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International Journal of Molecular... Nov 2021Skin aging is a complex process influenced by intrinsic and extrinsic factors. Together, these factors affect the structure and function of the epidermis and dermis.... (Review)
Review
Skin aging is a complex process influenced by intrinsic and extrinsic factors. Together, these factors affect the structure and function of the epidermis and dermis. Histologically, aging skin typically shows epidermal atrophy due to decreased cell numbers. The dermis of aged skin shows decreased numbers of mast cells and fibroblasts. Fibroblast senescence contributes to skin aging by secreting a senescence-associated secretory phenotype, which decreases proliferation by impairing the release of essential growth factors and enhancing degradation of the extracellular matrix through activation of matrix metalloproteinases (MMPs). Several molecular mechanisms affect skin aging including telomere shortening, oxidative stress and MMP, cytokines, autophagic control, microRNAs, and the microbiome. Accumulating evidence on the molecular mechanisms of skin aging has provided clinicians with a wide range of therapeutic targets for treating aging skin.
Topics: Atrophy; Cell Proliferation; Cellular Senescence; Epidermal Cells; Fibroblasts; Humans; Mast Cells; Matrix Metalloproteinases; Skin Aging; Telomere Shortening
PubMed: 34830368
DOI: 10.3390/ijms222212489 -
British Journal of Pharmacology Mar 2022Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in...
BACKGROUND AND PURPOSE
Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in mediating a variety of biological activities. However, its role in skin wound healing remains unknown.
EXPERIMENTAL APPROACH
Fgf21 knockout (Fgf21 KO) mice were used to determine the effect of FGF21 on wound healing. The source of FGF21 and its target cells were determined by immunohistochemistry, immunoblotting, and ELISA assay. Moreover, Sirt1 and Atg7 mice were constructed and injected with the epidermal-specific Cre virus to elucidate the underlying mechanisms. Migration and differentiation of keratinocytes were evaluated in vitro by cell scratch assays, immunofluorescence, and qRT-RCR. The effects were further assessed when SIRT1, ATG7, ATG5, BECN1, and P53 were silenced. Interactions between SIRT1 and autophagy-related genes were assessed using immunoprecipitation assays.
KEY RESULTS
FGF21 was active in fibroblasts and promoted migration and differentiation of keratinocytes following injury. After wounding, SIRT1 expression and autophagosome synthesis were lower in Fgf21 KO mice. Depletion of ATG7 in keratinocytes counteracted the FGF21-induced increases in migration and differentiation, suggesting that autophagy is required for the FGF21-mediated pro-healing effects. Furthermore, epithelial-specific Sirt1 knockout abolished the FGF21-mediated improvements of autophagy and wound healing. Silencing of SIRT1 in keratinocytes, which decreased deacetylation of p53 and autophagy-related proteins, revealed that FGF21-induced autophagy during wound healing was SIRT1-dependent.
CONCLUSIONS AND IMPLICATIONS
FGF21 is a key regulator of keratinocyte migration and differentiation during wound healing. FGF21 may be a novel therapeutic target to accelerate would healing.
Topics: Animals; Autophagy; Cell Movement; Epidermal Cells; Fibroblast Growth Factors; Keratinocytes; Mice; Mice, Knockout; Sirtuin 1; Tumor Suppressor Protein p53; Wound Healing
PubMed: 34608629
DOI: 10.1111/bph.15701 -
Science (New York, N.Y.) Nov 2021Immune and tissue stem cells retain an epigenetic memory of inflammation that intensifies sensitivity to future encounters. We investigated whether and to what...
Immune and tissue stem cells retain an epigenetic memory of inflammation that intensifies sensitivity to future encounters. We investigated whether and to what consequence stem cells possess and accumulate memories of diverse experiences. Monitoring a choreographed response to wounds, we found that as hair follicle stem cells leave their niche, migrate to repair damaged epidermis, and take up long-term foreign residence there, they accumulate long-lasting epigenetic memories of each experience, culminating in post-repair epigenetic adaptations that sustain the epidermal transcriptional program and surface barrier. Each memory is distinct, separable, and has its own physiological impact, collectively endowing these stem cells with heightened regenerative ability to heal wounds and broadening their tissue-regenerating tasks relative to their naïve counterparts.
Topics: Adaptation, Physiological; Animals; Cell Movement; Chromatin; Epidermal Cells; Epigenesis, Genetic; Hair Follicle; Homeostasis; Inflammation; Mice; Regeneration; Stem Cell Niche; Stem Cells; Transcriptome; Wound Healing
PubMed: 34822296
DOI: 10.1126/science.abh2444 -
Cell Host & Microbe Aug 2021The epidermis forms a barrier that defends the body from desiccation and entry of harmful substances, while also sensing and integrating environmental signals. The...
