Within days after birth, rapid surface colonization of infant skin coincides with significant functional changes. Gradual maturation of skin function, structure, and composition continues throughout ...the first years of life. Recent reports have revealed topographical and temporal variations in the adult skin microbiome. Here we address the question of how the human skin microbiome develops early in life. We show that the composition of cutaneous microbial communities evolves over the first year of life, showing increasing diversity with age. Although early colonization is dominated by Staphylococci, their significant decline contributes to increased population evenness by the end of the first year. Similar to what has been shown in adults, the composition of infant skin microflora appears to be site specific. In contrast to adults, we find that Firmicutes predominate on infant skin. Timely and proper establishment of healthy skin microbiome during this early period might have a pivotal role in denying access to potentially infectious microbes and could affect microbiome composition and stability extending into adulthood. Bacterial communities contribute to the establishment of cutaneous homeostasis and modulate inflammatory responses. Early microbial colonization is therefore expected to critically affect the development of the skin immune function.
Introduction
The fundamental function of the epidermis is to provide an inside‐out barrier to water loss and an outside‐in barrier to penetration of external irritants. Transepidermal water loss ...(TEWL) has been extensively used as a method of estimating the skin barrier quality, typically without any consideration of directionality. The validity of TEWL as an estimate of skin permeability to external substances has been controversial in vitro and in vivo. The aim of this work was to assess the relationship between TEWL and the penetration of a topically applied external marker (caffeine) in healthy skin in vivo before and following a challenge to the barrier.
Methods
The skin barrier was challenged by application of aqueous solutions of mild cleanser products under occlusion for 3 h on the forearms of nine human participants. Skin barrier quality was evaluated before and after the challenge by measuring the TEWL rate and the permeated amount of topically applied caffeine using in vivo confocal Raman microspectroscopy.
Results
No skin irritation was observed following the skin barrier challenge. TEWL rates and the caffeine penetrated amount in the stratum corneum after the challenge were not correlated. A weak correlation was observed when the changes were corrected to water‐only treatment. TEWL values can be influenced by environmental conditions as well as the skin temperature and water content.
Conclusions
Measuring TEWL rates is not always representative of the outside‐in barrier. TEWL may be useful in differentiating large changes in skin barrier function (e.g., between healthy and compromised skin) but is less sensitive to small variations following topical application of mild cleansers.
Skin water barrier development begins in utero and is believed to be complete by week 34 of gestational age. The goal of this investigation was to assess the dynamic transport and distribution of ...water of the stratum corneum of infants and compare it to those of adults. The interaction of water with the stratum corneum was assessed by measuring capacitance, transepidermal water loss (TEWL), rates of absorption–desorption as well as Raman spectra as a function of depth (a total of 124 infants (3–12 months) and 104 adults (14–73 years)). The results show that capacitance, TEWL, and absorption–desorption rates had larger values consistently for infant stratum corneum throughout the first year of life and showed greater variation than those of adults. The Raman spectra analyzed for water and for the components of natural moisturizing factor (NMF) showed the distribution of water to be higher and have a steeper gradient in infants than in adults; the concentration of NMF was significantly lower in infants. The results suggest that although the stratum corneum of infants may appear intact shortly after birth (<1 month), the way it stores and transports water becomes adult-like only after the first year of life.
Cutaneous adverse drug reactions (CADR) associated with oncology therapy involve 45-100% of patients receiving kinase inhibitors. Such adverse reactions may include skin inflammation, infection, ...pruritus and dryness, symptoms that can significantly affect the patient's quality of life. To prevent severe skin damages dose adjustment or drug discontinuation is often required, interfering with the prescribed oncology treatment protocol. This is particularly the case of Epidermal Growth Factor Receptor inhibitors (EGFRi) targeting carcinomas. Since the EGFR pathway is pivotal for epidermal keratinocytes, it is reasonable to hypothesize that EGFRi also affect these cells and therefore interfere with the epidermal structure formation and skin barrier function.
