Differentiation Of Skin Cells Research Articles

Biofabrication of biomimetic undulating microtopography at the dermal-epidermal junction and its effects on the growth and differentiation of epidermal cells.

The undulating microtopography located at the junction of the dermis and epidermis of the native skin is called rete ridges (RRs), which plays an important role in enhancing keratinocyte function, improving skin structure and stability, and providing three-dimensional (3D) microenvironment for skin cells. Despite some progress in recent years, most currently designed and manufactured tissue-engineered skin models still cannot replicate the RRs, resulting in a lack of biological signals in the manufactured skin models. In this study, a composite manufacturing method including electrospinning, 3D printing, and functional coating was developed to produce the epidermal models with RRs. Polycaprolactone (PCL) nanofibers were firstly electrospun to mimic the extracellular matrix environment and be responsible for cell attachment. PCL microfibers were then printed onto top of the PCL nanofibers layer by 3D printing to quickly prepare undulating microtopography and finally the entire structures were dip-coated with gelatin hydrogel to form a functional coating layer. The morphology, chemical composition, and structural properties of the fabricated models were studied. The results proved that the multi-process composite fabricated models were suitable for skin tissue engineering. Live and dead staining, cell counting kit-8 (CCK-8) as well as histology (haematoxylin and eosin (HE) methodology) and immunofluorescence (primary and secondary antibodies combination assay) were used to investigate the viability, metabolic activity, and differentiation of skin cells forin vitroculturing.In vitroresults showed that each model had high cell viability, good proliferation, and the expression of differentiation marker. It was worth noting that the sizes of the RRs affected the cell growth status of the epidermal models. In addition, the unique undulation characteristics of the epidermal-dermal junction can be reproduced in the developed epidermal models. Overall, thesein vitrohuman epidermal models can provide valuable reference for skin transplantation, screening and safety evaluation of drugs and cosmetics.

PDMS nanoparticles-decorated PDMS substrate promotes adhesion, proliferation and differentiation of skin cells

Polydimethylsiloxane (PDMS) is known to be a common substrate for various cell culture-based applications. However, native PDMS is not very conducive for cell culture and hence, surface modification via cell adhesion moieties is generally needed to make it suitable especially for long-term cell culture. To address this issue, we propose to coat PDMS nanoparticles (NPs) on the surface of PDMS film to improve adhesion, proliferation and differentiation of skin cells. The proposed modification strategy introduces necessary nanotopography without altering the surface chemical properties of PDMS. Due to resemblance in the mechanical properties of PDMS with skin, PDMS NPs can recreate the native extracellular nanoenvironment of skin on the PDMS surface and provide anchoring sites for skin cells to adhere and grow. Human keratinocytes, representing 95% of the epidermal skin cells maintained their characteristic well-spread morphology with the formation of interconnected cell-sheets on this coated PDMS surface. Moreover, our in vitro immunofluorescence studies confirmed expression of distinctive epidermal protein markers on the coated surface indicating close resemblance with the native skin epidermis. Conclusively, our findings suggest that introducing nanotopography via PDMS NPs can be an effective strategy for emulating the native cellular functions of keratinocytes on PDMS based cell culture devices.

A Potential Association of Zinc Deficiency and Tyrosine Kinase Inhibitor-Induced Hand-Foot Skin Reaction.

Hand-foot skin reaction (HFSR) is a common skin-related adverse event induced by multikinase inhibitors targeting both platelet-derived growth factor receptor and vascular endothelial growth factor receptor, possibly due to inadequate repair following frictional trauma. Zinc is a trace element and essential nutrient in humans that plays critical roles in the development and differentiation of skin cells. Zinc transporters (Zrt- and Irt-like proteins and Zn transporters) and metallothioneins are involved in zinc efflux, uptake, and homeostasis and have been reported to be involved in skin differentiation. The underlying mechanism of HFSR remains unclear, and the association between HFSR and zinc has not been previously studied. However, some case reports and case series provide potential evidence to suggest that zinc deficiency may be involved in HFSR development and zinc supplementation may relieve HFSR symptoms. However, no large-scale clinical studies have been conducted to examine this role. Therefore, this review summarizes the evidence supporting a possible link between HFSR development and zinc and proposes potential mechanisms underlying this association based on current evidence.

