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(a) Chronic trophic ulcers (CTU) especially located over plantar region are leading cause of deformity and disability in Hansen’s patients. Despite various treatment modalities available, it’s quite chronic and refractory to treatment. The successful use of topical insulin in various types of wounds led us to evaluate its safety and efficacy in the treatment of chronic trophic ulcers over the plantar region. (b) Forty two patients released from treatment of leprosy were recruited and randomized in two groups.
The skin is the human body’s largest organ and is occupied by a highly diverse microbiome. It is well established that certain species of probiotic bacteria confer health benefits to the human gut, such as epithelial repair, enhancement of the gut barrier and modulation of the immune response. However, recent research is starting to uncover potential benefits of probiotic bacteria and their extracts to influence skin health and disease. Previous work in our lab has shown that lysates of commensal bacteria, Lactobacillus rhamnosus GG (LGG), when applied to primary human keratinocytes enhance Tight Junctions and increase proliferation and migration of keratinocytes in scratch assays.
The development of new therapeutic approaches to chronic wounds hasn’t lost its relevance. In non-healing diabetic ulcers (diabetic foot) auto-transplantation (a common treatment approach) is not effective due to impaired fibroblast functionality and shifts in synthesis of ECM proteins (COL1, COL3, FN) and certain growth factors. It was shown that HIF1 (hypoxia-induced factor) is a key regulator of ECM remodeling by fibroblasts through control of collagen prolyl hydroxylase (P4HA1, P4HA2 – both required for collagen deposition) and lysylhydroxylase (PLOD2 – modulates collagen fibers strength) expression.
Adipose-derived stem cells (ADSCs) are a particular subset of mesenchymal stem cells present in the stromal-vascular fraction of the adipose tissue. These cells are considered very attractive for their relative abundance and accessibility in the human body. Keratinocytes and fibroblasts cells play important roles in the skin-wound healing process and are the cell types activated by trauma. The aim of our study was focused to evaluate ADSCs ability to build a dermal matrix to be potentially used as a dermal substitute in the field of wound healing.
Although numerous wound healing models have been established, a model to study re-epithelialization in vitro, without disrupting the underlying dermal compartment, is lacking. Therefore, we established a new standardized human ex vivo model based on application of negative pressure, inducing blistering and consequently dermal epidermal separation. Effects of this treatment for epidermal regeneration and immune cells were investigated. Immunostaining revealed type IV collagen expression on the remaining dermal compartment, indicating that the basement membrane and thus the underlying dermis remained intact after removal of the blister roof epidermis.
The use of formulations based on thrombocyte concentrate lysates (platelet-released growth factors, PRGF) revealed promising effects in the treatment of chronic wounds. The underlying mechanisms are not well understood. We could show that PRGF induced the expression of antimicrobial peptides (AMPs) such as the human beta-defensin-2 and -3 (hBD-2, hBD-3) in keratinocytes which may contribute to the observed beneficial effects of PRGF-based formulations in wound treatment. Given that it is unclear which components of platelets induce AMPs in keratinocytes we aimed to biochemically identify PRGF-derived factors that induce hBD-2 in human keratinocytes.
With age, dermis loose its elasticity. Its main component, Collagen, undergo decreased synthesis and degradation. Elastin and Fibronectin are also impacted. In addition, the extrafibrillar matrix shows decreased level of glycosaminoglycans, one of its abundant components. Fibroblasts, key players in the production and organisation of the extracellular matrix (ECM), present reduced growth and modified secretion patterns. Another aspect of ageing is the alteration of the microcirculation network that limits supply of nutrient to the dermis.
Human dermis is divided between the superficial papillary dermis and the deeper reticular dermis that show distinct extracellular matrix (ECM) and vasculature. Papillary and reticular fibroblasts have distinct phenotype and gene signature but the contribution of each subtype of fibroblasts in the generation of specific ECM and vasculature is poorly documented. This study aimed to determine if papillary and reticular fibroblasts generate specific microenvironments in vitro when cultivated as cell sheet and evaluate their impact on angiogenesis.
Brown adipocytes as well as beige adipocytes in white adipose tissues (WATs) can dissipate energy via adaptive non-shivering thermogenesis, and play a critical role in the regulation of energy balance. It is well known that cold exposure induces beiging/browning, which is defined as the emergence of beige adipocytes in WATs. Here we investigated whether heat stimuli induces beiging/browning of subcutaneous (SC) fat tissue in vitro and in vivo. Heat stimuli (>39 °C) to differentiated primary human SC adipocytes lowered triglycerides (TG) contents, similar to those exposed to cold stimuli (4, 15 °C).
Collagens are the most abundant component of the extracellular matrix. They largely contribute to tissue mechanical stability. In the skin, integrins α1β1, α2β1, α11β1 are the three main collagen receptors facilitating cell to collagen contact. Using single and double knockout mouse models lacking collagen-binding integrins, we were able to delineate their individual functions and functional redundancy. Here we address the overall significance of integrin-mediated direct interaction of cells with collagens.