To test this hypothesis, the effects of EGFRi and Vascular Endothelial Growth Factor Receptor inhibitors (VEGFRi) at therapeutically relevant concentrations (3, 10, 30, 100 nM) were assessed on proliferation and differentiation markers of human keratinocytes in a novel 3D micro-epidermis tissue culture model.
EGFRi directly affect basal keratinocyte growth, leading to tissue size reduction and switching keratinocytes from a proliferative to a differentiative phenotype, as evidenced by decreased Ki67 staining and increased filaggrin, desmoglein-1 and involucrin expression compared to control. These effects lead to skin barrier impairment, which can be observed in a reconstructed human epidermis model showing a decrease in trans-epidermal water loss rates. On the other hand, pan-kinase inhibitors mainly targeting VEGFR barely affect keratinocyte differentiation and rather promote a proliferative phenotype.
This study contributes to the mechanistic understanding of the clinically observed CADR during therapy with EGFRi. These in vitro results suggest a specific mode of action of EGFRi by directly affecting keratinocyte growth and barrier function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Reflectance confocal microscopy (RCM) allows for real‐time in vivo visualization of the epidermis at the cellular level noninvasively. Parameters relating to tissue architecture can be ...extracted from RCM images, however, analysis of such images requires manual identification of cells to derive these parameters, which can be time‐consuming and subject to human error, highlighting the need for an automated cell identification method.
Methods
First, the region‐of‐interest (ROI) containing cells needs to be identified, followed by the identification of individual cells within the ROI. To perform this task, we use successive applications of Sato and Gabor filters. The final step is post‐processing improvement of cell detection and removal of size outliers. The proposed algorithm is evaluated on manually annotated real data. It is then applied to 5345 images to study the evolution of epidermal architecture in children and adults. The images were acquired on the volar forearm of healthy children (3 months to 10 years) and women (25–80 years), and on the volar forearm and cheek of women (40–80 years). Following the identification of cell locations, parameters such as cell area, cell perimeter, and cell density are calculated, as well as the probability distribution of the number of nearest neighbors per cell. The thicknesses of the Stratum Corneum and supra‐papillary epidermis are also calculated using a hybrid deep‐learning method.
Results
Epidermal keratinocytes are significantly larger (area and perimeter) in the granular layer than in the spinous layer and they get progressively larger with a child's age. Skin continues to mature dynamically during adulthood, as keratinocyte size continues to increase with age on both the cheeks and volar forearm, but the topology and cell aspect ratio remain unchanged across different epidermal layers, body sites, and age. Stratum Corneum and supra‐papillary epidermis thicknesses increase with age, at a faster rate in children than in adults.
Conclusions
The proposed methodology can be applied to large datasets to automate image analysis and the calculation of parameters relevant to skin physiology. These data validate the dynamic nature of skin maturation during childhood and skin aging in adulthood.