Sphingosine 1-Phosphate as Essential Signaling Molecule in Inflammatory Skin Diseases.

Sphingolipids are crucial molecules of the mammalian epidermis. The formation of skin-specific ceramides contributes to the formation of lipid lamellae, which are important for the protection of the epidermis from excessive water loss and protect the skin from the invasion of pathogens and the penetration of xenobiotics. In addition to being structural constituents of the epidermal layer, sphingolipids are also key signaling molecules that participate in the regulation of epidermal cells and the immune cells of the skin. While the importance of ceramides with regard to the proliferation and differentiation of skin cells has been known for a long time, it has emerged in recent years that the sphingolipid sphingosine 1-phosphate (S1P) is also involved in processes such as the proliferation and differentiation of keratinocytes. In addition, the immunomodulatory role of this sphingolipid species is becoming increasingly apparent. This is significant as S1P mediates a variety of its actions via G-protein coupled receptors. It is, therefore, not surprising that dysregulation in the signaling pathways of S1P is involved in the pathophysiological conditions of skin diseases. In the present review, the importance of S1P in skin cells, as well as the immune cells of the skin, is elaborated. In particular, the role of the molecule in inflammatory skin diseases will be discussed. This is important because interfering with S1P signaling pathways may represent an innovative option for the treatment of inflammatory skin diseases.

Serum Levels of Tumor Necrosis Factor- Like Weak Inducer of Apoptosis (TWEAK) in Patients With Psoriasis Vulgaris

Background: Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines that alter the growth and differentiation of skin cells. Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of variety of inflammatory disorders and autoimmune diseases. However, studies conducted on the relationship of TWEAK and psoriasis patients are limited. Objective: We aimed to assess the serum level of TWEAK in psoriatic patients and determine whether levels are related with clinical variables, such as disease severity and duration. Patients and Methods: The study was conducted on 30 patients with psoriasis attending Dermatology, Venerology & Andrology Outpatient Clinic, Faculty of Medicine, Zagazig University Hospitals spanning the period from January 2019 to March 2019. They were divided into mild, moderate and severe according to Psoriasis Area and Severity Index (PASI) score, 10 patients in each group. The patients' age ranged from 10 to 60 years old. 10 healthy subjects with matched age and sex served as control group. Results: There was non-significant difference between the studied groups regarding age, BMI, sex, family history, DM and smoking. However, the difference between them was highly significant regarding itching and presence of stressors. The mean TWEAK levels were significantly higher in psoriasis patients than in control subjects, which was significantly associated with severity and duration of the disease. There was positive correlation (P < 0.001) between serum TWEAK levels and severity of psoriasis with highly significant level in severe cases. Conclusion: The serum TWEAK levels significantly correlated with the clinical state, as represented by the PASI score. Also, it was found that TWEAK measurement in serum of patients with psoriasis provides a tool for monitoring disease activity and its use as a marker of disease severity. Thus, they have prognostic significance.

Serum Levels of Tumor Necrosis Factor- Like Weak Inducer of Apoptosis (TWEAK) in Patients With Psoriasis Vulgaris

Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines that alter the growth and differentiation of skin cells. Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) has been implicated in the pathogenesis of variety of inflammatory disorders and autoimmune diseases. However, studies conducted on the relationship of TWEAK and psoriasis patients are limited.

Interleukin-17 alters the biology of many cell types involved in the genesis of psoriasis, systemic inflammation and associated comorbidities.

Psoriasis is a chronic, immune-mediated, systemic inflammatory disease that is defined by a characteristic skin reaction produced when elevated levels of inflammatory cytokines such as interleukin (IL)-17 alter the growth and differentiation of skin cells. The pathogenesis of comorbid conditions associated with psoriasis, including psoriatic arthritis, cardiovascular disease, obesity, metabolic syndrome, liver disorders, renal disease and depression, is also largely affected by inflammation. In this review, we examine the effect of IL-17 on the inflammatory pathways in a variety of different cell types, including keratinocytes, as well as epithelial cells of the colon, kidney, gut and liver. Additionally, we investigate the role of IL-17 in mediating the psoriasis-associated comorbidities detailed above.

