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

Guidelines for the prevention of diabetic ulcers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72321/1/j.1524-475X.2008.00357.x.pd

Gene array technology and pathogenesis of chronic wounds

Many of the limitations in treatment of chronic wounds are based on lack of knowledge of the molecular mechanism(s) of wound healing. Furthermore, diagnostic tools in wound healing are still primarily macroscopic, visual, and histologic. Thus, by understanding mechanisms of wound healing at a molecular level, new treatments can be designed, prevention programs developed, and a better understanding of current treatments provided. The ability to methodically analyze the expression patterns of thousands of genes simultaneously allows for identification of groups of molecular defects that lead to chronic inhibition of the wound-healing process. Gene array technology is having a major impact on the field of wound healing and has the potential to profoundly affect the way we understand the pathogenesis, diagnosis, prevention, and treatment of chronic wounds. Currently, gene array technology is used in the field of chronic wound healing to (1) understand the pathogenesis of pressure ulcers and venous ulcers, (2) understand the pathogenesis of diabetic foot ulcers, including the role that neuropathy may play in delayed healing of diabetic foot ulcers, and (3) determine the mechanism(s) of established and new local treatments, that is, pharmacogenomics for pressure ulcers and diabetic foot ulcers

Protocol for the successful treatment of venous ulcers

Venous ulcers affect up to 2.5 million patients per year in the United States. Although not usually fatal, these chronic wounds severely affect patients' quality of life because of impaired mobility and substantial loss of productivity. Although venous ulcers are typically small initially, they are often undertreated, progressing to larger ulcers that are associated with more serious complications requiring more complex treatments. In this report we detail the pathogenesis of venous ulcers together with potential complications, including exudate, erythema, cellulitis, dermatitis, pain, and possible malignancy. The clinician's regimen should always include a wide range of treatment modalities to ensure comprehensive care and effective wound closure. The treatment modalities and specific protocol for venous ulcers are discussed, and include topical dressings, antibiotics, debridement, compression therapy, and cellular therapy. These treatment modalities, in combination with early recognition and regular monitoring using digital photography and planimetry measurements, will ensure rapid healing and minimize complications and cost

Cellular and molecular basis of wound healing in diabetes

Diabetic foot ulcers (DFUs), a leading cause of amputations, affect 15% of people with diabetes. A series of multiple mechanisms, including decreased cell and growth factor response, lead to diminished peripheral blood flow and decreased local angiogenesis, all of which can contribute to lack of healing in persons with DFUs. In this issue of the JCI, Gallagher and colleagues demonstrate that in diabetic mice, hyperoxia enhances the mobilization of circulating endothelial progenitor cells (EPCs) from the bone marrow to the peripheral circulation (see the related article beginning on page 1249). Local injection of the chemokine stromal cell–derived factor–1α then recruits these EPCs to the cutaneous wound site, resulting in accelerated wound healing. Thus, Gallagher et al. have identified novel potential targets for therapeutic intervention in diabetic wound healing

Mesenchymal stem cell therapy and delivery systems in nonhealing wounds

The objective of the study was to inform wound care practitioners of mesenchymal stem cell application for nonhealing wounds. Recent advances in delivery systems are also discussed in order to highlight potential improvements toward clinical application of stem cell therapy for chronic wounds. MEDLINE and PubMed Central were searched for scientific studies regarding the use of mesenchymal stem cells and delivery systems in wound healing. Preclinical studies using stem cells as therapeutic modality for chronic wounds were selected for this review. Information on study design, sample size and characteristics, stem cell source, type of delivery systems, and rate and time of wound closure was abstracted. Application of mesenchymal stem cells improved wound healing in experimental and clinical settings. Advances in stem cell therapy and delivery vehicles offer promising alternatives to current limited therapeutic modalities for chronic wounds. Stem cell therapy has recently emerged as a promising therapeutic strategy for nonhealing wounds. Further research is needed to evaluate the relationship between the various delivery systems and stem cells in order to maximize their therapeutic effects. Development of novel delivery vehicles for stem cells can open new opportunities for more effective cell therapy of chronic wounds