Dose-dependent reduction of somatic expansions but not Htt aggregates by di-valent siRNA-mediated silencing of MSH3 in HdhQ111 mice.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline CAG expansions, somatic repeat expansions in neurons also contribute to HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as a genetic modifier of HD onset and progression, promotes somatic CAG expansions, and thus presents a potential therapeutic target.

A MicroRNA-29 Mimic (Remlarsen) Represses Extracellular Matrix Expression and Fibroplasia in the Skin.

MicroRNA-29 (miR-29) negatively regulates fibrosis and is downregulated in multiple fibrotic organs and tissues, including in the skin. miR-29 mimics prevent pulmonary fibrosis in mouse models but have not previously been tested in the skin. This study aimed to identify pharmacodynamic biomarkers of miR-29 in mouse skin, to translate those biomarkers across multiple species, and to assess the pharmacodynamic activity of a miR-29b mimic (remlarsen) in a clinical trial.

A synthetic microRNA-92a inhibitor (MRG-110) accelerates angiogenesis and wound healing in diabetic and nondiabetic wounds.

There is a strong unmet need for new therapeutics to accelerate wound healing across both chronic and acute indications. It is well established that local tissue hypoxia, vascular insufficiency, and/or insufficient angiogenesis contribute to inadequate wound repair in the context of diabetic foot ulcers as well as to other chronic wounds such as venous stasis and pressure ulcers. microRNA-92a-3p (miR-92a) is a potent antiangiogenic miRNA whose inhibition has led to increases in angiogenesis in multiple organ systems, resulting in an improvement in function following myocardial infarction, limb ischemia, vascular injury, and bone fracture.

Connexin 43 regulates the expression of wound healing-related genes in human gingival and skin fibroblasts.

Fibroblasts are the most abundant connective tissue cells and play an important role in wound healing. It is possible that faster and scarless wound healing in oral mucosal gingiva relative to skin may relate to the distinct phenotype of the fibroblasts residing in these tissues. Connexin 43 (Cx43) is the most ubiquitous Cx in skin (SFBLs) and gingival fibroblasts (GFBLs), and assembles into hemichannels (HCs) and gap junctions (GJs) on the cell membrane.

Elevated CD26 Expression by Skin Fibroblasts Distinguishes a Profibrotic Phenotype Involved in Scar Formation Compared to Gingival Fibroblasts.

Compared to skin, wound healing in oral mucosa is faster and produces less scarring, but the mechanisms involved are incompletely understood. Studies in mice have linked high expression of CD26 to a profibrotic fibroblast phenotype, but this has not been tested in models more relevant for humans. We hypothesized that CD26 is highly expressed by human skin fibroblasts (SFBLs), and this associates with a profibrotic phenotype distinct from gingival fibroblasts (GFBLs).

Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing.

Transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in all aspects of wound healing. TGF-β accelerates wound healing, but an excess of its presence at the wound site has been implicated in pathological scar formation. Our group has recently identified CD109, a glycophosphatidylinositol-anchored protein, as a novel TGF-β coreceptor and inhibitor of TGF-β signaling in vitro.

ΔNp63α utilizes multiple mechanisms to repress transcription in squamous cell carcinoma cells.

ΔNp63α is a potent oncogene in squamous cell carcinomas (SCCs) and a pro-proliferative factor expressed by basal epithelial cells. ΔNp63α functions both as a transcriptional repressor and activator, but it is not clear how these activities contribute to its oncogenic potential. ΔNp63α was proposed to function as a dominant negative of the related factor p53.

ΔNp63α represses anti-proliferative genes via H2A.Z deposition.

ΔNp63α is a member of the p53 family of transcription factors that functions as an oncogene in squamous cell carcinomas (SCCs). Because ΔNp63α and p53 bind virtually identical DNA sequence motifs, it has been proposed that ΔNp63α functions as a dominant-negative inhibitor of p53 to promote proliferation and block apoptosis. However, most SCCs concurrently overexpress ΔNp63α and inactivate p53, suggesting the autonomous action of these oncogenic events.

The p53 circuit board.

The p53 tumor suppressor is embedded in a large gene network controlling diverse cellular and organismal phenotypes. Multiple signaling pathways converge onto p53 activation, mostly by relieving the inhibitory effects of its repressors, MDM2 and MDM4. In turn, signals originating from increased p53 activity diverge into distinct effector pathways to deliver a specific cellular response to the activating stimuli.

Exploring scarless healing of oral soft tissues.

Our research group is comparing clinical, histological and molecular healing profiles of oral and skin wounds using human and pig models. The goal is to determine the molecular cues that lead to scarless healing in the oral mucosa and use that information to develop scar prevention therapies for skin and prevent aberrant wound healing in the oral cavity. Wound healing in human and pig palatal mucosa is almost identical, and scar formation is reduced in oral wounds compared with skin.

Epithelial regulation of mesenchymal tissue behavior.

Fibroproliferative scars are an important clinical problem, and yet the mechanisms that regulate scar formation remain poorly understood. This study explored the hypothesis that the epithelium has a critical role in dictating scar formation, and that these interactions differ in skin and mucosa. Paired skin and vaginal mucosal wounds on New Zealand white (NZW) rabbits diverged significantly; the cutaneous epithelium exhibited a greater and prolonged response to injury when compared with the mucosa.

Occlusion regulates epidermal cytokine production and inhibits scar formation.

