Journal Of Investigative Dermatology

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591 A New 3D Skin Model Containing Autologous Immune Cells Reconstructed by Tissue Engineering

Sun, 2019-09-01 00:00
The majority of current in vitro skin models lack an inflammatory system, vasculature, and other characteristics of native skin, making them less relevant for the study of biological or pathological processes related to the human skin. To fill this gap, we developed a skin model containing immune and endothelial cells. Skin biopsies were enzymatically treated to isolate epidermal and dermal cells. Following isolation, the epidermal fraction contained keratinocytes, melanocytes, lymphocytes T and Langerhans cells while the dermal fraction contained fibroblasts, endothelial cells and immune cells (macrophages, lymphocytes, dendritic cells).

590 Morphological and functional analysis on M3R mediated sweating in TSC1 k/o mouse

Sun, 2019-09-01 00:00
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with hyperactivation of mTOR signaling pathway. Previously, we have reported that GSK3β signaling was involved in sweating (Matsui S et al J Invest Dermatol 2014). More recent report suggested that hyperactivation of mTOR signaling pathway also downregulates melanin synthesis through alteration of GSK3β signaling However, that whether mTOR, the upstream of GSK3β, was also involved in sweating, is still unknown. To investigate whether the sweating function was impaired in TSC patients, and to further elucidate whether m-TOR was responsible for sweating dysfunction.

589 Loss of GATA6 contributes to acne pathogenesis in human skin

Sun, 2019-09-01 00:00
Although acne vulgaris is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the epidermal infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation.

588 Skin fibroblast heterogeneity and plasticity are determined by the local niche

Sun, 2019-09-01 00:00
Mouse dermal fibroblasts arise from two distinct fibroblast lineages with unique functions in skin development, homeostasis, regeneration and fibrosis. Fibroblasts of the two lineages display differential expression of Wnt/β-catenin, Hedgehog and TGFβ pathway and ECM components and respond to different signals derived from neoplastic epidermal cells. Intriguingly, fibroblast subset abundance and distribution as well as their expression profile change as mice age and during the hair cycle, indicating a high plasticity within the dermal mesenchyme.

587 The dual role of stem cell-specific Bcl-2 function for epidermal regeneration and cancer

Sun, 2019-09-01 00:00
Self-renewing tissues like the mammalian epidermis and its appendages go through cycles of proliferation, terminal differentiation and apoptosis. To maintain tissue integrity and stem cell (SC) function, these diverse processes need to sustain constant environmental assaults. In the mammalian epidermis, multiple SC compartments have been identified, including SCs in the hair follicle (HF) bulge. Bulge SCs are the primary cellular source for HF renewal. Previous work has shown that bulge SCs are equipped with specific surveillance mechanisms protecting them against accumulation of DNA damage and cell loss.

586 New concept of cytokine balance in alopecia areata with atopic dermatitis

Sun, 2019-09-01 00:00
Alopecia areata (AA) is regarded as an organ-specific and cell-mediated autoimmune disorder. In cytokine balance of AA, several reports have suggested AA as Th1 disease. For example, Murine IFN-γ-injected C3H/HeJ mice showed AA like hair loss with infiltration of CD4+and CD8+T cells Th1 cytokine. In human, IFN-γ-producing cells were detected in the perifollicular infiltrate, and serum Th1 cytokines were increased in AA patients. On the other hand, AA often complicates atopic dermatitis (AD). However, the immunological aspects of AA with AD are still poorly understood.

585 Identifying cancer stem cells in patient specimens through high-content imaging - biological insights and prognostic potential

Sun, 2019-09-01 00:00
Cancer stem cells undergo epithelial-to-mesenchymal transition (EMT) to acquire a migratory phenotype, break away from the primary tumour body and invade into the stroma. They then undergo the reverse process of mesenchymal-to-epithelial transition (MET) at a distant site to form a metastatic tumour. Our group has identified a subpopulation of oral cancer stem cells that possess a hybrid EMT/MET phenotype characterised by vimentin (VIM), Epcam (ESA) and CD24 expression. These hybrid cancer stem cells are associated with aggressive invasion, chemotherapeutic resistance and metastatic potential in in vitro assays.

