The Fate of Epidermal Tight Junctions in the stratum corneum: Their Involvement in the Regulation of Desquamation and Phenotypic Expression of Certain Skin Conditions.

We evaluated the presence of tight junction (TJ) remnants in the stratum corneum (SC) of in vitro reconstructed human epidermis and human skin explants subjected or not to an aggressive topical treatment with beta-lipohydroxy salicylic acid (LSA) for 24 h. LSA-treated samples showed an increased presence of TJ remnants in the two lowermost layers of the SC, as quantified with standard electron microscopy. The topical aggression-induced overexpression of TJ-like cell-cell envelope fusions may influence SC functions: (1) directly, through an enhanced cohesion, and (2) indirectly, by impeding accessibility of peripheral corneodesmosomes to extracellular hydrolytic enzymes and, thus, slowing down desquamation. Observations of ichthyotic epidermis in peeling skin disease (PSD; corneodesmosin deficiency; two cases) and ichthyosis hypotrichosis sclerosing cholangitis syndrome (IHSC/NISCH; absence of claudin-1; two cases) also demonstrated increased persistence of TJ-like intercellular fusions in pathological SC and contributed to the interpretation of the diseases' pathological mechanisms

Implication of glycans and junctional elements in the stratum corneum barrier function

La barrière épidermique du stratum corneum (SC) est doublée par une barrière secondaire des jonctions serrées (JS) qui influent sur la formation de barrière principale. Dans mes travaux, je me suis concentré sur l'étude de la présence et l'évolution des éléments jonctionnelles composants ces deux barrières ; les cornéodesmosomes au niveau du SC et les JSs au niveau de la granuleuse. En plus, je me suis intéressé à l'implication des glycanes dans la fonction barrière épidermique. Ces travaux ont été réalisés soit dans un contexte physiologique soit par la modulation de la barrière épidermique par des facteurs intrinsèques et extrinsèques. Nos résultats confirment que les JSs jouent un rôle subalterne par rapport à la barrière du SC et montrent que les glycanes persistent à la surface des cornéocytes humains. La composition et la répartition utlrastructurale des glycanes évoluent à travers les assises du SC jusqu'à la desquamation d'une manière concordante avec la répartition des cornéodesmosomes. Certaines modifications intrinsèques naturelles lors du vieillissement ou pathologiques notamment l'état pelliculaire et la dermatite atopique, ont permis d'appréhender le rôle de ces composants dans la cohésion du SC et la prestance d'une barrière fonctionnelle. Les modifications extrinsèques de la barrière par l'application de solvants, d'excipients ou de formulations perméabilisantes montrent l'importance de l'organisation utlrastructurale des composants jonctionnelles et non jonctionnelles du SC dans le maintien d'une barrière efficaceThe stratum corneum (SC) barrier is doubled by the secondary barrier of tight junctions which influences the formation of the main barrier. In my work, I focused on the study of the junctional elements composing those two barriers; corneodesmosomes in the SC and the tight junction at the granular layer level. In addition, I got interested in the involvement of glycans in the epidermal barrier function. This work was carried out either in skin physiological conditions or by the modulation of the epidermal barrier by intrinsic or extrinsic factors. Our results confirm that tight junctions play a subordinate role compared to the SC barrier and that glycans remain present at the surface of human corneocytes. The composition and the ultrastructure distribution of glycans evolve from the SC compactum to the SC disjunctum, towards desquamation in a comparable manner to the repartition of corneodesmosomes. Natural intrinsic changes during aging and pathological changes, including dandruff and atopic dermatitis, helped us to understand the role of those components in the cohesion of the SC and the conservation of functional barrier. Extrinsic modulation of the barrier by the application of solvents, excipients or topical formulations shows the importance of the ultrastructural organization of junctional and non-junctional SC components in maintaining an effective barrie

