Journal of Investigative Dermatology RSS feed.
Updated: 1 hour 18 min ago
Wounding results in inflammation, synthesis and remodeling of granulation tissue with extracellular matrix deposition and scar-formation which might reduce function of affected areas representing a challenging medical problem. During development and even in the presence of inflammation skin repair is scarless until fibroblasts become lineage-committed and express DPP4. The exact functions of this molecule remain unknown. It is hypothesized that through its peptidase activity DPP4 is able to modulate the microenvironment around fibroblasts at specific time points during wound healing and repair and thus determine the fate and function of these cells and others.
Basonuclin 1 (BNC1) is a transcription factor primarily expressed in keratinocytes. BNC1 levels are correlated with proliferative potential of keratinocytes, but the mechanisms of cell cycle control are undefined. Physiologically, Bnc1 knock-out mice exhibit thinner epithelial tissues and have defects in corneal wound healing. BNC1 has been shown to promote the expression of ribosomal DNA genes as well as a small number of RNA polymerase II-regulated promoters, however, it is unclear if this accounts for the phenotypes observed or whether BNC1 directly controls specific transcriptional programs involved in proliferation and migration.
Background: Adaptive immune responses play a significant role in mediating tissue repair. Hyaluronan(HA), a major extracellular matrix component in skin, can influence the stiffness of the tissue and thus impact T-cell activation. However, the mechanism of action on lymphocytes is unclear. We hypothesize that lymphocytes are mechanosensitive and help govern fibrosis and wound healing. Methods: First, we tested endogenous lymphocytes response to tension in mouse skin, and the response of human lymphocytes to hydrogels of varied stiffness.
Staphylococcus aureus wound infections delay healing and result in invasive complications such as osteomyelitis, especially in the setting of diabetic foot ulcers. In preclinical animal models of S. aureus skin infection, antibody neutralization of α-toxin (AT), a S. aureus secreted pore-forming cytolytic toxin, reduces disease severity by inhibiting skin necrosis and restoring effective host immune responses. However, whether therapeutic neutralization of α-toxin is effective against S. aureus-infected wounds is unclear.
During cellular senescence cells undergo permanent cell cycle arrest, and this protects from malignant transformation. Though important to control cancerous neoplasia, the same mechanisms may fundamentally drive aging and age-related disorders. Senescent cells in many instances release a battery of soluble factors, collectively termed as senescence associated secretory phenotype (SASP). Depending on histogenetic origin of cells, SASP can vary in components and composition. Of note, SASP spreads senescence within tissues and organs and promotes several age associated disorders, including skin aging and impairment of chronic wound healing.
Previously we have shown that transplantation of aged human skin onto young SCID mice results in a rejuvenated human epidermal phenotype. Here, we demonstrate that the rejuvenation of old human skin xenotransplants onto young SCID/beige mouse skin well extends beyond the epidermis and leads to statistically significant improvements in multiple skin aging-associated read-outs assessed by quantitative histomorphometry, which showed e.g. thickening of the epidermis, along with basal layer keratinocyte proliferation, increased vascularization, significantly more collagen type I and III and elastic fibers, and number of epidermal melanocytes in aged human skin xenotransplants.Gene expression RNA-Seq analyses of DEGs showed in 1week versus pre-transplant numerous transcripts related to hypoxia, VEGF and angiogenesis, inflammation, the Notch, TGF-β and IGF pathways, genes related to reinnervation, as well as keratins and epidermal regulators.
Wound exudates are considered liquid biopsies of wounds and contain the pathogenic drivers of chronicity. Previous studies have shown elevated levels of pro-inflammatory cytokines and proteases in chronic wound exudates. Platelet-derived growth factor (PDGF) is used for the treatment of chronic wounds, but is effective only in a limited number of patients. The reason for this may be abrogation of the growth-promoting effect of PDGF in the environment of the wound, e.g., by its degradation by proteases or dysfunctionality of the PDGF receptor.
Background: Pressure ulcers (PU) result from disturbances in blood supply to the epidermis and underlying tissues, thereby leading to ischemia and necrosis of the areas under pressure in a given length of time. Hibernating bears (HB), despite 5 months of inactivity in the den and absence of food intake in the winter, do not show any signs of PU. Putative mechanisms: based on the present data in the literature, the mechanisms can be represented in groups A&B. A) Blood factors: 1, ALBUMIN is higher in HB than non-HB.
Diabetic foot ulcers (DFU) account for significant morbidity and immense biomedical burden. The long-term effectiveness of advanced therapies has yet to be determined. Our hypothesis is that timolol, a non-selective beta adrenergic antagonist (BAA) will be effective in achieving wound closure compared to standard of care (SOC) treatment for DFU, and is a safe therapeutic alternative. We will conduct a prospective, randomized, double-blinded, controlled and parallel-group trial with 2 arms: SOC plus topical timolol and SOC plus a non-biologically active gel (hydrogel) as placebo control.
Aging decreases tissue function in many organs. Yet, surprisingly, skin wounds in the elderly heal with less scarring compared to young individuals. Here we show that a full-thickness skin wound in aged but not young mice fully regenerates. Exposure of aged animals to young blood by parabiosis counteracted this regenerative ability. Compared to aged mice, injured young mouse skin expressed more stromal-derived-factor-1 (SDF1), a secreted cytokine. Deletion of SDF1 in young skin enhanced in vivo tissue regeneration, and parabiosis with aged mice confirmed that skin-secreted SDF1 in young blood promoted scarring.
