytes move to the upper layers of the epidermis, they undergo sequential and programmed differentiation process culminating in cell death. The enucleated and fully differentiated keratinocytes thus formed and termed corneocytes, are embedded in a lipid-rich extracellular matrix to form a keratinized multilayer structure, the stratum corneum. Cutaneous homeostasis is finely orchestrated by the cross talk among mesenchymal, epithelial, and immune cells through the release of different growth factors, cytokines, and lipid mediators acting via paracrine/autocrine signaling. The molecular mechanisms which regulate keratinocyte differentiation program have been studied for a long time. Calcium is a major regulator of keratinocyte differentiation in vivo and in vitro. The increase in intracellular calcium is associated with the recruitment of kinases and phospholipases which, in turn, activate second messengers crucial for the modulation of the differentiation process. Several studies have demonstrated that an imbalance between keratinocyte proliferation and differentiation associates with dysfunctions and/or altered expression of proteins related to cell growth/differentiation, cell-cell adhesion, and lipid metabolism regulators. These deregulations impair the skin architecture and lead to an ineffective barrier function, thus contributing to the appearance of skin diseases and tumors. Due to the relevance of these aspects, there is the need to deepen the mechanisms that regulate keratinocyte differentiation to identify the bioactive mediators involved in the onset and maintenance of skin diseases characterized by defects of keratinization and barrier function. These biomarkers could be considered as new targets for the development of therapeutic approaches more effective in the treatment of skin disorders.

This Special Issue aims to collect advances in the field of keratinocyte biology useful to provide novel findings in the knowledge of the mechanisms underlying physiological and pathological skin conditions. Studies employing innovative organotypic models and skin-on-a-chip as more physiological systems to better mimic the in vivo skin complexity are also welcome.

Dr. Giorgia Cardinali
Dr. Daniela Kovacs
Guest Editors

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Keywords

  • skin homeostasis and barrier function
  • stratum corneum
  • keratinocyte growth and differentiation
  • calcium signaling
  • growth factors/growth factor receptors
  • lipid metabolism/lipid mediators
  • intracellular signal transduction
  • filaggrin
  • cell-cell adhesions
  • inflammatory signals
  • skin diseases/cancer
  • 3D reconstructed skin models

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Published Papers (5 papers)