The dark side of the light: mechanisms of photocarcinogenesis

Ultraviolet radiation (UVR) can have a beneficial biologic impact on skin, but it is also the most significant environmental risk factor for skin cancer development. Photocarcinogenesis comprises a complex interplay between the carcinogenic UVR, skin, and the immune system. UVB is absorbed by the superficial skin layers and is mainly responsible for direct DNA damage, which, if unrepaired, can lead to mutations in key cancer genes. UVA is less carcinogenic, penetrates deeper in the dermis, and mainly causes indirect oxidative damage to cellular DNA, proteins, and lipids, via photosensitized reactions. UVR not only induces mutagenesis, altering proliferation and differentiation of skin cells, but also has several immunosuppressive effects that compromise tumor immunosurveillance by impairing antigen presentation, inducing suppressive cells, and modulating the cytokine environment. This review focuses upon molecular and cellular effects of UVR, regarding its role in skin cancer development.

Intercellular and intracellular functions of ceramides and their metabolites in skin (Review).

The skin consists of the epidermis, dermis and subcutis. The epidermis is primarily comprised of keratinocytes and is separated into four layers according to the stage of differentiation of the keratinocytes. Corneocytes are terminally differentiated keratinocytes that closely interact with other corneocytes through corneodesmosomes, and synthesize lamellar bodies and the intercellular multilamellar barrier, which protects the body from the external environment. As ceramides are the principal components of lamellar bodies and the multilamellar barrier, it is important to understand the biosynthesis of ceramides and their functions in skin. Ceramides are synthesized by amide bond‑mediated interactions between sphingoid bases, long‑chain amino alcohols [long-chain base] and fatty acids through a denovo pathway, a sphingomyelin(SM) hydrolysis pathway and a catabolic pathway. The majority of ceramides produced by the denovo pathway form the epidermal barrier. Ceramides used as signaling molecules are synthesized by the SM and catabolic pathways. Synthesized ceramides are released from corneocytes and form the multilamellar barrier. Additionally, ceramides and their metabolites regulate the apoptosis, proliferation and differentiation of skin cells as well as the formation of the skin barrier. Thus, the study of ceramides and their metabolites is crucial to understanding the function and regulation of the skin barrier.

Endocannabinoid system in dermatoses

Endocannabinoid system has a broad spectrum of physiological effects in human body, is associated with analgesia, immune regulation and energy metabolism, plays an important role in the regulation of pruritus, and affects the occurrence and development of pruritus. Endocannabinoid receptors, a kind of G protein-coupled receptor, can protect nerves, counteract inflammation and inhibit tumor cell growth. Recent research has found that the endocannabinoid system is involved in the regulation of survival, proliferation and differentiation of skin cells, and is a key factor for maintaining skin homeostasis. More and more studies have also demonstrated that the endocannabinoid system is closely related to the occurrence and development of numerous dermatoses, and targeted regulation of the system may benefit the treatment of related dermatoses. Key words: Endocannabinoids; Receptors, cannabinoid; Skin diseases; Analgesia; Immunomodulation; Pruritus

Stimulation of the Proliferation and Differentiation of Skin Cells by Ferrous Ferric Chloride from a Distance

Ferrous ferric chloride (FFC) is a distinct form of aqueous iron composed of a complex of ferrous chloride and ferric chloride that participates in both oxidation and reduction reactions, and stimulates the proliferation and differentiation of mammalian keratinocytes, melanocytes, and fibroblasts. However, it is not known whether FFC can stimulate their proliferation and differentiation without being added into culture media or painted on the skin. This study aims to clarify whether FFC can stimulate their proliferation and differentiation from a distance without being added to culture media. In this study, FFC-containing skin lotions were painted under the culture dishes (1 mm away from cells) or on the top of the covers of 1 to 5 polystyrene culture dishes (1 to 5 cm away) and tested for their proliferation- and differentiation-stimulating effects. FFC lotions stimulated the proliferation and differentiation of human keratinocytes, melanocytes, and fibroblasts from a distance of 1 mm to 1 cm. However, FFC lotions failed to stimulate the proliferation and differentiation of melanocytes from distances of 2 to 5 cm. Results using Teflon covers were similar to those of polystyrene covers. Moreover, the effects of FFC lotions painted on the top of the Teflon covers were completely lost by lead disks. These results suggest that FFC can stimulate the proliferation and differentiation of skin cells from a distance of 1 cm without being added into culture media through physical factors rather than chemical factors.

