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Despite decades of skin research, regulation of proliferation and homeostasis in human epidermis is still insufficiently understood. To address the role of mitoses in tissue regulation, we utilized human long-term skin equivalents and systematically assessed mitoses during early epidermal development and long-term epidermal regeneration. We now demonstrate four different orientations: (1) horizontal, i.e., parallel to the basement membrane (BM) and suggestive of symmetric divisions; (2) oblique with an angle of 45°-70°; or (3) perpendicular, suggestive of asymmetric division. In addition, we demonstrate a fourth substantial fraction of suprabasal mitoses, many of which are committed to differentiation (Keratin K10-positive). As verified also for normal human skin, this spatial mitotic organization is part of the regulatory program of human epidermal tissue homeostasis. As a potential marker for asymmetric division, we investigated for Numb and found that it was evenly spread in almost all undifferentiated keratinocytes, but indeed asymmetrically distributed in some mitoses and particularly frequent under differentiation-repressing low-calcium conditions. Numb deletion (stable knockdown by CRISPR/Cas9), however, did not affect proliferation, neither in a three-day follow up study by life cell imaging nor during a 14-day culture period, suggesting that Numb is not essential for the general control of keratinocyte division.
This paper proposes a methodology for plant analysis and identification based on extracting texture features from microscopic images of leaf epidermis. All the experiments were carried out using 32 plant species with 309 epidermal samples captured by an optical microscope coupled to a digital camera. The results of the computational methods using texture features were compared to the conventional approach, where quantitative measurements of stomatal traits (density, length and width) were manually obtained. Epidermis image classification using texture has achieved a success rate of over 96%, while success rate was around 60% for quantitative measurements taken manually. Furthermore, we verified the robustness of our method accounting for natural phenotypic plasticity of stomata, analysing samples from the same species grown in different environments. Texture methods were robust even when considering phenotypic plasticity of stomatal traits with a decrease of 20% in the success rate, as quantitative measurements proved to be fully sensitive with a decrease of 77%. Results from the comparison between the computational approach and the conventional quantitative measurements lead us to discover how computational systems are advantageous and promising in terms of solving problems related to Botany, such as species identification.
The skin is largely comprised of keratinocytes within the interfollicular epidermis. Over approximately two weeks these cells differentiate and traverse the thickness of the skin. The stage of differentiation is therefore reflected in the positions of cells within the tissue, providing a convenient axis along which to study the signaling events that occur in situ during keratinocyte terminal differentiation, over this extended two-week timescale. The canonical ERK-MAPK signaling cascade (Raf-1, MEK-1/2 and ERK-1/2) has been implicated in controlling diverse cellular behaviors, including proliferation and differentiation. While the molecular interactions involved in signal transduction through this cascade have been well characterized in cell culture experiments, our understanding of how this sequence of events unfolds to determine cell fate within a homeostatic tissue environment has not been fully characterized.
Many tissues in our body experience mechanical stresses caused by both internal and external forces. The skin, for example, must tolerate diverse mechanical insults. In this paper, we report a role for β-catenin in providing stability to epithelia under stress. Loss of β-catenin during epidermal development caused perinatal lethality. Mutant embryos up-regulated stress responses at sites of active morphogenesis, which became more widespread after the stresses associated with birth. In addition, selective loss of tight junctions occurred in focal regions. This was recapitulated in cultured β-catenin-null cells exposed to externally applied forces. In addition, mutant cells were defective in tension-induced engagement of adherens junctions. We found that β-catenin was required to recruit vinculin to the cell cortex and to strengthen the junction's association with the underlying cytoskeleton in response to tension. These data demonstrate that a complete understanding of the functions of cell adhesion proteins must take into account their roles in response to mechanical stresses.
Nanoparticles are utilized in a wide range of industries. The most studied silver nanoparticles (AgNPs) are used in medicine and also in several wound dressings due to their antimicrobial properties. The inflammatory response or potential morphological changes of skin cells after their application are not well known yet. In our study we used the model of human reconstructed epidermis (RHE), prepared in our laboratory, to evaluate whether the AgNPs penetrate through RHE, induce some morphological changes of keratinocytes or influence the production of pro-inflammatory cytokines (IL-6 and IL-8). After the application of three different concentrations (25 ppm, 2.5 ppm, 0.25 ppm) of AgNPs to of RHE for 24 hours we verified that AgNPs did not affect the production of pro-inflammatory cytokines (IL-6 and IL-8) and neither did they influence the expression of keratin K14 and loricrin. The morphology of the cells was likewise unchanged. Based on these results we conclude that AgNPs do not have any negative effect on the morphological changes and do not increase the production of pro-inflammatory cytokines.
