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During healing of large excisional skin wounds in adult mice, hair follicles and then dermal adipocytes regenerate de novo in the wound center. New hair follicles regenerate from wound epidermis and wound fibroblasts by reactivating embryonic hair morphogenesis program. New adipocytes regenerate around new hair follicles from myofibroblasts, a specialized contractile wound fibroblast, via the process of reprogramming. We studied diversity of fibroblasts in large skin wounds using single-cell RNA-sequencing.
Skin fibroblasts expressing dipeptidyl-peptidase 4 (DPP4) were shown previously to be responsible for the bulk of extracellular matrix (ECM)-deposition and pro-fibrotic action in mouse skin. However, this finding was hitherto not confirmed in the human system. Previous expression studies in the human skin reported presence of DPP4 in melanocytes, fibroblasts, and, at lower levels, in endothelial cells and dendritic cells. We investigated DPP4 expression in the tissue context, using single cell transcriptomic analysis (scRNAseq) on all cells of the human skin.
SWI/SNF ATP-dependent chromatin remodelling complexes alter nucleosome structure, positioning and chromatin compaction state resulting in target gene activation or repression. The SWI/SNF complexes contain either BRG1 or BRM as the core ATPase together with other common and variable subunits. BRG1 is required for epidermal terminal differentiation in both mice and human; and for hair follicle stem cell activation during mouse hair regeneration and cutaneous wound healing. However, the role of SWI/SNF complexes in human skin wound healing remains unknown.
Topical nitrogen mustard (NM) is approved to treat Stage IA-IIA CTCL and is known to induce blisters and skin irritation as a direct effect of treatment through mechanisms including DNA alkylation and activation of a pro-inflammatory cascade. In murine models, 25-hydroxyvitamin D3 mitigates the inflammatory and vesicating effects from exposure to high concentrations of topical NM. Recently, vitamin D3 is shown to rapidly reduce skin inflammation in human subjects from experimental sunburns by increasing expression of arginase-1, a key tissue repair and anti-inflammatory factor.
The dermis is divided into two distinct compartments, the upper papillary dermis and the lower reticular dermis. Their structure and function are well characterized and even if differences in blood vessel density and organization between them have already been described, there is only little information regarding the composition of the microenvironment and the angiogenic properties of those two fibroblast sub-populations. The aim of this study was to describe and compare the angiogenic properties of the two fibroblast sub-populations.
Wound healing models are essential for investigating the pathogenesis of tissue repair; however, the limited utility and often varied responses of these models when compared to the human in vivo system has created a demand for a more capable model that can be used for identifying new biomarkers and testing new therapeutics. We have evaluated wound healing in a recently developed skin explant system that allows the use of ex vivo human skin without significant loss of viability. This increased viability is a result of culturing the tissue at an empirically-optimized tension designed to mimic physiological tension, thus maintaining the biological and structural integrity of the skin.
Each year, more than one million patients are hospitalized in the U.S. for significant skin loss due to thermal and pressure injuries, chronic diabetic ulcers or genetic skin diseases. The ability to generate engineered human skin constructs (HSCs) has provided a promising therapy for these patients. However, it remained an unsolved challenge to incorporate hair follicles (HFs) into HSCs in order to improve wound healing and skin function. We initially employed a 3D-printing strategy to induce human HF formation within HSCs through guiding physiological 3D organization of cells in the HF microenvironment.
Stretch marks are dermal scars characterized by an alteration of structural proteins of the skin, like collagen, which thus have a dramatic impact on skin properties. They are observed in diverse contexts: pregnancy, cuts, burns and surgical procedures. One method of actively targeting the scar is to massage the skin. We designed a micro-emulsion that transforms into a pro-massage fluid oil after circular motion on the skin. It contains complementary active ingredients stimulating skin regeneration and fight marks, in particular Rhealba® Oat Plantlet Extract.
Hypertrophic scar (HS) is a dermal fibroproliferative disease characterized by the overproduction and deposition of extracellular matrix, cell over-proliferation, enhanced angiogenesis, and enhanced differentiation of fibroblasts to myofibroblasts. Although there has been extensive research on botulinum toxin type A (BTX) treatment for the prevention of HS formation, its effectiveness in the attenuation of skin fibrosis and the related mechanism are unclear. In this study, we investigated the inhibitory effect of BTX on HS-derived fibroblasts (HSFs) in vitro and explored the possible associated molecular mechanism by examining cell proliferation, cell migration, protein expression of scar-related factors, and intracellular signaling.
Following large full-thickness skin wounding, African spiny mice (acomys cahirinus) demonstrated robust regenerative ability, while laboratory mice (mus musculus) regenerate some hairs from the wound center. Although some studies have reported the molecular expression differences between the two species after wounding, whether there is a shared mechano-chemical mechanism mediating their common and different responses remains to be explored. We first characterized skin features of both laboratory and spiny mice such as hair types, hair cycling, and the response to small and large wounds.