Skin Minerals: Key Roles of Inorganic Elements in Skin Physiological Functions

As odd as it may seem at first glance, minerals, it is what we are all about…or nearly. Although life on Earth is carbon-based, several other elements present in the planet’s crust are involved in and often indispensable for functioning of living organisms. Many ions are essential, and others show supportive and accessory qualities. They are operative in the skin, supporting specific processes related to the particular situation of this organ at the interface with the environment. Skin bioenergetics, redox balance, epidermal barrier function, and dermal remodeling are amongst crucial activities guided by or taking advantage of mineral elements. Skin regenerative processes and skin ageing can be positively impacted by adequate accessibility, distribution, and balance of inorganic ions

Changes in nano-mechanical properties of human epidermal cornified cells depending on their proximity to the skin surface

During formation of the stratum corneum (SC) barrier, terminally differentiated keratinocytes continue their maturation process within the dead superficial epidermal layer. Morphological studies of isolated human corneocytes have revealed differences between cornified envelopes purified from the deep and superficial SC. We used atomic force microscopy to measure the mechanical properties of native human corneocytes harvested by tape-stripping from different SC depths. Various conditions of data acquisition have been tested and optimized, in order to obtain exploitable and reproducible results. Probing at 200 nN allowed us to investigate the total stiffness of the cells (at 50 nm indentation) and that of the cornified envelopes (at 10 to15 nm), and lipid envelopes (at 5 to 10 nm). The obtained data indicated statistically significant differences between the superficial (more rigid) and deep (softer) corneocytes, thus confirming the existence of depth and maturation-related morphological changes within the SC. The proposed approach can be potentially used for minimally invasive evaluation of various skin conditions such as aging, skin hydration, and pathologies linked to SC

Synthesis and biological evaluation of novel heterocyclic derivatives of combretastatin A-4.

International audienceA novel series of combretastatin A-4 heterocyclic analogues was prepared by replacement of the B ring with indole, benzofurane or benzothiophene, attached at the C2 position. These compounds were evaluated for their abilities to inhibit tubulin assembly: derivative cis3b, having a benzothiophene, showed an activity similar to those of colchicine or deoxypodophyllotoxine. The antiproliferative and antimitotic properties of cis3b against keratinocyte cancer cell lines were also evaluated and the intracellular organization of microtubules in the cells after treatment with both stereoisomers of 3b was also determined, using confocal microscopy

Filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis

Loss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status. We sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD. We studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anti-corneodesmosin antibody and visualized with scanning electron microscopy. We found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r = -0.80 and -0.75, P < .001 and P = .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients. NMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrin-deficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutation

Filaggrin breakdown products determine corneocyte conformation in patients with atopic dermatitis

BackgroundLoss-of-function (LOF) mutations in the filaggrin gene (FLG) are a well-replicated risk factor for atopic dermatitis (AD) and are known to cause an epidermal barrier defect. The nature of this barrier defect is not fully understood. Patients with AD with FLG LOF mutations are known to have more persistent disease, more severe disease, and greater risk of food allergies and eczema herpeticum. Abnormalities in corneocyte morphology have been observed in patients with AD, including prominent villus-like projections (VP); however, these ultrastructural features have not been systematically studied in patients with AD in relation to FLG genotype and acute and convalescent status.ObjectiveWe sought to quantitatively explore the relationship between FLG genotype, filaggrin breakdown products (natural moisturizing factor [NMF]), and corneocyte morphology in patients with AD.MethodsWe studied 15 children at first presentation of AD and after 6 weeks of standard therapy. We applied atomic force microscopy to study corneocyte conformation in patients with AD stratified by FLG status and NMF level. By using a new quantitative methodology, the number of VPs per investigated corneocyte area was assessed and expressed as the Dermal Texture Index score. Corneocytes were also labeled with an anti-corneodesmosin antibody and visualized with scanning electron microscopy.ResultsWe found a strong correlation between NMF levels and Dermal Texture Index scores in both acute and convalescent states (respective r = −0.80 and −0.75, P < .001 and P = .002). Most, but not all, VPs showed the presence of corneodesmosin abundantly all over the cell surface in homozygous/compound heterozygous FLG patients and, to a lesser extent, in heterozygous and wild-type patients.ConclusionsNMF levels are highly correlated with corneocyte morphology in patients with AD. These corneocyte conformational changes shed further insight into the filaggrin-deficient phenotype and help explain the barrier defect in patients with AD with FLG LOF mutations