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Research

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20 pages, 2529 KiB  
Article
Olive Oil Based Methotrexate Loaded Topical Nanoemulsion Gel for the Treatment of Imiquimod Induced Psoriasis-like Skin Inflammation in an Animal Model
by Sheikh Abdur Rashid, Sajid Bashir, Faiza Naseem, Arshad Farid, Irfan A. Rather and Khalid Rehman Hakeem
Biology 2021, 10(11), 1121; https://doi.org/10.3390/biology10111121 - 31 Oct 2021
Cited by 32 | Viewed by 4331
Abstract
Psoriasis, a chronic inflammatory illness, is on the rise and is linked to several other life-threatening diseases. The primary goal of this study was to create a nanoemulsion gel loaded with methotrexate and olive oil (MTX NEG). The formulation was evaluated for physicochemical [...] Read more.
Psoriasis, a chronic inflammatory illness, is on the rise and is linked to several other life-threatening diseases. The primary goal of this study was to create a nanoemulsion gel loaded with methotrexate and olive oil (MTX NEG). The formulation was evaluated for physicochemical characterization, entrapment efficiency, drug release kinetics, skin permeation studies and stability tests. In addition, the efficacy of MTX NEG against psoriasis was tested using imiquimod-induced psoriasis in a rat model. The final optimized MTX NEG was developed with a particle size of 202.6 ± 11.59 nm and a PDI of 0.233 ± 0.01, with a 76.57 ± 2.48% average entrapment efficiency. After 20 h, the release kinetics predicted a 72.47% drug release at pH 5.5. FTIR findings demonstrated that the optimized MTX NEG formulation effectively fluidized both the epidermis and dermis of the skin, potentially increasing drug permeability and retention. The application of Tween 80 and PEG 400, on the other hand, significantly enhanced these effects, as these are well known penetration enhancers. After 24 h, an average of 70.78 ± 5.8 μg/cm2 of methotrexate was permeated from the nanoemulsion gel with a flux value of 2.078 ± 0.42 μg/cm2/h, according to permeation measurements. Finally, in vivo experiments on rabbit skin revealed that the increased skin penetration of methotrexate-loaded nanoemulsion gel was not due to structural alterations in intercellular lipid layers in the stratum corneum. In vivo antipsoriatic studies on rats revealed that MTX NEG produced a PASI decrease that was extremely similar and even better than the 91% reduction seen in the MTX tablet group. According to the pharmacokinetic profile, Cmax was 8.5 μg/mL, Tmax was 12 h, and t1/2 was 15.5 ± 2.37 h. These findings reinforce that MTX-NEG based on olive oil could be a possible treatment for psoriasis and could decrease the remission of psoriasis-like symptoms. Full article
(This article belongs to the Special Issue An Overview on Keratinocyte Fate: Physiological and Pathological Aspects)
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22 pages, 4003 KiB  
Article
Altered Expression of Candidate Genes in Mayer–Rokitansky–Küster–Hauser Syndrome May Influence Vaginal Keratinocytes Biology: A Focus on Protein Kinase X
by Paola Pontecorvi, Francesca Megiorni, Simona Camero, Simona Ceccarelli, Laura Bernardini, Anna Capalbo, Eleni Anastasiadou, Giulia Gerini, Elena Messina, Giorgia Perniola, Pierluigi Benedetti Panici, Paola Grammatico, Antonio Pizzuti and Cinzia Marchese
Biology 2021, 10(6), 450; https://doi.org/10.3390/biology10060450 - 21 May 2021
Cited by 5 | Viewed by 2967
Abstract
Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare and complex disease defined by congenital aplasia of the vagina and uterus in 46,XX women, often associated with kidney and urinary tract anomalies. The aetiopathogenesis of MRKH syndrome is still largely unknown. Herein, we investigated the role [...] Read more.
Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a rare and complex disease defined by congenital aplasia of the vagina and uterus in 46,XX women, often associated with kidney and urinary tract anomalies. The aetiopathogenesis of MRKH syndrome is still largely unknown. Herein, we investigated the role of selected candidate genes in the aetiopathogenesis of MRKH syndrome, with a focus on PRKX, which encodes for protein kinase X. Through RT-qPCR analyses performed on vaginal dimple samples from patients, and principal component analysis (PCA), we highlighted a phenotype-related expression pattern of PRKX, MUC1, HOXC8 and GREB1L in MRKH patients. By using an in vitro approach, we proved that PRKX ectopic overexpression in a cell model of vaginal keratinocytes promotes cell motility through epithelial-to-mesenchymal transition (EMT) activation, a fundamental process in urogenital tract morphogenesis. Moreover, our findings showed that PRKX upregulation in vaginal keratinocytes is able to affect transcriptional levels of HOX genes, implicated in urinary and genital tract development. Our study identified the dysregulation of PRKX expression as a possible molecular cause for MRKH syndrome. Moreover, we propose the specific role of PRKX in vaginal keratinocyte biology as one of the possible mechanisms underlying this complex disease. Full article
(This article belongs to the Special Issue An Overview on Keratinocyte Fate: Physiological and Pathological Aspects)
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16 pages, 2408 KiB  
Article
Expression Profile of Fibroblast Growth Factor Receptors, Keratinocyte Differentiation Markers, and Epithelial Mesenchymal Transition-Related Genes in Actinic Keratosis: A Possible Predictive Factor for Malignant Progression?
by Flavia Persechino, Danilo Ranieri, Luisa Guttieri, Monica Nanni, Maria Rosaria Torrisi and Francesca Belleudi
Biology 2021, 10(4), 331; https://doi.org/10.3390/biology10040331 - 15 Apr 2021
Cited by 6 | Viewed by 2546
Abstract
Actinic keratosis (AK) is the ultra violet (UV)-induced preneoplastic skin lesion clinically classified in low (KIN I), intermediate (KIN II), and high (KIN III) grade lesions. In this work we analyzed the expression of Fibroblast Growth Factor Receptors (FGFRs), as well as of [...] Read more.
Actinic keratosis (AK) is the ultra violet (UV)-induced preneoplastic skin lesion clinically classified in low (KIN I), intermediate (KIN II), and high (KIN III) grade lesions. In this work we analyzed the expression of Fibroblast Growth Factor Receptors (FGFRs), as well as of keratinocyte differentiation and epithelial-to-mesenchymal transition (EMT)-related markers in differentially graded AK lesions, in order to identify specific expression profiles that could be predictive for direct progression of some KIN I lesions towards squamous cell carcinoma (SCC). Our molecular analysis showed that the keratinocyte differentiation markers keratin 1 (K1), desmoglein-1 (DSG1), and filaggrin (FIL) were progressively downregulated in KIN I, II, and III lesions, while the modulation of epithelial/mesenchymal markers and the induction of the transcription factors Snail1 and Zinc finger E-box-binding homeobox 1 (ZEB1) compatible with pathological EMT, even if observable, did not appear to correlate with AK progression. Concerning FGFRs, a modulation of epithelial isoform of FGFR2 (FGFR2b) and the mesenchymal FGFR2c isoform compatible with an FGFR2 isoform switch, as well as FGFR4 upregulation were observed starting from KIN I lesions, suggesting that they could be events involved in early steps of AK pathogenesis. In contrast, the increase of FGFR3c expression, mainly appreciable in KIN II and KIN III lesions, suggested a correlation with AK late progression. Interestingly, the strong modulation of FIL, Snail1, as well as of FGFR2c, FGFR4, and of their ligand FGF2, observed in some of the KIN I samples, may indicate that they could be molecular markers predictive for those low graded lesions destined to a direct progression to SCC. In conclusion, our data point on the identification of molecular markers predictive for AK rapid progression through the “differentiated” pathway. Our results also represent an important step that, in future, will help to clarify the molecular mechanisms underlying FGFR signaling deregulation in epithelial tissues during the switch from the pre-neoplastic to the oncogenic malignant phenotype. Full article
(This article belongs to the Special Issue An Overview on Keratinocyte Fate: Physiological and Pathological Aspects)
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Review