A growing body of evidence suggests that β-catenin, the major downstream driver of canonical Wnt signaling, is activated during physiologic wound healing and that aberrantly sustained activation may conversely inhibit wound healing. We have previously shown that nuclear localization of β-catenin in the epidermal edge of chronic ulcers is predictive of a non-healing clinical outcome. The purpose of this study was to identify the transcriptional targets of β-catenin signaling in wound edge biopsies from chronic diabetic foot ulcers (DFUs) using chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq).
Myofibroblast activation is a major feature of skin fibrosis, but the origins of myofibroblasts are yet uncertain. While pericytes have been suggested as myofibroblast progenitors in various organs, their contribution to skin fibrosis is not clear. Our previous data suggest that SARA is an anti-fibrotic molecule that acts by modulating cell phenotype. Here, we studied a role for SARA in pericyte activation in a mouse model of skin fibrosis. To test role of SARA, we generated a mouse that constitutively expresses human full-length SARA cDNA specifically in pericytes under the control of PDGFRβ promoter-driven Cre recombinase activity (SARATg; PDGFRβ-Cre), and further crossed them with the Z/EG strain to mark the PDGFRβ+ pericytes with GFP.
A key component in the resolution of cutaneous wounds is the re-epithelialization of the wound bed by migrating keratinocytes using a mechanism called collective cell migration (CCM). Resolution of wounds induces stress in the skin and a central mechanism used by cells to sense and respond to stress signals is the Integrated Stress Response (ISR). Distinct stress-activated protein kinases phosphorylate the translation factor eIF2 (eIF2-P), leading to diminished global protein synthesis coincident with preferential translation of stress-related gene transcripts.
Acne vulgaris is a common skin disease that impacts an estimated 50 million people in the US annually. Acne often affects teenagers and young adults, however in more recent years women in their 30s and 40s are increasingly affected. There are several over-the-counter (OTC) drugs available, including actives such as benzoyl peroxide and salicylic acid. In order to improve the efficacy of acne actives, different strategies are created, such as using newly approved OTC adapalene and/or dermatologist prescribed drugs including antibiotics.
Cutaneous bacterial infection by Gram-positive bacteria induces an essential innate immune response in dermal fibroblasts resulting in rapid differentiation of a subset of fibroblasts into adipocytes (reactive adipogenesis). Induction of adipogenesis is accompanied by a large yet transient increase in production of the antimicrobial peptide (AMP) cathelicidin (Camp) by preadipocytes during transition to mature adipocytes. Exposure to retinoic acid (RA) further enhanced Camp expression in 3T3-L1 preadipocytes (129-fold vs.
The control of wound healing and regeneration is not fully clear. To learn, we study 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. Both tissue injury or exogenous dsRNA (polyI:polyC) treatment stimulate transcription of OAS genes (within top 15 of 19,234 transcripts, P=8.3*10-13), already known to activate the antiviral endoribonuclease RNase L that cleaves viral RNA.
Fibrosis in SSc leads to failure of the skin, lungs and other organs and has no effective treatments. Myofibroblast activation underlies fibrosis in different organs, but the key extracellular cues driving the process are poorly understood. We had shown that IL6, a multifunctional cytokine, is elevated in SSc patients. An unbiased multi-ethnic genetic approach identified SSc-associated SNPs at for JAK-STAT, implicated in IL6 signaling. Here we investigated the IL6/JAK/STAT axis in SSc skin and lung, and the effect of the JAK inhibitor tofacitinib in preclinical models of organ fibrosis.
Wound care is a major public health burden, frequently in patients with diabetes, pressure ulcers, prolonged immobilization, and venous insufficiency. To find better wound treatments, we and others have shown the importance of the innate immune response in coordinating the earliest events after wounding. To determine the role of neutrophils in wound healing, we performed full-thickness punch biopsies on mouse back skin and measured neutrophil recruitment by FACS analysis. We find that shortly after wounding, neutrophils are rapidly recruited to the wound site, where they can prevent infection and facilitate repair.
Macroautophagy (hereafter autophagy) is a cellular catabolic process that is implicated in many physiological and pathological processes. However, the role of autophagy in skin wound healing is unknown. Here we show that epidermal autophagy deficiency impairs wound healing in mice. Epidermis-specific deletion of the autophagy essential genes Atg5 or Atg7 inhibited wound healing in mice. Epidermal autophagy deficiency inhibited wound closure, re-epithelialization, dermal granulation tissue formation, and inflammatory immune cell infiltration.
Scleroderma is characterized by synchronous fibrosis in the skin and other organs with the myofibroblast as the main pathogenic cell driver. The mechanisms underlying mesenchymal progenitor-to-myofibroblast transition and sustained activation remain unknown. By unbiased RNAseq transcriptome analysis, we identified SPAG17, a gene encoding a cilia-related protein, as the most differentially-expressed gene in scleroderma skin biopsies (reduced 4.18-fold; p< 0.0001). SPAG17 mRNA abundance was negatively correlated with the Modified Rodnan Skin Score.