Maintenance of epidermal thickness is critical to the barrier function of the skin. Decreased tissue thickness, specifically in the stratum corneum (the outermost layer of the tissue), causes discomfort and inflammation, and is related to several severe diseases of the tissue. In order to maintain both stratum corneum thickness and overall tissue thickness it is necessary for the system to balance cell proliferation and cell loss. Cell proliferation in the epidermis occurs in the basal layer and causes constant upwards movement in the tissue. Cell loss occurs when dead cells at the top of the tissue are lost to the environment through a process called desquamation. Desquamation is thought to occur through a gradual reduction in adhesion between cells, due to the cleaving of adhesion proteins by enzymes, in the stratum corneum. In this paper we will investigate combining a (mass action) subcellular model of desquamation with a three dimensional (cell centre based) multicellular model of the interfollicular epidermis to better understand maintenance of epidermal thickness. Specifically, our aim is to determine if a hypothesised biological model for the degradation of cell-cell adhesion, from the literature, is sufficient to maintain a steady state tissue thickness. These investigations show the model is able to provide a consistent rate of cell loss in the multicellular model. This loss balances proliferation, and hence maintains a homeostatic tissue thickness. Moreover, we find that multiple proliferative cell populations in the basal layer can be represented by a single proliferative cell population, simplifying investigations with this model. The model is used to investigate a disorder (Netherton Syndrome) which disrupts desquamation. The model shows how biochemical changes can cause disruptions to the tissue, resulting in a reduced tissue thickness and consequently diminishing the protective role of the tissue. A hypothetical treatment result is also investigated: we compare the cases of a partially effective homogeneous treatment (where all cells partially recover) and a totally effective heterogeneous treatment (in which a proportion of the cells totally recover) with the aim to determine the difference in the response of the tissue to these different scenarios. Results show an increased benefit to corneum thickness from the heterogeneous treatment over the homogeneous treatment.
Mechanical forces have emerged as coordinating signals for most cell functions. Yet, because forces are invisible, mapping tensile stress patterns in tissues remains a major challenge in all kingdoms. Here we take advantage of the adhesion defects in the Arabidopsis mutant quasimodo1 (qua1) to deduce stress patterns in tissues. By reducing the water potential and epidermal tension in planta, we rescued the adhesion defects in qua1, formally associating gaping and tensile stress patterns in the mutant. Using suboptimal water potential conditions, we revealed the relative contributions of shape- and growth-derived stress in prescribing maximal tension directions in aerial tissues. Consistently, the tension patterns deduced from the gaping patterns in qua1 matched the pattern of cortical microtubules, which are thought to align with maximal tension, in wild-type organs. Conversely, loss of epidermis continuity in the qua1 mutant hampered supracellular microtubule alignments, revealing that coordination through tensile stress requires cell-cell adhesion.
Previous evidence suggested the presence of two distinct desmocollin isoforms in human epidermis. These isoforms have now been distinguished at the protein level using monoclonal and polyclonal antibodies against N-terminal fragments of desmosomal glycoprotein (DG) IV/V isolated from plantar callus and antibodies against a fusion protein containing the extracellular domain of DGII/III. Immune blotting of glycoprotein fractions from whole epidermis, plantar callus, psoriatic scales and cultured keratinocytes showed that intact DGIV/V and its proteolytic fragments consistently migrated faster than DGII/III during SDS-PAGE. The apparent Mr difference between the two isoforms was in the range 2-5 kD. DGIV/V was the predominant species in epidermal tissue but was much less prominent in cultured cells by immune-blotting and immune precipitation. This is consistent with the differentiation-related expression of desmocollins revealed by immunofluorescence. DGIV/V was strongly expressed in the upper spinous/granular layer of the epidermis whereas DGII/III was more prominent in the basal layers of the tissue. The DGIV/V monoclonal (LH50) recognized an N-terminal, Ca(++)-sensitive epitope, because its staining of unfixed epidermal tissue was markedly influenced by Ca++ levels. Ca++ inhibition was observed at concentrations as low as 50 microM, suggesting its possible physiologic significance. Ca++ inhibition of LH50 binding was also observed in an enzyme-linked immunosorbent assay system using denatured glycoproteins although higher concentrations were required. It remains to be seen whether direct effects of Ca++ on desmocollin conformation are involved in the regulation of keratinization by extracellular Ca++.