“High mobility group box 1” (HMGB1) is a well-known nuclear protein that stabilizes DNA and facilitates gene transcription, but at outside the membrane, it functions as an alarmin, causing an inflammatory response in combination with other cytokines. Recently, we confirmed that HMGB1 shows the proinflammatory activity depending on the redox status, which is in the reduced, disulfide, or oxidized form. The reduced-HMGB1 exerts a chemoattractive effect, and the disulfide-HMGB1 has proinflammatory cytokine activity, but the oxidized form has no inflammatory activity.
Several skin-expressed Transient Receptor Potential (TRP) channels act as sensors of temperature, mechanical, and chemical stimuli. In the skin, TRPV4 is expressed in many nonneuronal cell populations including keratinocytes, immune cells and on skin appendages. This thermo- and osmosensitive protein has a high impact on the epidermal barrier, regulation of hair growth and sebum production and the secretion of inflammatory cytokines. Since we have less information about the role of TRPV4 in the dermis we aimed to investigate the functional presence of TRPV4 on human dermal fibroblasts (FB).
Lymphatic vessels play important roles in immune defense, inflammatory diseases, and cancer. In the steady state, lymphatic vessels are responsible for collecting fluid and cells from the dermis to maintain fluid homeostasis. The structures of lymphatic vessels have been reported by enzyme histochemistry, immunohistochemistry, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). However, the detailed morphology of lymphatic vessels is still unknown. Here, we investigated the ultrastructure of human cutaneous lymphatic vessels by immuno-TEM and focused ion beam (FIB)-SEM that generates high resolution and back scattered images resembling those of a transmission electron micrograph.
Previous studies described the involvement of extracellular signal-related kinase (ERK) in systemic fibrotic diseases, but the role of ERK in cutaneous scarring is unknown. Although hypoxia drives tissue fibrosis by activating hypoxia-inducible factor-1α (HIF-1α), the specific roles of hypoxia and associated ERK phosphorylation in abnormal fibroblast activity during cutaneous scarring are unclear. Here, we investigated whether pathologic myofibroblast-like keloid fibroblast activity is promoted by hypoxia-induced epithelial–mesenchymal transition mediated by ERK activation.
Keloid scar formation is associated with aberrant inflammatory signalling however the underlying causes remain poorly understood. Additionally, keloid scars have been shown to be 10-50 times stiffer than normal skin and often form in areas of the body where skin tension is high. As a result, it is thought that the formation of keloid scars may be influenced by mechanical forces. The aim of this study was to investigate the direct effects of tissue stiffness on the behaviour of normal (NF) and keloid fibroblasts (KF) and explore the potential cross-talk with inflammatory signalling pathways.
In skin, lymphatic systems play important roles in the maintenance of fluid homeostasis by draining the interstitial fluid and we have previously showed that UV irradiation resulted in the impairment of lymphatic function leading to photo-damage. Recently, Schlemm’s canal, a small duct with properties similar to lymphatic vessels, undergoes an endothelial-to-mesenchymal transition (EndMT) during aging. In addition, transforming growth factor-β (TGF-β) induces the EndMT of blood vascular endothelial cells, which share a number of characteristics with lymphatic endothelial cells (LECs).
Diabetes Mellitus (DM) can result in chronic non-healing wounds ultimately leading to lower limb amputations. Studies have shown haired punch grafts can accelerate wound closure when compared with non-haired grafts, however the contribution of different populations of fibroblasts from haired skin to wound healing under elevated glucose levels and the effects of high glucose concentrations (as seen in DM) on these cells are unknown. We aimed to determine the effect of basal (1g/L) and high glucose (4.5g/L) concentrations on three different fibroblast subpopulations cultured from haired skin (papillary dermis (DF), hair follicle dermal sheath (DS) and hair follicle dermal papilla (DP)).
Although constituting the majority of the transcriptional output of the human genome, the functional importance of long noncoding RNAs (lncRNAs) has only recently been recognized. The role of lncRNAs in wound healing is virtually unknown. Our study focused on a skin-specific lncRNA, termed “wound and keratinocyte migration-associated lncRNA 1” (WAKMAR1), which is down-regulated in wound-edge keratinocytes of human chronic nonhealing wounds compared with normal wounds under reepithelialization. We identified WAKMAR1 as being critical for keratinocyte migration and its deficiency as impairing wound reepithelialization.
Transforming growth factor-beta (TGFβ) is a pleiotropic cytokine with cell type-specific effects modulating growth, survival and differentiation. It is a crucial regulator of inflammation and the most potent inducer of tissue fibrosis. Fibroblasts are the key cells to deposit and remodel extracellular matrix in fibrotic stroma and this ability crucially depends on autocrine TGFβ1 signaling. Our previous work has demonstrated that TGF-β secretion is strictly linked to autophagy in fibroblasts and macrophages, thus identifying a potent control mechanism influencing TGF-β activity.