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Wound healing is an interactive biological process, involving resident cells as well as distant cells issued from bone barrow. The 3 steps of wound healing, namely inflammation, proliferation and remodeling are finely regulated. Our team has recently shown that a peculiar subpopulation of Microchimeric Fetal Cells (MFCs), transferred from the fetus to the mother during pregnancy, specifically migrated to wounded skin and enhanced skin healing though Ccl2/Ccr2 pathway. Pregnancy is characterized by increased hormonal levels and also a high number of circulating fetal cells.
Keloids represent one extreme of aberrant dermal wound healing and are characterized by fibroblast proliferation, excessive deposition of extracellular matrix and cytokine overexpression. Molecular pathology underlying keloid formation and progression remain unclear. P53 signaling plays a key role in keloid formations. However, the regulatory mechanism for p53 in the keloid pathogenic process remains elusive. Here, we show that expression of TRAF4 was markedly higher in keloid fibroblasts, whereas expression of p53 was decreased.
Over the last 25 years, developments in injectable dermal fillers have revolutionized soft-tissue augmentation, in part due to their lower invasiveness than cosmetic surgeries, but can still be improved upon. Dermal fillers with microspheres (Artefill, Radiesse, Sculptra) can allow new collagen to form, but rely on carriers (bovine collagen and carboxymethylcellulose gel, respectively) that degrade over time generate foreign body reactions. Hyaluronic acid fillers can swell up to three times their size as water diffuses into them and have hydrogel mesh sizes that are sub-micron (Radiesse), making it difficult for new collagen to form within it.
Some chronic wounds fail to heal despite standard therapy. Recently, the armamentarium available to treat chronic wounds has been enriched with the newly discovered functions of beta-blockers (BB). BB are relatively safe and been in use for decades for various indications and therefore represent exciting potential for translation to the bedside. Herein we present clinical outcomes to support existing in vitro evidence for use of BB for wound epithelialization. Three patients were treated with topical timolol maleate 0.5% at a 1 drop/cm2 dose.
Chronic wounds affect over 5 million patients and costing an estimated $20 billion annually, representing a significant burden to patients and the US health care system. Naturally sourced cellular and tissue/growth factor therapies exist to treat chronic wounds but their cost prevents reimbursed use until wounds are chronic, decreasing effectiveness and hindering outcome. Cost-effective, simple treatments are needed that can accelerate healing in acute wounds and prevent development of chronic wounds.
The African spiny mouse (Acomys) can regenerate up to 70% of its skin, including all appendages, after full-thickness skin wounding. This wound-induced hair neogenesis (WIHN) begins from the wound periphery on post-wound day 15 (PWD15), and later in the wound center (PWD21). In contrast, WIHN only occurs in the center of the wound for C57Bl/6 mouse. The spatiotemporal stiffness of the spiny mouse wounds was measured using the atomic force microscopy, which showed a gradual increase from 2.35 kPa (wound center) and 7.87 kPa (wound periphery) on PWD15 to 7.19 kPa and 11.45 kPa on PWD21, respectively.
Epidermolysis bullosa (EB) is a genetic mechanobullous disorder characterized by skin fragility susceptible to blistering with minimal trauma due to malfunction or lack of anchoring proteins within different levels of the basement membrane zone. EB patients often experience chronic wounds due to multiple factors such as prolonged inflammatory phase, infection, nutrition, tissue oxygenation and medications (corticosteroids). BPM315103.0% is a Coenzyme Q10 containing cream that has shown to increase the expression of structural proteins (collagens, plectin, laminins, KRT13, KRT14 and KRT17) in fibroblasts and keratinocytes.
Keloids are pathological scars prone to form in body sites with increased skin tension. Caveolin-1 (CAV1) has been associated with the regulation of cell mechanics, including cell softening and loss of stiffness sensing ability. Although CAV1 is present in low amounts in keloid fibroblasts (KFs), the causal association between CAV1 downregulation and its aberrant responses to mechanical stimuli remain unclear. In this study, atomic force microscopy showed that KFs were softer than normal fibroblasts with a loss of stiffness sensing.
Cysteinyl leukotrienes (CysLTs; LTC4, LTD4, and LTE4) are inflammatory mediators known for their involvement in bronchoconstriction, asthma and allergy, and primarily signal through the receptors CysLT1 and CysLT2. Interestingly, recent studies have found that CysLT receptors are expressed in normal skin, and that CysLT signaling may interfere with wound healing. Furthermore, our preliminary data show that enzymes associated with CysLT synthesis are highly upregulated in burned murine skin compared to healthy skin, while a previous study showed that blister fluids from burn patients contain high LTC4 levels.
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.