Background: E-cadherin is the major adhesion receptor in epithelial adherens junctions (AJs). On established epidermis, E-cadherin performs fine-tuned cell-cell contact remodeling to maintain tissue integrity, which is characterized by modulation of cell shape, size and packing density. In zebrafish, the organization and distribution of E-cadherin in AJs during embryonic epidermis development remain scarcely described. Methods: Combining classical immunofluorescence, deconvolution microscopy and 3D-segmentation of AJs in epithelial cells, a quantitative approach was implemented to assess the spatial and temporal distribution of E-cadherin across zebrafish epidermis between 24 and 72 hpf. Results: increasing levels of E-cadh protein parallel higher cell density and the appearance of hexagonal cells in the enveloping layer (EVL) as well as the establishments of new cell-cell contacts in the epidermal basal layer (EBL), being significantly between 31 and 48 hpf .Conclusions: Increasing levels of E-cadherin in AJs correlates with extensive changes in cell morphology towards hexagonal packing during the epidermis morphogenesis.
Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
Recent advances in sequencing technologies have enabled metagenomic analyses of many human body sites. Several studies have catalogued the composition of bacterial communities of the surface of human skin, mostly under static conditions in healthy volunteers. Skin injury will disturb the cutaneous homeostasis of the host tissue and its commensal microbiota, but the dynamics of this process have not been studied before. Here we analyzed the microbiota of the surface layer and the deeper layers of the stratum corneum of normal skin, and we investigated the dynamics of recolonization of skin microbiota following skin barrier disruption by tape stripping as a model of superficial injury.
Tissue homeostasis requires a balance between progenitor cell proliferation and loss. Mechanisms that maintain this robust balance are needed to avoid tissue loss or overgrowth. Here we demonstrate that regulation of spindle orientation/asymmetric cell divisions is one mechanism that is used to buffer changes in proliferation and tissue turnover in mammalian skin. Genetic and pharmacologic experiments demonstrate that asymmetric cell divisions were increased in hyperproliferative conditions and decreased under hypoproliferative conditions. Further, active K-Ras also increased the frequency of asymmetric cell divisions. Disruption of spindle orientation in combination with constitutively active K-Ras resulted in massive tissue overgrowth. Together, these data highlight the essential roles of spindle orientation in buffering tissue homeostasis in response to perturbations.
Chemerin is a protein ligand for the G protein-coupled receptor CMKLR1 and also binds to two atypical heptahelical receptors, CCRL2 and GPR1. Chemerin is a leukocyte attractant, adipokine, and antimicrobial protein. Although chemerin was initially identified as a highly expressed gene in healthy skin keratinocytes that was downregulated during psoriasis, the regulation of chemerin and its receptors in the skin by specific cytokines and microbial factors remains unexplored. Here we show that chemerin, CMKLR1, CCRL2 and GPR1 are expressed in human and mouse epidermis, suggesting that this tissue may be both a source and target for chemerin mediated effects. In human skin cultures, chemerin is significantly downregulated by IL-17 and IL-22, key cytokines implicated in psoriasis, whereas it is upregulated by acute phase cytokines oncostatin M and IL-1β. Moreover, we show that human keratinocytes in vitro and mouse skin in vivo respond to specific microbial signals to regulate expression levels of chemerin and its receptors. Furthermore, in a cutaneous infection model, chemerin is required for maximal bactericidal effects in vivo. Together, our findings reveal previously uncharacterized regulators of chemerin expression in skin and identify a physiologic role for chemerin in skin barrier defense against microbial pathogens.
During embryonic and postnatal development, organs and tissues grow steadily to achieve their final size at the end of puberty. However, little is known about the cellular dynamics that mediate postnatal growth. By combining in vivo clonal lineage tracing, proliferation kinetics, single-cell transcriptomics, and in vitro micro-pattern experiments, we resolved the cellular dynamics taking place during postnatal skin epidermis expansion. Our data revealed that harmonious growth is engineered by a single population of developmental progenitors presenting a fixed fate imbalance of self-renewing divisions with an ever-decreasing proliferation rate. Single-cell RNA sequencing revealed that epidermal developmental progenitors form a more uniform population compared with adult stem and progenitor cells. Finally, we found that the spatial pattern of cell division orientation is dictated locally by the underlying collagen fiber orientation. Our results uncover a simple design principle of organ growth where progenitors and differentiated cells expand in harmony with their surrounding tissues.
Epithelial folding is a fundamental morphogenetic process that shapes planar epithelial sheets into complex three-dimensional structures. Multiple mechanisms can generate epithelial folds, including apical constriction, which acts locally at the cellular level, differential growth on the tissue scale, or buckling because of compression from neighboring tissues. Here, we investigate the formation of dorsally located epithelial folds at segment boundaries during the late stages of Drosophila embryogenesis. We found that the fold formation at the segment boundaries occurs through the juxtaposition of two key morphogenetic processes: local apical constriction and tissue-level compressive forces from posterior segments. Further, we found that epidermal spreading and fold formation are accompanied by spatiotemporal pulses of Hedgehog (Hh) signaling. A computational model that incorporates the local forces generated from the differential tensions of the apical, basal, and lateral sides of the cell and active forces generated within the whole tissue recapitulates the overall fold formation process in wild-type and Hh overexpression conditions. In sum, this work demonstrates how epithelial folding depends on multiple, separable physical mechanisms to generate the final morphology of the dorsal epidermis. This work illustrates the modularity of morphogenetic unit operations that occur during epithelial morphogenesis.
