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Focal Dermal Hypoplasia (FDH) is an X-linked dominant disease characterized by dermal thinning and fat herniation, with additional integumentary, ocular, tooth, and skeletal abnormalities. Skin disease flares throughout life and there is no treatment. Mutations in PORCN, which palmitoylates Wnt for ß-catenin signal activation, cause FDH. A mouse model of FDH was previously developed using a lox-cre system but studies were limited to the immediate post-natal period. We aimed to optimize and characterize this mouse model with the express purpose of evaluating its utility to test therapeutics; in-so-doing we tested Li2CO3 as a potential treatment.
Dermal injury repair occurs via fibroblast-mediated scar formation, which is potentiated by mechanical tension. There is a significant heterogeneity in how people scar. It is unknown if this is attributable to differences between fibroblasts, their response to tension, and if there is a role for exosomes in this process. We hypothesize there are distinct differences in fibroblasts’ responses to mechanical tension via exosomes that contribute to scar heterogeneity. Skin and scar paired samples were obtained from women who had c-section scars and underwent abdominoplasty.
Macroautophagy (hereafter autophagy) is a cellular “self-eating” process that is implicated in many physiological and pathological processes. However, the role of autophagy in regulation of skin wound healing is unknown. Here we show that epidermal autophagy deficiency impairs wound repair in mice. Mice with epidermis-specific deletion or the autophagy essential genes Atg5 or Atg7 showed significant decrease in wound healing. Epidermal autophagy deficiency inhibited wound closure, re-epithelialization, dermal granulation tissue formation, and inflammatory immune cell infiltration.
Extracellular matrix plays critical roles in wound repair and tissue regeneration. Laminins are major non-collagenous extracellular components in the basement membrane (BM) of skin dermal-epidermal junction and microvascular blood vessels. In this study we used a porcine burn wound model to explore the expression and functions of laminins and some important dermal matrix proteins and regulators in wound repair. Swine were used for our animal model since their skin is morphologically similar to human skin.
The nuclear envelope protein nesprin-2G is a component of the LINC (linker of nucleoskeleton and cytoskeleton) complex and is responsible for mechanical and signaling crosstalk between the nucleus and cytoskeleton. A published mouse model indicates that nesprin-2G knockout (KO) mice show delayed wound healing. Our goal was to elucidate the mechanism underlying delayed wound closure in this mouse model. To do so, we isolated primary keratinocytes and fibroblasts from wildtype (WT) and KO neonatal mice.
Growth factor therapies for chronic wounds did not achieve expected therapeutic potential. To better understand why, we used laser captured epidermis of diabetic foot ulcers (DFUs) and genomic approach. We identified a set of deregulated miRs, including miR-31-5p and miR-15-5b as the top induced. One of predicted targets of miR-31-5p is KGF/FGF7, stimulator of keratinocyte migration made by fibroblasts. Consistent with epidermal miR-31-5p induction, we found suppression of FGF7 in DFU dermis and fibroblasts.
The interplay between epithelial plasticity and other cellular processes, such as migration and proliferation that are essential for stem cell activity, remains to be elucidated. Cutaneous wound healing entails the collective migration and enhanced proliferation of wound-adjacent epidermal cells. Likewise, regeneration of a new hair follicle during physiological hair cycle involves the activation and proliferation of hair follicle stem cells as they migrate downwards. The molecular mechanisms that ensure collective cell migration and its coordination with cell division are not well-understood.
Wound healing is a dynamic biological process that can be difficult to track objectively. Currently the main methodologies to evaluate wound healing are clinical photo systems or serial histological assessments, which can be subjective and invasive. We propose a novel system combining CellutomeTM and RCM to assess wound healing at the cellular level, particularly evaluating responses to topical therapeutics or in the setting of clinical trials. CelluTome creates uniform subepidermal wounds of 1.8 mm by suctioning the skin.
Wrinkles are characterized by deterioration of the dermal fiber network due to a decreased expression of extracellular matrix proteins and their disorganization. Tenascin-X, a matrix glycoprotein, is known to regulate the structure and stability of elastic fibers and the organization of collagen fibrils in the extra-cellular matrix (ECM), influencing cellular rigidity and elasticity. Therefore, the impact of the modulating tenascin-X expression in the skin is of great interest. To counteract these processes, we have developed a natural Australian plant extract of Anigozanthos Flavidus flower (AF), enabling the regeneration in vitro and in vivo the expression, organization and the functionality of the ECM proteins implicated in the tensor effect on skin aging.
In the clinic, it is generally accepted that wound healing is delayed in aged individuals, however the evidence about the causes of delay are conflicting and incomplete. Older patients are known to have systemic inflammation and exhausted T cell populations, both of which may contribute to impaired wound healing. We hypothesized that splinted, full-thickness cutaneous wounds healed slower in aged (2+ yr old) compared to young (10-12 wk old) Balb/C mice because their immune responses were skewed toward pro-inflammatory cells and increased local and systemic inflammatory mediators.