Hypertrophic scars are a major clinical problem, yet there are few therapeutics available to prevent or treat scar formation. One of the oldest known and most effective treatments is occlusion with silicone gel. However, little is known about its mode of action.

Scarless healing of oral mucosa is characterized by faster resolution of inflammation and control of myofibroblast action compared to skin wounds in the red Duroc pig model.

Background: Scar formation following skin trauma can have devastating consequences causing physiological and psychosocial concerns. Currently, there are no accepted predictable treatments to prevent scarring which emphasizes a need for a better understanding of the wound healing and scar formation process.

Objectives: Previously it was shown that healing of small experimental wounds in the oral mucosa of red Duroc pigs results in significantly reduced scar formation as compared with equivalent full-thickness skin wounds.

Wound healing in oral mucosa results in reduced scar formation as compared with skin: evidence from the red Duroc pig model and humans.

Scar formation is a common, unwanted result of wound healing in skin, but the mechanisms that regulate it are still largely unknown. Interestingly, wound healing in the oral mucosa proceeds faster than in skin and clinical observations have suggested that mucosal wounds rarely scar. To test this concept, we created identical experimental wounds in the oral mucosa and skin in red Duroc pigs and compared wound healing and scar development over time.

Biomechanical behavior of scar tissue and uninjured skin in a porcine model.

A new method to test axial and transverse tensile properties of skin was developed to improve our understanding of skin mechanical behavior, and how it changes following injury and formation of a scar. Skin tissue was evaluated at 70 days following full-thickness wounding in juvenile female pigs (N=14). Samples were taken in the axial (cranial-caudal) and transverse (dorsal-ventral) directions, for both scar tissue and uninjured skin, and were evaluated mechanically in vitro using a protocol of stress relaxation followed by tensile failure.

Expression of integrin alphavbeta6 and TGF-beta in scarless vs scar-forming wound healing.

Oral mucosal wounds heal with reduced scar formation compared with skin. The epithelial integrin alphavbeta6 is induced during wound healing, and it can activate fibrogenic transforming growth factor beta1 (TGF-beta1) and anti-fibrogenic TGF-beta3 that play key roles in scar formation. In this study, expression of beta6 integrin and members of the TGF-beta pathway were studied in experimental wounds of human gingiva and both gingiva and skin of red Duroc pigs using real-time PCR, gene microarrays, and immunostaining.

The mast cell stabilizer ketotifen prevents development of excessive skin wound contraction and fibrosis in red Duroc pigs.

Skin wound healing in Yorkshire pigs closely approximates human wound healing. Conversely, red Duroc pigs form fibroproliferative, hypercontractile scars. As mast cells have been implicated in several fibrotic conditions, the present study used these models to evaluate the potential role of mast cells in wound contraction and fibrosis.

Dermal fibroblasts from red Duroc and Yorkshire pigs exhibit intrinsic differences in the contraction of collagen gels.

Previous studies have shown that the Yorkshire (Y) pig is a model for normal skin wound healing, while red Duroc (RD) pigs form hypercontracted scars similar to human hypertrophic scars. In order to determine potential intrinsic differences in fibroblast phenotypes, the ability of normal dorsal and ventral dermal fibroblasts from Y and RD pigs to contract collagen gels was assessed. Cells plated in gels were cultured in media supplemented with 2% or 10% FBS +/- 1 or 10 ng/mL transforming growth factor beta1.

Genetic involvement in skin wound healing and scarring in domestic pigs: assessment of molecular expression patterns in (Yorkshire x Red Duroc) x Yorkshire backcross animals.

Yorkshire, red Duroc, and F1 (first-generation cross) pigs heal with normal, fibroproliferative/hypercontractile, and intermediate levels of scarring, respectively. The purpose of this study was to evaluate the healing phenotype of Yorkshire x F1 backcross animals, to address the molecular basis for genetic transmission of the red Duroc scarring phenotype. Macroscopically and histologically, full-thickness wounds on backcross animals followed the Yorkshire phenotype, with one exception; the backcross wounds exhibited contraction following re-epithelialization.

Cytokine and growth factor mRNA expression patterns associated with the hypercontracted, hyperpigmented healing phenotype of red duroc pigs: a model of abnormal human scar development?

Background: Skin wounds in red Duroc pigs heal with the formation of hypercontractile, hyperpigmented scars, similar in some respects to human hypertrophic scars.

Objective: The goal of this study was to characterize the mRNA expression patterns for a subset of relevant cytokines, growth factors, receptors, and transcription factors involved in the red Duroc scarring phenotype.

Methods: Full-thickness and deep dermal wounds were created on the backs of juvenile female red Duroc pigs.

Genetic analysis of skin wound healing and scarring in a porcine model.

Contraction is a normal part of skin wound healing and wound closure; however, excessive contraction and severe scarring concern patients and physicians alike. The present study has investigated the degree and kinetics of wound contraction in a porcine model of wound healing, to elucidate the genetic and molecular basis for abnormal skin wound healing and scarring. Healing of excisional skin wounds in juvenile female Yorkshire pigs closely resembled normal healing in humans.

Comparison of in vitro disc diffusion and time kill-kinetic assays for the evaluation of antimicrobial wound dressing efficacy.

There is a plethora of new silver-containing dressings on the market today. Various manufacturers attempt to show that their dressings are the most efficacious and therefore should be preferentially employed by health care workers based on the results of their in vitro tests. However, there have been no studies that clearly identify which tests are appropriate for comparison purposes.