The Book of Opposites: The Role of the Nuclear Receptor Co-regulators in the Suppression of Epidermal Genes by Retinoic Acid and Thyroid Hormone Receptors

Transcriptional regulation by nuclear receptors occurs through complex interactions that involve DNA response elements, co-activators/co-repressors, and histone modifying enzymes. Very little is known about how molecular interplay of these components may determine tissue specificity of hormone action. We have shown previously that retinoic acid (RA) and thyroid hormone (T3) repress transcription of a specific group of epidermal keratin genes through a novel mechanism that utilizes receptors homodimers. In this paper, we have analyzed the epidermal specificity of RA/T3 action by testing the role of co-repressors and co-activators in regulation of epidermal genes. Using transient co-transfections, northern blots, antisense oligonucleotides, and a histone deacetylase (HDAC) inhibitor, trichostatin A, we found that in the context of specific keratin RE (KRE), co-activators and histone acetylase become co-repressors of the RA/T3 receptors in the presence of their respective ligands. Conversely, co-repressors and HDAC become co-activators of unliganded T3Rα. The receptor–co-activator interaction is intact and occurs through the NR-box. Therefore, the role of co-activator is to associate with liganded receptors whereas the KRE–receptor interaction determines specific transcriptional signal, in this case repression. This novel molecular mechanism of transcriptional repression conveys how RA and T3 target specific groups of epidermal genes, thus exerting intrinsic tissue specificity

Primary cultured fibroblasts derived from patients with chronic wounds: a methodology to produce human cell lines and test putative growth factor therapy such as GMCSF

<p>Abstract</p> <p>Background</p> <p>Multiple physiologic impairments are responsible for chronic wounds. A cell line grown which retains its phenotype from patient wounds would provide means of testing new therapies. Clinical information on patients from whom cells were grown can provide insights into mechanisms of specific disease such as diabetes or biological processes such as aging.</p> <p>The objective of this study was 1) To culture human cells derived from patients with chronic wounds and to test the effects of putative therapies, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) on these cells. 2) To describe a methodology to create fibroblast cell lines from patients with chronic wounds.</p> <p>Methods</p> <p>Patient biopsies were obtained from 3 distinct locations on venous ulcers. Fibroblasts derived from different wound locations were tested for their migration capacities without stimulators and in response to GM-CSF. Another portion of the patient biopsy was used to develop primary fibroblast cultures after rigorous passage and antimicrobial testing.</p> <p>Results</p> <p>Fibroblasts from the non-healing edge had almost no migration capacity, wound base fibroblasts were intermediate, and fibroblasts derived from the healing edge had a capacity to migrate similar to healthy, normal, primary dermal fibroblasts. Non-healing edge fibroblasts did not respond to GM-CSF. Six fibroblast cell lines are currently available at the National Institute on Aging (NIA) Cell Repository.</p> <p>Conclusion</p> <p>We conclude that primary cells from chronic ulcers can be established in culture and that they maintain their <it>in vivo </it>phenotype. These cells can be utilized for evaluating the effects of wound healing stimulators <it>in vitro</it>.</p

Human Ex Vivo Wound Healing Model

Wound healing is a spatially and temporally regulated process that progresses through sequential, yet overlapping phases and aims to restore barrier breach. To study this complex process scientists use various in vivo and in vitro models. Here we provide step-by-step instructions on how to perform and employ an ex vivo wound healing model to assess epithelization during wound healing in human skin

Innate and Adaptive Immune Responses in Wound Epithelialization

Significance: Over the years, it has become clear that, in addition to performing their regular duties in immune defense, the innate and adaptive arms of the immune system are important regulators of the complex series of events that lead to wound healing. Immune cells modulate wound healing by promoting cellular cross-talk; they secrete signaling molecules, including cytokines, chemokines, and growth factors. In line with the major effort in wound healing research to find efficient therapeutic agents for the constantly increasing number of patients with chronic wounds, findings regarding the contributions of innate and adaptive immune responses to the re-epithelialization of damaged skin may bring novel therapeutics. Recent Advances: Increasing evidence suggests that induction of the adaptive immune response requires activation of innate immunity and that there is a dependent relationship between the two systems. Consequently, the bridge between the innate and the acquired immune systems has become an area of emerging exploration. It is clear that a better understanding of the epithelial cells (keratinocytes), immune cells, and mechanisms that contribute to an effective wound healing process is necessary so that new strategies for successful wounds treatment can be devised. Critical Issues: A greater understanding of the biology of skin innate and adaptive immune cells during wound epithelialization may have an impact on development of novel strategies for significant improvements in the quality of tissue repair. Future Directions: Future studies should clarify the importance of particular molecules and mechanisms utilized for development and functions of skin-resident γδT and Langerhans cells, as well as identify therapeutic targets for manipulation of these cells to combat epithelial diseases

Folliculitis Decalvans and Lichen Planopilaris Phenotypic Spectrum-A Series of 7 New Cases With Focus on Histopathology

Folliculitis decalvans (FD) and lichen planopilaris (LPP) are classified as neutrophilic and lymphocytic cicatricial alopecias according to the North American Hair Research Society. Recently, a clinical phenotype combining concomitant or sequential features for both was described as a FD LPP phenotypic spectrum (FDLPPPS). To review the most common phenotypic presentation of FDLPPPS with a main focus on histopathology. We reviewed retrospectively series of 7 patients with a similar phenotypic presentation with special focus on the histologic pattern. All patients presented with concomitant features for FD and LPP and recalcitrant course unresponsive to topical and systemic immunomodulatory/anti-inflammatory agents. The most common clinical phenotype was that of hairless patches on the vertex with lost follicular ostia and perifollicular scale and the following diagnostic findings: (1) polytrichia; (2) positive bacterial culture for Staphylococcus in over 50% of the samples isolated from pustules and hemorrhagic crusts; (3) "mixed" histologic features for primary cicatricial alopecia including multicompound follicular structures of average 2-5 follicles (follicular packs), atrophy of the follicular epithelium, lymphohistiocytic infiltrate with granulomas, and prominent plasma cells, but absence of neutrophilic infiltrate in all cases except scarce neutrophils in one; and (4) clinical improvement with adjuvant systemic antimicrobials. The FDLPPPS may be underreported and should be considered in all cases of LPP recalcitrant to treatment. Dermatologists and dermatopathologists should recognize this phenotypic spectrum to guide optimal clinical management consisting of immunomodulatory and anti-inflammatory agents along with systemic antimicrobials

Hair cycling and wound healing: to pluck or not to pluck?

The incidence of nonhealing wounds (diabetic foot, pressure, venous, and arterial ulcers) is reaching epidemic proportions, underscoring the need for new treatment modalities. Understanding hair follicle biology and its potential to accelerate wound healing may offer new treatment strategies. In this issue, Ansell et al. show that wounds on anagen skin heal faster than those on telogen skin, suggesting that hair cycle stages may influence healing outcome

Wound Dressings

It is estimated that 50 million surgical procedures are performed in the United States annually, with surgical site infections estimated to be one of the leading causes of hospital‐acquired infections with associated direct and indirect medical costs estimated to be between $1 and 10 billion. An appropriate wound dressing is important when treating the wound. Various modalities of wound dressings: low adherent, occlusive hydrocolloid, gauze, transparent film, hydrogel, foam, alginates, hydrofibers, and antimicrobial dressings are available on the market. This chapter summarizes current knowledge about wound dressings and their use in the acute and chronic wound setting