The stratum corneum (SC) provides a permeability barrier that limits the inflow and outflow of water. The permeability barrier is continuously and dynamically formed, maintained, and degraded along ...the depth, from the bottom to the top, of the SC. Naturally, its functioning and structure also change dynamically in a depth-dependent manner. While transepidermal water loss is typically used to assess the function of the SC barrier, it fails to provide any information about the dynamic mechanisms that are responsible for the depth-dependent characteristics of the permeability barrier. This paper aims to quantitatively characterize the depth-dependency of the permeability barrier using in vivo non-invasive measurement data for understanding the underlying mechanisms for barrier formation, maintenance, and degradation. As a framework to combine existing experimental data, we propose a mathematical model of the SC, consisting of multiple compartments, to explicitly address and investigate the depth-dependency of the SC permeability barrier. Using this mathematical model, we derive a measure of the water permeability barrier, i.e. resistance to water diffusion in the SC, from the measurement data on transepidermal water loss and water concentration profiles measured non-invasively by Raman spectroscopy. The derived resistance profiles effectively characterize the depth-dependency of the permeability barrier, with three distinct regions corresponding to formation, maintenance, and degradation of the barrier. Quantitative characterization of the obtained resistance profiles allows us to compare and evaluate the permeability barrier of skin with different morphology and physiology (infants vs adults, different skin sites, before and after application of oils) and elucidates differences in underlying mechanisms of processing barriers. The resistance profiles were further used to predict the spatial-temporal effects of skin treatments by in silico experiments, in terms of spatial-temporal dynamics of percutaneous water penetration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pediatricians and parents report diaper dermatitis (DD) to be one of the most common skin diseases that affects almost every child at some point during the early months and years of life. Diapered ...skin is exposed to friction and excessive hydration, has a higher pH than nondiapered skin, and is repeatedly soiled with feces that contains enzymes with high irritation potential for the skin. The combination of these factors frequently results in skin damage, leading to visible erythematous lesions that can be irritating and painful to the child. Behavioral changes such as increased crying and agitation and changes in eating and sleeping patterns indicate emotional distress. Appropriate skin care can help to prevent the occurrence of DD and to speed up the healing of affected skin. This includes frequent diaper changes and aeration, gentle cleansing, and the use of a barrier cream. Mild to moderate cases usually resolve after a few days of following this routine, but the use of harsh cleaning products can exacerbate DD.
Skin surface pH has been identified as a key regulator of the epidermal homeostasis through its action on serine protease activity. These enzymes, like kallikreins (KLK), are responsible for the ...degradation of corneodesmosomes, the protein structures linking together corneocytes, and are regulated by Lympho‐Epithelial Kazal‐Type‐related Inhibitor (LEKTI). KLK activity increases at pH levels higher than physiological. An increase in skin surface pH has been observed in patients suffering from skin diseases characterized by impaired barrier function, like atopic dermatitis. In this work, we introduce an agent‐based model of the epidermis to study the impact of a change in skin surface pH on the structural and physiological properties of the epidermis, through the LEKTI‐KLK mechanism. We demonstrate that a less acidic pH, compared to the slightly acidic pH observed in healthy skin, is sufficient to significantly affect the water loss at the surface and the amount of irritant permeating through the epidermis. This weakening of the skin barrier function eventually results in a more intense skin inflammation following exposure to an external irritant. This work provides additional evidence that skin surface pH and serine proteases can be therapeutic targets to improve skin barrier integrity.
: Functional differences between infant and adult skin may be attributed to putative differences in skin microstructure. The purpose of this study was to examine infant skin microstructure in vivo ...and to compare it with that of adult skin. The lower thigh area of 20 healthy mothers (ages 25–43) and their biological children (ages 3–24 months) was examined using in vivo noninvasive methods including fluorescence spectroscopy, video microscopy, and confocal laser scanning microscopy. Stratum corneum and supra‐papillary epidermal thickness as well as cell size in the granular layer were assessed from the confocal images. Adhesive tapes were used to remove corneocytes from the outer‐most layer of stratum corneum and their size was computed using image analysis. Surface features showed differences in glyph density and surface area. Infant stratum corneum was found to be 30% and infant epidermis 20% thinner than in adults. Infant corneocytes were found to be 20% and granular cells 10% smaller than adult corneocytes indicating a more rapid cell turnover in infants. This observation was confirmed by fluorescence spectroscopy. Dermal papillae density and size distribution also differed. Surprisingly, a distinct direct structural relationship between the stratum corneum morphology and the dermal papillae was observed exclusively in infant skin. A change in reflected signal intensity at ∼100 μm indicating the transition between papillary and reticular dermis was evident only in adult skin. We demonstrate in vivo qualitative and quantitative differences in morphology between infant and adult skin. These differences in skin microstructure may help explain some of the reported functional differences.
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