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17 pages, 1167 KiB  
Review
Role of mTOR Signaling Cascade in Epidermal Morphogenesis and Skin Barrier Formation
by Juan Wang, Sabine A. Eming and Xiaolei Ding
Biology 2022, 11(6), 931; https://doi.org/10.3390/biology11060931 - 19 Jun 2022
Cited by 1 | Viewed by 3708
Abstract
The skin epidermis, with its capacity for lifelong self-renewal and rapid repairing response upon injury, must maintain an active status in metabolism. Mechanistic target of rapamycin (mTOR) signaling is a central controller of cellular growth and metabolism that coordinates diverse physiological and pathological [...] Read more.
The skin epidermis, with its capacity for lifelong self-renewal and rapid repairing response upon injury, must maintain an active status in metabolism. Mechanistic target of rapamycin (mTOR) signaling is a central controller of cellular growth and metabolism that coordinates diverse physiological and pathological processes in a variety of tissues and organs. Recent evidence with genetic mouse models highlights an essential role of the mTOR signaling network in epidermal morphogenesis and barrier formation. In this review, we focus on the recent advances in understanding how mTOR signaling networks, including upstream inputs, kinases and downstream effectors, regulate epidermal morphogenesis and skin barrier formation. Understanding the details of the metabolic signaling will be critical for the development of novel pharmacological approaches to promote skin barrier regeneration and to treat epidermal barrier defect-associated diseases. Full article
(This article belongs to the Special Issue An Overview on Keratinocyte Fate: Physiological and Pathological Aspects)
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12 pages, 1497 KiB  
Review
Sphingosine 1-Phosphate Signaling at the Skin Barrier Interface
by Kana Masuda-Kuroki and Anna Di Nardo
Biology 2022, 11(6), 809; https://doi.org/10.3390/biology11060809 - 25 May 2022
Cited by 18 | Viewed by 3456
Abstract
Sphingosine 1-phosphate (S1P) is a product of membrane sphingolipid metabolism. S1P is secreted and acts via G-protein-coupled receptors, S1PR1-5, and is involved in diverse cellular functions, including cell proliferation, immune suppression, and cardiovascular functions. Recent studies have shown that the effects of S1P [...] Read more.
Sphingosine 1-phosphate (S1P) is a product of membrane sphingolipid metabolism. S1P is secreted and acts via G-protein-coupled receptors, S1PR1-5, and is involved in diverse cellular functions, including cell proliferation, immune suppression, and cardiovascular functions. Recent studies have shown that the effects of S1P signaling are extended further by coupling the different S1P receptors and their respective downstream signaling pathways. Our group has recently reported that S1P inhibits cell proliferation and induces differentiation in human keratinocytes. There is a growing understanding of the connection between S1P signaling, skin barrier function, and skin diseases. For example, the activation of S1PR1 and S1PR2 during bacterial invasion regulates the synthesis of inflammatory cytokines in human keratinocytes. Moreover, S1P-S1PR2 signaling is involved in the production of inflammatory cytokines and can be triggered by epidermal mechanical stress and bacterial invasion. This review highlights how S1P affects human keratinocyte proliferation, differentiation, immunoreaction, and mast cell immune response, in addition to its effects on the skin barrier interface. Finally, studies targeting S1P-S1PR signaling involved in inflammatory skin diseases are also presented. Full article
(This article belongs to the Special Issue An Overview on Keratinocyte Fate: Physiological and Pathological Aspects)
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