Wound healing generally leads to scarring in mature skin, but wounds created at early stages of development heal scarlessly. The exact mechanisms leading to scarless healing are not fully understood, but unique characteristics of fetal fibroblasts are believed to be important. Dermal fibroblasts from embryonic day 15 (E15) skin, which heals scarlessly, and embryonic day 18 (E18) skin, which heals with a scar, were compared by proteomics. Fetuin A (Fet A), a protein that has been suggested to be involved in inflammation, was identified as one of the top three differentially expressed proteins.
Chronic wounds are major and rising disease worldwide, which are characterized with excessive and prolonged inflammation. We found that both microRNA-34a-5p (miR-34a) and microRNA-34c-5p (miR-34c) were upregulated in the wound-edge epidermis of venous ulcers (VU), the most common chronic wounds, compared with acute wound or intact skin biopsies from healthy donors. Our study showed that FGF1 promoted miR-34 expression in keratinocytes. In line with this, higher FGF1 expression was detected in VUs compared to acute wounds or intact skin.
The skin is a highly innervated organ but while the sensory role of cutaneous nerves is well characterized there is significant clinical and experimental evidence to suggest that proper innervation is critical for normal skin physiology and regeneration. A major challenge in uncovering the functional interactions between cutaneous nerves and stem cells is the ability to image and manipulate their activity in vivo, in the intact live skin. We developed state-of-the-art imaging tools to visualize the 3-dimensional network of cutaneous nerves in live mouse skin by 2-photon microscopy.
The secretion of cytokine mediators between keratinocytes and T cells plays a major role in the development of chronic skin disease such as psoriasis. Some drugs that inhibit these inflammatory intermediates relatively improve the symptoms associated with psoriasis. To overcome the lack of a physiologically relevant organotypic model and to better understand psoriatic cellular and molecular interactions, we developed a unique reconstructed skin model in which positive CD3 T cells are seeded and interact with the three-dimensional local microenvironment.
The molecular and physiological processes governing wound healing and regeneration have not yet been fully defined. Here we investigate the mechanisms of skin regeneration after injury through a rare event of mammalian regeneration known as Wound Induced Hair Neogenesis (WIHN). We have shown that non-coding dsRNA released by tissue damage stimulates TLR3 and β-catenin to promote WIHN. However, the RNases which either promote or inhibit dsRNA biogenesis remain unresolved. Following injury or exogenous dsRNA (polyI:polyC) treatment, we find significant overlap and upregulation of OAS transcripts (≤15/19,234 transcripts, p=8.3*10-13) in microarray data.
Inflammation plays an important role in cutaneous wounds. Disruption of the normal influx and resolution of inflammatory cells can lead to impaired wound healing in diabetes and other pathological conditions. Tumor necrosis factor stimulated gene-6 (TSG-6) is an enzyme that transfers heavy chains (HC) from inter-a-trypsin inhibitor (IaI) to hyaluronan (HA), forming HC-HA complexes (HC-HA) that are associated with various inflammatory conditions such as arthritis, asthma, and colitis. TSG-6 is thought to play important roles in neutrophil recruitment and macrophage polarization, two events critical to proper wound healing.
The prevalence of inflammatory skin diseases in United States is 11%, suggesting that approximately 1 in 10 people suffer from an inflammatory skin disease. Most drug development for these diseases is conducted using animal models or 2D cell culture systems, which make it difficult to predict patient-specific drug responses. Here, we developed new 3D skin models for psoriasis and vitiligo by combining skin components together with disease-relevant immune cell populations. We isolated T cells from peripheral blood mononuclear cells (PBMCs) of psoriasis patients and incorporated them into healthy control derived 3D skin constructs to reproduce patient-specific psoriatic inflammation.
Cutaneous exposure to alkylating agents such as nitrogen mustard (NM) causes severe blistering with systemic complications long after the exposure. We have previously shown that a single dose of vitamin D (VD) is sufficient to rescue NM-exposed mice from pancytopenia and death and that early intervention with VD is of critical importance. However, the effect of VD on cellular infiltration and local milieu in the skin is unknown. Here we propose that VD promotes skin recovery by preventing dermal infiltration including pro-inflammatory macrophages to maintain a cellular distribution that accelerates skin repair to restore immune equilibrium.
Human skin contains sensory neurons to transduce sensations such as itch. Atopic dermatitis (AD) is an inflammatory skin disease and pruritus is a characteristic symptom of this disorder. AD is driven by interleukins (IL4/13) and there is a link between inflammation and itch, but it is unknown whether the driver cytokines (IL4/13) sensitize the sensory neurons to itch stimuli. Previously, we manipulated the Wnt, TGF-β, BMP4 and Notch signaling pathways to enhance sensory neuronal differentiation of iPSCs and obtained iPSC-derived neurons (iNCs) from different iPSC lines.