The process of wound healing is complex and involves coordination of multiple cell types required to regenerate the 3D architecture of skin. In adults, upon completion of wound healing a scar is formed, which is composed of fibrous matrix generated by fibroblasts, and the healed skin lacks hair follicles. Skin fibroblasts arise from a homogenous population during early embryonic development but differentiate into heterogenous populations that have non-overlapping functions in development, skin maturation and wound healing.
Wound keratinocytes restore the epidermal barrier and also secrete paracrine factors that regulate wound cell functions. Dysregulation of this paracrine signaling can contribute to a spectrum of pathologies. Previously, we established that keratinocyte integrin α3β1 promotes angiogenesis through paracrine stimulation of endothelial cells, while keratinocyte α9β1 negatively regulates such α3β1-dependent effect. We hypothesize that integrin-dependent paracrine signaling from keratinocytes plays a similar role in regulating differentiation of myofibroblasts that deposit and contract ECM during scarring and fibrosis.
We here investigated a unique capacity of mesenchymal stem cells (MSCs) to re-establish tissue homeostasis using their premonitory potential to sense danger associated molecular pattern (DAMP) and to mount an adaptive response in the interest of tissue repair. Injection of MSCs pretreated with heterodimeric DAMP protein S100A8/A9 into murine full-thickness wounds, led to a significant acceleration of healing even exceeding that of wounds with non-treated MSCs. This correlates with a fundamental reprogramming of the transcriptome in S100A8/A9 treated MSCs as deduced from in-depth validation via global RNAseq, RT-PCR, and immunostaining.
Non-healing foot ulcers develop in 10-25% of type 2 diabetics. We have previously shown that reduction in ganglioside GM3 by GM3 synthase (GM3S) gene knockdown or topically applied GM3S siRNA nanoconstructs normalizes wound healing in diet-induced obese (DIO) diabetic mice. The mechanism is reversal of IGF-1 and EGF receptor resistance, leading to accelerated keratinocyte migration and normal cutaneous innervation. A small molecule inhibitor of glucosylceramide synthase (GCSI) also reduces GM3 and, given GCSI's small size, could be moved towards clinical trials of topical application should it replicate the ameliorative effects on wound healing.
Repair of the skin requires efficient directed migration of a sheet of epidermal cells over the wound bed. This involves collective cell migration (CCM) where the leader keratinocytes at the migrating front regulate the motility of follower cells. The role of hemidesmosome proteins in both the motility of single and groups of keratinocytes is controversial. Some data indicate that hemidesmosome proteins retard migration while others suggest that hemidesmosome proteins regulate directed migration.
Large excisional wounds in mice prominently regenerate new hair follicles (HFs) and fat, yet humans are deficient for this regenerative behavior. Currently, wound-induced regeneration remains a clinically desirable, but only partially understood phenomenon. We show that large excisional wounds in rats, across seven strains fail to regenerate new HFs. We compared wound transcriptomes between mice and rats at the time of scab detachment, which coincides with the onset of HF regeneration in mice. In both species, wound dermis and epidermis share core dermal and epidermal transcriptional programs respectively, yet prominent inter-species differences exist.
Long term diabetes often leads to chronic wounds refractory to usual treatments, thus representing a major challenge for the healthcare system. Cell-based therapies are actively investigated to enhance wound repair. Various cell types can be used to produce biological dressings that can be applied on wounds. Adipose-derived stem cells (ASC) are an attractive cell source considering their abundancy and therapeutic properties. In this study, ASC-based dressings improved global skin healing in a diabetic murine model.
Venous leg ulcers affect >600,000 Americans costing $2 billion USDs yearly costs. Compression stockings and bandages are the standard of care in speeding healing rate. However, this therapeutic benefit requires a sub-garment pressure of at least 30-40 mmHg. Several medical associations have echoed the need for sensors capable of accurately, and repeatedly measuring interface pressure. PicoPress® (Microlabitalia, Padua, Italy) is the gold-standard. While accurate and repeatable, the air-bladder requires a larger base unit that precludes wearability, lacks wireless communication, and highly expensive (>$2,000 USDs).
Photobiomodulation(PBM) is a safe and non-invasive method that can provide various clinical effects. At present, conventional PBM devices using point light sources such as Light-Emitting Diode and laser have various problems such as low flexibility, relatively heavy weight, and non-uniform effects. In this study, we present a novel wearable PBM patch using a flexible red-wavelengths Organic Light-Emitting Diode (OLED) light source which can be attached to the human body. It will provide practical performance (> 10mW/cm2) even at low voltage (< 10V).
Human skin constructs (HSCs) have the potential to provide an effective therapy for patients with significant skin injuries and to enable human-relevant drug screening. However, incorporation of engineered skin appendages, such as hair follicles (HFs), into HSCs has been a long-standing challenge. Employing 3D-printing technology, we initially developed a biomimetic approach for generation of human HFs within HSCs through guiding physiological 3D organization of cells in the HF microenvironment.