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Wound healing generally leads to scarring in mature skin, but wounds created at early stages of development heal scarlessly. The exact mechanisms leading to scarless healing are not fully understood, but unique characteristics of fetal fibroblasts are believed to be important. Dermal fibroblasts from embryonic day 15 (E15) skin, which heals scarlessly, and embryonic day 18 (E18) skin, which heals with a scar, were compared by proteomics. Fetuin A (Fet A), a protein that has been suggested to be involved in inflammation, was identified as one of the top three differentially expressed proteins.
Chronic wounds are major and rising disease worldwide, which are characterized with excessive and prolonged inflammation. We found that both microRNA-34a-5p (miR-34a) and microRNA-34c-5p (miR-34c) were upregulated in the wound-edge epidermis of venous ulcers (VU), the most common chronic wounds, compared with acute wound or intact skin biopsies from healthy donors. Our study showed that FGF1 promoted miR-34 expression in keratinocytes. In line with this, higher FGF1 expression was detected in VUs compared to acute wounds or intact skin.
The skin is a highly innervated organ but while the sensory role of cutaneous nerves is well characterized there is significant clinical and experimental evidence to suggest that proper innervation is critical for normal skin physiology and regeneration. A major challenge in uncovering the functional interactions between cutaneous nerves and stem cells is the ability to image and manipulate their activity in vivo, in the intact live skin. We developed state-of-the-art imaging tools to visualize the 3-dimensional network of cutaneous nerves in live mouse skin by 2-photon microscopy.
The secretion of cytokine mediators between keratinocytes and T cells plays a major role in the development of chronic skin disease such as psoriasis. Some drugs that inhibit these inflammatory intermediates relatively improve the symptoms associated with psoriasis. To overcome the lack of a physiologically relevant organotypic model and to better understand psoriatic cellular and molecular interactions, we developed a unique reconstructed skin model in which positive CD3 T cells are seeded and interact with the three-dimensional local microenvironment.
The molecular and physiological processes governing wound healing and regeneration have not yet been fully defined. Here we investigate the mechanisms of skin regeneration after injury through a rare event of mammalian regeneration known as Wound Induced Hair Neogenesis (WIHN). We have shown that non-coding dsRNA released by tissue damage stimulates TLR3 and β-catenin to promote WIHN. However, the RNases which either promote or inhibit dsRNA biogenesis remain unresolved. Following injury or exogenous dsRNA (polyI:polyC) treatment, we find significant overlap and upregulation of OAS transcripts (≤15/19,234 transcripts, p=8.3*10-13) in microarray data.
Inflammation plays an important role in cutaneous wounds. Disruption of the normal influx and resolution of inflammatory cells can lead to impaired wound healing in diabetes and other pathological conditions. Tumor necrosis factor stimulated gene-6 (TSG-6) is an enzyme that transfers heavy chains (HC) from inter-a-trypsin inhibitor (IaI) to hyaluronan (HA), forming HC-HA complexes (HC-HA) that are associated with various inflammatory conditions such as arthritis, asthma, and colitis. TSG-6 is thought to play important roles in neutrophil recruitment and macrophage polarization, two events critical to proper wound healing.
The prevalence of inflammatory skin diseases in United States is 11%, suggesting that approximately 1 in 10 people suffer from an inflammatory skin disease. Most drug development for these diseases is conducted using animal models or 2D cell culture systems, which make it difficult to predict patient-specific drug responses. Here, we developed new 3D skin models for psoriasis and vitiligo by combining skin components together with disease-relevant immune cell populations. We isolated T cells from peripheral blood mononuclear cells (PBMCs) of psoriasis patients and incorporated them into healthy control derived 3D skin constructs to reproduce patient-specific psoriatic inflammation.
Cutaneous exposure to alkylating agents such as nitrogen mustard (NM) causes severe blistering with systemic complications long after the exposure. We have previously shown that a single dose of vitamin D (VD) is sufficient to rescue NM-exposed mice from pancytopenia and death and that early intervention with VD is of critical importance. However, the effect of VD on cellular infiltration and local milieu in the skin is unknown. Here we propose that VD promotes skin recovery by preventing dermal infiltration including pro-inflammatory macrophages to maintain a cellular distribution that accelerates skin repair to restore immune equilibrium.
Human skin contains sensory neurons to transduce sensations such as itch. Atopic dermatitis (AD) is an inflammatory skin disease and pruritus is a characteristic symptom of this disorder. AD is driven by interleukins (IL4/13) and there is a link between inflammation and itch, but it is unknown whether the driver cytokines (IL4/13) sensitize the sensory neurons to itch stimuli. Previously, we manipulated the Wnt, TGF-β, BMP4 and Notch signaling pathways to enhance sensory neuronal differentiation of iPSCs and obtained iPSC-derived neurons (iNCs) from different iPSC lines.
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.