DNA methylation is a fundamental epigenetic modification, important across biological processes. The maintenance methyltransferase DNMT1 is essential for lineage differentiation during development, but its functions in tissue homeostasis are incompletely understood. We show that epidermis-specific DNMT1 deletion severely disrupts epidermal structure and homeostasis, initiating a massive innate immune response and infiltration of immune cells. Mechanistically, DNA hypomethylation in keratinocytes triggered transposon derepression, mitotic defects, and formation of micronuclei. DNA release into the cytosol of DNMT1-deficient keratinocytes activated signaling through cGAS and STING, thus triggering inflammation. Our findings show that disruption of a key epigenetic mark directly impacts immune and tissue homeostasis, and potentially impacts our understanding of autoinflammatory diseases and cancer immunotherapy.
Aged and photoaged skin exhibit fine wrinkles that are signs of epidermal inflammation and degeneration. It has been shown that healthy elderly skin expresses amyloidogenic proteins, including α-Synuclein, which are known to oligomerize and trigger inflammation and neurodegeneration. However, little is known about their putative role in skin physiology and sensitivity. To unravel this possible role, we investigated the impact of oligomeric α-Synuclein (Oα-Syn) in 2D and 3D keratinocyte human models. Exogenous Oα-Syn caused degeneration of reconstructed human epidermis (RHE) by diminishing proliferation and thickness of the stratum basale. Oα-Syn also increased NF-kB nuclear translocation in keratinocytes and triggered inflammation in the RHE, by increasing expression of interleukin-1β and tumor necrosis factor-alpha, and the release of tumor necrosis factor-alpha in a time-dependent manner. Dexamethasone and an IL-1β inhibitor partially diminished RHE degeneration caused by Oα-Syn. These findings suggest that Oα-Syn induces epidermal inflammation and decreases keratinocyte proliferation, and therefore might contribute to epidermal degeneration observed in human skin aging.
Deep sequencing can detect somatic DNA mutations in tissues permitting inference of clonal relationships. This has been applied to human epidermis, where sun exposure leads to the accumulation of mutations and an increased risk of skin cancer. However, previous studies have yielded conflicting conclusions about the relative importance of positive selection and neutral drift in clonal evolution. Here, we sequenced larger areas of skin than previously, focusing on cancer-prone skin spanning five decades of life. The mutant clones identified were too large to be accounted for solely by neutral drift. Rather, using mathematical modelling and computational lattice-based simulations, we show that observed clone size distributions can be explained by a combination of neutral drift and stochastic nucleation of mutations at the boundary of expanding mutant clones that have a competitive advantage. These findings demonstrate that spatial context and cell competition cooperate to determine the fate of a mutant stem cell.
Intercellular movement of transcription factor proteins is essential for plant development. The R3 type MYB transcription factor protein, CAPRICE (CPC), moves from non-hair cells to root-hair cells where it promotes root hair formation in Arabidopsis root epidermis. In contrast, the CPC homolog of ENHANCER OF TRY AND CPC1 (ETC1) cannot move in root epidermal cells. In this work, we present protein localization data of CPC-ETC1 chimeric proteins. Localization of CPC-ETC1-GFP fusion proteins of chimera1 and chimera2 transgenic plants was observed using confocal laser scanning microscope. Insertion of ETC1-specific amino acids into CPC somewhat prevents normal protein localization of CPC in root epidermal cells. Cell-to-cell movement of chimera1 and chimera2 proteins from non-hair cells to root-hair cells was interfered. Nuclear localization was also inhibited, especially in chimera1.
Progenitor cells must balance self-amplification and production of differentiated progeny during development and homeostasis. In the epidermis, progenitors divide symmetrically to increase surface area and asymmetrically to promote stratification. In this study, we show that individual epidermal cells can undergo both types of division, and therefore, the balance is provided by the sum of individual cells' choices. In addition, we define two control points for determining a cell's mode of division. First is the expression of the mouse Inscuteable gene, which is sufficient to drive asymmetric cell division (ACD). However, there is robust control of division orientation as excessive ACDs are prevented by a change in the localization of NuMA, an effector of spindle orientation. Finally, we show that p63, a transcriptional regulator of stratification, does not control either of these processes. These data have uncovered two important regulatory points controlling ACD in the epidermis and allow a framework for analysis of how external cues control this important choice.
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