Upregulation of P2Y2 receptors by retinoids in normal human epidermal keratinocytes

Retinoids, vitamin A derivatives, are important regulators of the growth and differentiation of skin cells. Although retinoids are therapeutically used for several skin ailments, little is known about their effects on P2 receptors, known to be involved in various functions in the skin. DNA array analysis showed that treatment of normal human epidermal keratinocytes (NHEKs) with all-trans-retinoic acid (ATRA), an agonist to RAR (retinoic acid receptor), enhanced the expression of mRNA for the P2Y2 receptor, a metabotropic P2 receptor that is known to be involved in the proliferation of the epidermis. The expression of other P2 receptors in NHEKs was not affected by ATRA. ATRA increased the mRNA for the P2Y2 receptor in a concentration-dependent fashion (1 nM to 1 μM). Am80, a synthesized agonist to RAR, showed a similar enhancement, whereas 9-cis-retinoic acid (9-cisRA), an agonist to RXR (retinoid X receptor), enhanced P2Y2 gene expression to a lesser extent. Ca2+ imaging analysis showed that ATRA also increased the function of P2Y2 receptors in NHEKs. Retinoids are known to enhance the turnover of the epidermis by increasing both proliferation and terminal differentiation. The DNA microarray analysis also revealed that ATRA upregulates various genes involved in the differentiation of NHEKs. Our present results suggest that retinoids, at least in part, exert their proliferative effects by upregulating P2Y2 receptors in NHEKs. This effect of retinoids may be closely related to their therapeutic effect against various ailments or aging events in skins such as over-keratinization, pigmentation and re-modeling.

Wingless signaling regulates the maintenance of ovarian somatic stem cells in Drosophila.

Identifying the signals involved in maintaining stem cells is critical to understanding stem cell biology and to using stem cells in future regenerative medicine. In the Drosophila ovary, Hedgehog is the only known signal for maintaining somatic stem cells (SSCs). Here we report that Wingless (Wg) signaling is also essential for SSC maintenance in the Drosophila ovary. Wg is expressed in terminal filament and cap cells, a few cells away from SSCs. Downregulation of Wg signaling in SSCs through removal of positive regulators of Wg signaling, dishevelled and armadillo, results in rapid SSC loss. Constitutive Wg signaling in SSCs through the removal of its negative regulators, Axin and shaggy, also causes SSC loss. Also, constitutive wg signaling causes over-proliferation and abnormal differentiation of somatic follicle cells. This work demonstrates that wg signaling regulates SSC maintenance and that its constitutive signaling influences follicle cell proliferation and differentiation. In mammals, constitutive beta-catenin causes over-proliferation and abnormal differentiation of skin cells, resulting in skin cancer formation. Possibly, mechanisms regulating proliferation and differentiation of epithelial cells, including epithelial stem cells, is conserved from Drosophila to man.

1,25-Dihydroxyvitamin D3 Prevents the Conversion of Adipose Tissue into Fibrous Tissue in Skin Exposed to Chronic UV Irradiation

The hormonally active form of vitamin D (1,25(OH)2D3) is known to be a physiological regulator of the proliferation and differentiation of skin cells including keratinocytes, fibroblasts, and adipocytes. In the present study, the efficacy of 1,25(OH)2D3 on the conversion of adipose tissue to fibrous tissue in photodamaged skin was investigated in a murine animal model. Groups of hairless mice were exposed to solar-simulating UV irradiation (λmax, 352 nm; UV distribution: 300–310 nm, 0.9%; 310–320 nm, 2.0%; 320–420 nm, 97.1%) for 20 weeks at a dose of 10.8 J/cm2 five times weekly on weekdays. At the end of 20 weeks irradiation, wrinkling in the dorsal skin was induced. The histological and biochemical studies indicated that UV irradiation caused a disappearance of adipocytes and concomitant accumulation of the extracellular matrix components (fibrosis), including collagen, hyaluronan, and chondroitin/dermatan, which are synthesized by fibroblasts. Application of 1,25(OH)2D3 on the dorsal skin prior to UV irradiation dramatically prevented both the disappearance of adipocytes and the accumulation of extracellular matrix components in the lower dermis, resulting in antiwrinkling. These findings indicate that 1,25(OH)2D3 prevents the UV-induced abnormal differentiation and proliferation of adipocytes and fibroblasts, which arise from a common progenitor, mesenchymal cells.