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Whether graft rejection occurs by direct or indirect presentation of antigen is still controversial. However, using a mouse ear skin allograft model and a two-photon intravital imaging approach, Susanna Celli and her colleagues have been able to dissect some of the dynamic processes involved in graft rejection, including early- and late-stage events at the transplant site, as well as intermediate events in the draining lymph node. Transplant rejection involves a coordinated attack of the innate and the adaptive immune systems of the host. To investigate this dynamic process and the contributions of both donor and host cells, we developed an ear skin graft model suitable for intravital imaging. We found that donor dermal dendritic cells (DCs) migrated rapidly from the graft and were replaced by host CD11b + mononuclear cells. The infiltrating host cells captured donor antigen, reached the draining lymph node and cross-primed graft-reactive CD8 + T cells. Furthermore, we defined the mechanisms by which host T cells target graft cells. We found that primed T cells entered the graft from the surrounding tissue and localized selectively at the dermis-epidermis junction. Later, CD8 + T cells disseminated throughout the graft and many became arrested. These results provide insights into the antigen presentation pathway and the stepwise progression of CD8 + T cell activity, thereby offering a framework for evaluating how immunotherapy might abrogate the key steps in allograft rejection.

Purpose To gather sub-surface in situ images of microneedle-treated human skin, in vivo, using optical coherence tomography (OCT). This is the first study to utilise OCT to investigate the architectural changes that are induced in skin following microneedle application. Methods Steel, silicon and polymer microneedle devices, with different microneedle arrangements and morphologies, were applied to two anatomical sites in human volunteers following appropriate ethical approval. A state-of-the-art ultrahigh resolution OCT imaging system operating at 800 nm wavelength and <3 µm effective axial resolution was used to visualise the microneedle-treated area during insertion and/or following removal of the device, without any tissue processing. Results Transverse images of a microneedle device, in situ, were captured by the OCT system and suggest that the stratified skin tissue is compressed during microneedle application. Following removal of the device, the created microchannels collapse within the in vivo environment and, therefore, for all studied devices, microconduit dimensions are markedly smaller than the microneedle dimensions. Conclusions Microchannels created in the upper skin layers by microneedles are less invasive than previous histology predicts. OCT has the potential to play a highly influential role in the future development of microneedle devices and other transdermal delivery systems.

MicroRNAs play important roles in animal development. Numerous conditional knockout (cKO) studies of Dicer have been performed to interrogate the functions of microRNA during mammalian development. However, because Dicer was recently implicated in the biogenesis of endogenous siRNAs in mammals, it raises the question whether the Dicer cKO defects can be attributable to the loss of microRNAs. Previously, we and others conditionally targeted Dicer and identified its critical roles in embryonic skin morphogenesis. Here, we focus explicitly on microRNAs by taking a parallel strategy with Dgcr8, encoding an essential component of the microprocessor complex that is exclusively required for microRNA biogenesis. With this comparative analysis, we show definitively that the Dicer- and Dgcr8-null skin defects are both striking and indistinguishable. By deep sequencing analysis of microRNA depletion in both Dicer- and Dgcr8-null skin, we demonstrate that most abundantly expressed skin microRNAs are dependent on both Dicer and DGCR8. Our results underscore a specific importance of microRNAs in controlling mammalian skin development.

Background/Aims: Dry skin, or xerosis, is a common condition and a key feature of skin diseases like atopic dermatitis (AD) and ichthyosis vulgaris. Foot xerosis may exist without underlying disease and could be related to very mild forms of AD or ichthyosis vulgaris. The synthesis of important skin lipids (cholesterol, free fatty acids and ceramides) is reduced in xerosis and AD, and reduced lipid synthesis is responsible for a lack of lipids and enzymes in the skin barrier. This slows down reorganisation of the lipid lamellae in the stratum corneum (SC). Methods: Skin barrier integrity was measured by morphometric analysis of the lipid lamellae in the SC after 4 weeks of treatment with a foam cream (active agent vs. placebo). Results: Significant treatment effects were shown after 2 and 4 weeks by an increasing amount of intercellular lipids in the SC. Conclusion: This study shows that a quick reorganisation of the SC lipids initiates a good restoration of the whole skin barrier after 4 weeks of treatment with a foam cream.

Confocal laser endomicroscopy (pCLE) provides real-time histologic imaging of human tissues at a depth of 60–70 μm during endoscopy. pCLE of the extrahepatic bile duct after fluorescein injection demonstrated a reticular pattern within fluorescein-filled sinuses that had no known anatomical correlate. Freezing biopsy tissue before fixation preserved the anatomy of this structure, demonstrating that it is part of the submucosa and a previously unappreciated fluid-filled interstitial space, draining to lymph nodes and supported by a complex network of thick collagen bundles. These bundles are intermittently lined on one side by fibroblast-like cells that stain with endothelial markers and vimentin, although there is a highly unusual and extensive unlined interface between the matrix proteins of the bundles and the surrounding fluid. We observed similar structures in numerous tissues that are subject to intermittent or rhythmic compression, including the submucosae of the entire gastrointestinal tract and urinary bladder, the dermis, the peri-bronchial and peri-arterial soft tissues, and fascia. These anatomic structures may be important in cancer metastasis, edema, fibrosis, and mechanical functioning of many or all tissues and organs. In sum, we describe the anatomy and histology of a previously unrecognized, though widespread, macroscopic, fluid-filled space within and between tissues, a novel expansion and specification of the concept of the human interstitium.