584 Footprint-free gene mutation correction in induced pluripotent stem cell (iPSC) derived from recessive dystrophic epidermolysis bullosa (RDEB) using CRISPR/Cas9 and piggyBac transposon system

Sun, 2019-09-01 00:00
Recessive dystrophic epidermolysis bullosa is a monogenic skin blistering disorder caused by the mutations in the type VII collagen (COL7A1) gene. Combination of biological technologies, including induced pluripotent stem cells (iPSCs) and several gene-editing tools, allows us to realize gene and cell therapies for such inherited diseases. However, the methodology of gene and cell therapies must be consistently innovated for safety clinical use. In this study, we used CRISPR/Cas9 technology to correct the pathogenic mutation in RDEB-specific iPSCs, and piggyBac transposon system not to remain any residual gene fragments in the genome of iPSCs after correcting the mutation.

583 Selective epidermal removal is a robust platform for understanding context-dependent epithelial cell activation

Sun, 2019-09-01 00:00
The epidermis is a stratified epithelium whose homeostasis is coordinated by stem cell self-renewal, cell proliferation and cell differentiation. The epidermis is attached to its covering dermis by basement membrane zone proteins. The inherited dysfunction of those proteins (as seen in epidermolysis bullosa) or autoimmune reactions to those proteins (as seen in pemphigoid diseases) typically results in skin in which even gentle mechanical forces produce blisters at the basement membrane zone. However, the healing processes of subepidermal blisters have not been fully characterized.

582 Differentiation of human skin-derived precursors (SKPs) into functional sensory neurons

Sun, 2019-09-01 00:00
Skin-derived precursor cells (SKPs) have been shown as a population of stem cells that express some markers common to the neural crest stem cells (NCSCs) as progenitor neural nestin, the low affinity neurotrophin receptor p75 and transcription factors as Sox9 and 10 and Pax3, Slug, Snail. SKPs are NCSCs that persist in certain adult tissues, particularly in the skin, which can generate a large part of the peripheral nervous system, particularly sensory neurons (SN). In this study, we reported a protocol to obtain SNs from SKPs.

581 A genome-wide screen identifies YAP/WBP2/TEAD interplay conferring growth advantage on human epidermal stem cells

Sun, 2019-09-01 00:00
Tissue-resident stem cells (SCs) have the capacity to generate self-assembling organ-like structures, a property that was first demonstrated in cultures of primary human epidermal cells (keratinocytes). There is however marked heterogeneity in the proliferative potential of individual human keratinocytes. To uncover the molecular mechanisms underlying this heterogeneity, we performed genome-wide pooled RNAi screens in normal human keratinocytes (NHKs) and cutaneous squamous cell carcinoma (cSCC) cells.

580 Spontaneous replication stress in Hair Follicle Stem Cells leads to inflammation in Hidradenitis Suppurativa

Sun, 2019-09-01 00:00
Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease. HS appears to be a primary abnormality in the pilosebaceous-apocrine unit. We characterized hair follicle stem cells (HF-SC) isolated from HS patients and more precisely the Outer Root Sheath Cells (ORS). We previously showed that ORS isolated from HS patients (HS-ORS) secrete spontaneously IP-10 and RANTES. In this study, we aim to characterize the molecular mechanisms involved in the pro-inflammatory phenotype of HS-ORS.

579 Single cell transcriptome and epigenome analyses in a murine model of dystrophic epidermolysis bullosa

Sun, 2019-09-01 00:00
Recessive Dystrophic epidermolysis bullosa (RDEB) is a skin genetic disease caused by mutations in COL7A1 (coding type VII collagen). Type VII collagen is essential to maintain the fully functional dermal-epidermal junction, and the loss of type VII collagen results in detachment of epidermis. RDEB patients, without functional type VII collagen, suffer from the repetitive blistering and have high risk of early-onset aggressive squamous cell carcinoma. Currently, no fundamental treatment is available for RDEB.

