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Vitamin D (VD) has been implicated in modulating acute immune responses including dampening inflammation and promoting skin repair. We have previously shown in a randomized placebo-controlled human study that a single dose of VD rapidly reduces redness and swelling from experimentally-induced sunburns and was associated with the presence of alternatively-activated CD163+ Arginase1+ macrophages (M2-macs) in the skin. To determine the mechanism by which VD regulates macrophage polarization in the skin following UV exposure, the study was recapitulated in mice.
Cellular senescence, known as an intrinsic growth control mechanism that prevents the transformation of pre-malignant lesions into overt malignancy, plays an important role in tissue development, homeostasis and cancer control. Besides endogenous stress signals, exogenously delivered Th1-cytokines (IFNγ & TNF) can initiate senescence in a variety of human and murine cancer cells. However, these senescent cancer cells remain a potential harm due to their senescence associated secretory phenotype (SASP).
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disorder, caused by heterozygous mutations of the NF1 gene. NF1 protein has been suggested to be a downregulator of the Ras-signaling pathway which increases the cell growth and proliferation in most tissues. Although the surgical treatment is major therapeutic option to remove the neurofibroma (NF), there are few studies regarding the complex process of wound healing in the skin of NF1.To investigate expression of wound healing markers in the skin of NF1 compared with normal skin and hypertrophic scar (HTS).
Substantial induction of type I collagen (COL1) production is essential for regeneration of the dermal extracellular matrix during wound repair. Skin resident fibroblasts are the major cell type responsible for increased COL1. Fibrocytes are circulating bone marrow-derived cells that have the capacity to produce COL1. In tissues, fibrocytes are identified as CD45+ positive (pan hemopoietic marker) cells that express COL1. The involvement of fibrocytes in human wound healing is unclear. We have investigated the presence of fibrocytes in experimental human wounds.
Regeneration of human epidermis after injury is a key function of progenitor cells. Understanding of decision-making mechanisms for self-renewal and differentiation relies on the development of experimental approaches, including surrogate cell culture-based epidermal regeneration models for assessment of progenitor cell activation, autonomous growth and spontaneous differentiation at the clonal level. Here we propose a 3D epidermal cell culture system which satisfies aforementioned criteria. Growth from single epidermal cells in thick basal membrane-derived gel results in the formation of multilayered spheroids with an inward differentiation.
Platelet rich plasma (PRP) obtained from patient's own blood has prominent, yet poorly understood positive effects upon chronic wound healing in diabetic patients. These effects can be associated with multiple growth factors (PDGF, EGF, FGF, VEGF, TGF-b, etc.) enriched in the PRP. Supplementation with recombinant growth factors is also a useful approach in bioengineering of dermal substitutes used for wound healing therapy, but it is costly and not safe. Here, we have assessed the pro-angiogenic and wound healing properties of sodium alginate polymeric sponge scaffolds modified with human PRP in comparison with appropriate controls.
Wound healing is a complex multistep process that involves an inflammatory phase that conditions many of the subsequent stages of healing. Skin barrier rupture results in exposure to bacterial compounds suggesting a key role of the wound microbiome in the healing process. We here aimed to systematically study the healing of skin excisional wounds in 72 different strains of mice from the collaborative cross to evaluate wound healing. In 30 strains we also evaluated associations between bacterial composition in normal and wounded skin at different time points and healing speed.
Several physiological functions in the skins, such as the skin surface pH, temperature, capacitance, sebum production and barrier recover, show diurnal variation. In the previous study, we showed that clock gene plays an important role in skin capacitance and epidermal barrier recovery. On the other hand, it has been reported that the oscillation of clock gene expression is declined by psychological stress, aging, UV rays, light pollution and irregular life style such as shift work. expression was suppressed in the UV-irradiated skin.
Preclinical studies have demonstrated the ability of the beta adrenergic antagonist, timolol, to heal wounds in in vitro, ex vivo and in vivo animal wound models. This has prompted the off-label use of the ophthalmic solution to heal chronic wounds of diabetic, venous and other etiologies, as demonstrated by the growing numbers of case reports. Here we sought to elucidate the cellular mechanisms that underpin the observed improvement in healing in the chronic wounds of patients treated with topical timolol.
Glutamate, acts as an excitatory neurotransmitter in the CNS. While the important role of glutamate as a modulator of pain and central sensitization has been studied previously in details, the peripheral role of extracellular glutamate has not been clarified yet. First, we investigated whether glutamate is released by mechanical stimulation (MS). Our findings show that in the human skin explant system, glutamate is released upon superficial skin resurfacing procedures such as microdermabrasion. Following a single microdermabration treatment, we observed a rapid but temporary induction of stress response molecules such as IFN-alpha and beta followed by a pronounced proliferative response in the basal layer of the epidermis as indicated by the increase of Ki67-positive keratinocytes.
Therapeutic reprogramming with personalized tissue manufacturing represents a curative approach to treating skin diseases like epidermolysis bullosa (EB), yet a major roadblock is a complete understanding of the mechanisms driving fate commitment by the master regulator p63. Using a defined in vitro differentiation protocol that produces keratinocytes upon addition of morphogens RA and BMP, and gain/loss of function p63 stem cells, we investigate the transcriptional and chromatin dynamics governing fate commitment through a multi-dimensional genomics approach.
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.