Stefan Mundlos and colleagues report the identification of mutations in PYCR1 that cause autosomal recessive cutis laxa. PYCR1 encodes an enzyme involved in proline metabolism and localizes to mitochondria. Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation 1 , 2 , 3 . Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1 . We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.

Tear resistance is of vital importance in the various functions of skin, especially protection from predatorial attack. Here, we mechanistically quantify the extreme tear resistance of skin and identify the underlying structural features, which lead to its sophisticated failure mechanisms. We explain why it is virtually impossible to propagate a tear in rabbit skin, chosen as a model material for the dermis of vertebrates. We express the deformation in terms of four mechanisms of collagen fibril activity in skin under tensile loading that virtually eliminate the possibility of tearing in pre-notched samples: fibril straightening, fibril reorientation towards the tensile direction, elastic stretching and interfibrillar sliding, all of which contribute to the redistribution of the stresses at the notch tip. It is known that skin has a large tear resistance, but little is known of the mechanism behind this. Here, the authors carry out a structural analysis of rabbit skin to show how the deformation of collagen fibrils in the skin results in a strong resistance to tear propagation.

Mechanosensation electronics (or Electronic skin, e-skin) consists of mechanically flexible and stretchable sensor networks that can detect and quantify various stimuli to mimic the human somatosensory system, with the sensations of touch, heat/cold, and pain in skin through various sensory receptors and neural pathways. Here we present a skin-inspired highly stretchable and conformable matrix network (SCMN) that successfully expands the e-skin sensing functionality including but not limited to temperature, in-plane strain, humidity, light, magnetic field, pressure, and proximity. The actualized specific expandable sensor units integrated on a structured polyimide network, potentially in three-dimensional (3D) integration scheme, can also fulfill simultaneous multi-stimulus sensing and achieve an adjustable sensing range and large-area expandability. We further construct a personalized intelligent prosthesis and demonstrate its use in real-time spatial pressure mapping and temperature estimation. Looking forward, this SCMN has broader applications in humanoid robotics, new prosthetics, human–machine interfaces, and health-monitoring technologies. Electronic skins have been developed to emulate human sensory systems, but simultaneous detection of multiple stimuli remains a big challenge due to coupling of electronic signals. Here, Hua et al. overcome this problem in a stretchable and conformable matrix network integrated with seven different modes.

Age-related changes in skin mechanics have a major impact on the aesthetic perception of skin. The link between skin microstructure and mechanics is crucial for therapeutic and cosmetic applications as it bridges the micro- and the macro-scale. While our perception is governed by visual and tactile changes at the macroscopic scale, it is the microscopic scale (molecular assemblies, cells) that is targeted by topical treatments including active compounds and energies. We report here a large dataset on freshly excised human skin, and in particular facial skin highly relevant for cosmetics and aesthetic procedures. Detailed layer-by-layer mechanical analysis revealed significant age-dependent decrease in stiffness and elastic recoil of full-thickness skin from two different anatomical areas. In mammary skin, we found that the onset of mechanical degradation was earlier in the superficial papillary layer than in the deeper, reticular dermis. These mechanical data are linked with microstructural alterations observed in the collagen and elastic networks using staining and advanced imaging approaches. Our data suggest that with ageing, the earliest microstructural and mechanical changes occur in the top-most layers of dermis/skin and then propagate deeper, providing an opportunity for preventive topical treatments acting at the level of papillary dermis.

Skin color patterns are ubiquitous in nature, impact social behavior, predator avoidance, and protection from ultraviolet irradiation. A leading model system for vertebrate skin patterning is the zebrafish; its alternating blue stripes and yellow interstripes depend on light-reflecting cells called iridophores. It was suggested that the zebrafish’s color pattern arises from a single type of iridophore migrating differentially to stripes and interstripes. However, here we find that iridophores do not migrate between stripes and interstripes but instead differentiate and proliferate in-place, based on their micro-environment. RNA-sequencing analysis further reveals that stripe and interstripe iridophores have different transcriptomic states, while cryogenic-scanning-electron-microscopy and micro-X-ray diffraction identify different crystal-arrays architectures, indicating that stripe and interstripe iridophores are different cell types. Based on these results, we present an alternative model of skin patterning in zebrafish in which distinct iridophore crystallotypes containing specialized, physiologically responsive, organelles arise in stripe and interstripe by in-situ differentiation. The skin of zebrafish is patterned by alternating blue stripes and yellow interstripes which arises from guanine crystal-containing cells called iridophores that reflect light. Here the authors track iridophores and see that they do not migrate between stripes and interstripes, but instead differentiate and proliferate in place based on their micro-environment.