578 Immunometabolic imbalance fosters skin ageing

Sun, 2019-09-01 00:00
The skin is a complex organ that contains a plethora of cell types and annexed structures, including hair follicles. Altogether they conduct essential functions, such as temperature control, tissue sensing, barrier maintenance and immune defense. Our study is focused on the role of immunometabolism in age-associated skin processes and how controlling T cell metabolism can contribute to regulate skin homeostasis, hair growth and tissue regeneration. To address this aim, we have used a mouse model lacking the mitochondrial transcription factor A (Tfam) in CD4-expressing cells (Tfamfl/fl CD4Cre mice).

577 The atypical kinase C regulates epidermal adhesive junctions and the cytoskeleton essential for epidermal stratification

Sun, 2019-09-01 00:00
The atypical kinase C (aPKC) is a central coordinator of cell polarity. Previously, our laboratory has identified a key role for the mammalian aPKCl in balancing epidermal stem cell renewal and differentiation. Loss of aPKCl in the epidermis resulted in a loss of stem cells and increased differentiation, as well as cell shape changes, ultimately resulting in premature skin aging. To address the underlying mechanisms by which aPKC control cell shape and cell fate alterations we combined knockout primary cells, multi-layered proteomics and bioinformatics.

576 The role of hepatocyte growth factor in human hair follicle – dermal white adipose tissue communication

Sun, 2019-09-01 00:00
Although human dermal white adipose tissue (DWAT) envelopes scalp hair follicles (HFs), their underlying bidirectional communication remains unexplored. Recently, we determined that culturing human HFs with surrounding DWAT promoted hair growth and pigmentation ex vivo. The current study aimed to further expand knowledge of the human DWAT-HF axis. Intriguingly, proteomic analysis identified hepatocyte growth factor (HGF) as the most abundantly-secreted DWAT product within long-term HF+DWAT ex vivo cultures.

575 Characterization of aged dermal stem cell phenotype: implications for skin homeostasis

Sun, 2019-09-01 00:00
Functional decline of aged organisms is associated to tissue-specific stem cell impairment, which leads to homeostasis alterations. Dermal stem cells (DSC) lose regenerative capacity with age. The DSC pool includes Schwann cell precursors and perivascular cells, their stemness being mediated by Sox2 expression levels. We hypothesized that DSC activity may decrease during the skin ageing process as a consequence of Sox2+ cell population impairment. To test this hypothesis, we characterized in vitro and in vivo the DSC niches in young (2 month) vs aged (>18 month) C57BL/6 and Sox2EGFP mice (heterozygous for Sox2).

574 Murine sebaceous gland homeostasis requires intact cutaneous innervation in a hair cycle-dependent context

Sun, 2019-09-01 00:00
The existence of neurobiological controls of sebaceous gland (SG) biology is indicated by clinical observations, such as reduced sebum secretion observed in botulinum toxin-treated skin and following nerve injury. We have examined whether murine SGs are functionally dependent on nervous system inputs, by using a method for cutaneous surgical denervation. In parallel, we have examined the neuroanatomy surrounding mouse SGs, using transmission electron microscopy and immunofluorescent staining for neuronal and synaptic markers.

573 Hair follicles employ a 2-dimensional healing strategy to repair 3-dimensional injuries

Sun, 2019-09-01 00:00
Epithelial organs vary from 2-dimensional sheets to 3-dimensional folded architectures. While wounds in 2-dimensional sheets are healed through collective movement along the basement membrane (BM), how injuries in 3-dimensional architecture are repaired remains elusive. Using post-radiation anagen hair follicle repair (AHFR), we studied this process through multiphoton intravital imaging. Before radiation, the growth of hair follicles (HFs) is primarily supported by proliferative germinative/matrix cells surrounding dermal papilla at the base.

572 Epidermal stem cell competition orchestrates skin organ homeostasis and aging

Sun, 2019-09-01 00:00
Stem cell systems underlie homeostatic tissue maintenance, yet the involvement of cell competition in organ maintenance and aging are largely unknown. Here we report that the expression of Collagen XVII (COL17A1), a hemidesmosome component, by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis and the resulting differential expression of COL17A1 in individual stem cells promotes cell-cell competition. In vivo clonal analysis in mice and in vitro 3D modeling revealed that COL17A1+ clones, which divide symmetrically, outcompete adjacent COL17A1low/- stressed clones, which divide asymmetrically to select stem cells with higher potential and quality for youthfulness.

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