The epidermis forms a barrier that defends the body from desiccation and entry of harmful substances, while also sensing and integrating environmental signals. The tightly orchestrated cellular changes needed for the formation and maintenance of this epidermal barrier occur in the context of the skin microbiome. Using germ-free mice, we demonstrate the microbiota is necessary for proper differentiation and repair of the epidermal barrier. These effects are mediated by microbiota signaling through the aryl hydrocarbon receptor (AHR) in keratinocytes, a xenobiotic receptor also implicated in epidermal differentiation. Mice lacking keratinocyte AHR are more susceptible to barrier damage and infection, during steady-state and epicutaneous sensitization. Colonization with a defined consortium of human skin isolates restored barrier competence in an AHR-dependent manner. We reveal a fundamental mechanism whereby the microbiota regulates skin barrier formation and repair, which has far-reaching implications for the numerous skin disorders characterized by epidermal barrier dysfunction.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Line; Epidermal Cells; Epidermis; Female; Humans; Keratinocytes; Male; Mice; Mice, Inbred C57BL; Microbiota; Receptors, Aryl Hydrocarbon; Signal Transduction; Skin; Skin Diseases
PubMed: 34214492
DOI: 10.1016/j.chom.2021.05.011 -
Cell Stem Cell Sep 2021Epidermal stem cells display remarkable capacities to restore the barrier upon skin injury. In this issue of Cell Stem Cell, Huang et al. (2021) use innovative...
Epidermal stem cells display remarkable capacities to restore the barrier upon skin injury. In this issue of Cell Stem Cell, Huang et al. (2021) use innovative high-resolution intravital imaging to identify a vital function of sensory nerves in regulating a subset of epidermal stem cells for wound repair.
Topics: Epidermal Cells; Nerve Tissue; Stem Cells; Wound Healing
PubMed: 34478625
DOI: 10.1016/j.stem.2021.08.009 -
Journal of Visualized Experiments : JoVE Jul 2017The keratinocyte (KC) is the predominant cell type in the epidermis, the outermost layer of the skin. Epidermal KCs play a critical role in providing skin defense by...
The keratinocyte (KC) is the predominant cell type in the epidermis, the outermost layer of the skin. Epidermal KCs play a critical role in providing skin defense by forming an intact skin barrier against environmental insults, such as UVB irradiation or pathogens, and also by initiating an inflammatory response upon those insults. Here we describe methods to isolate KCs from neonatal mouse skin and from adult mouse tail skin. We also describe culturing conditions using defined growth supplements (dGS) in comparison to chelexed fetal bovine serum (cFBS). Functionally, we show that both neonatal and adult KCs are highly responsive to high calcium-induced terminal differentiation, tight junction formation and stratification. Additionally, cultured adult KCs are susceptible to UVB-triggered cell death and can release large amounts of TNF upon UVB irradiation. Together, the methods described here will be useful to researchers for the setup of in vitro models to study epidermal biology in the neonatal mouse and/or the adult mouse.
Topics: Animals; Animals, Newborn; Apoptosis; Calcium; Cell Differentiation; Cells, Cultured; Epidermal Cells; Keratinocytes; Mice; Skin; Tumor Necrosis Factor-alpha; Ultraviolet Rays; Video Recording
PubMed: 28745643
DOI: 10.3791/56027 -
Developmental Cell Dec 2022Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly...
Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here, we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and, when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support human keratinocyte stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.
Topics: Humans; Cadherins; Desmoglein 1; Endosomes; Epidermal Cells; Epidermis; Keratinocytes
PubMed: 36495876
DOI: 10.1016/j.devcel.2022.11.010 -
Biomedicine & Pharmacotherapy =... Mar 2019Promoting epidermal cell survival in an oxidative stress microenvironment is vital for skin regeneration after burns and/or wounds. However, few studies have explored...
Promoting epidermal cell survival in an oxidative stress microenvironment is vital for skin regeneration after burns and/or wounds. However, few studies have explored the mediators related to epidermal cell apoptosis in an oxidative stress microenvironment. Cellular viability was determined using the MTT assay, TUNEL staining, western blot analysis and LDH release assay. Two independent siRNAs were transfected into HaCaT cell to repress INF2 and/or HIF1 in the presence of HO. Mitochondrial function was determined using JC-1 staining, mitochondrial ROS staining, immunofluorescence staining and western blotting. In the present study, our data demonstrated that the expression of inverted formin-2 (INF2) increased rapidly when the cells were exposed to HO. Interestingly, INF2 knockdown promoted HaCaT cell survival via reducing HO-mediated cell apoptosis. Molecular investigations demonstrated that INF2 deletion attenuated mitochondrial ROS overloading, restored the cellular redox balance, sustained the mitochondrial membrane potential, improved mitochondrial respiratory function and corrected the mitochondrial dynamics disorder in an HO-mimicking oxidative stress microenvironment. In addition, INF2 deletion upregulated the expression of HIF1. Interestingly, the inhibition of HIF1 increased cell death and caused mitochondrial stress despite the deletion of INF2, suggesting that the HIF1 signaling pathway is required for INF2 deletion-mediated HaCaT cell survival and mitochondrial protection. Altogether, our results identified INF2 as a novel apoptotic mediator for oxidative stress-mediated HaCaT cell death via modulating mitochondrial stress and repressing the HIF1 signaling pathway. This finding provides evidence to support the critical role played by the INF2-HIF1 axis in regulating mitochondrial stress and epidermal cell viability in an oxidative stress microenvironment.
Topics: Apoptosis; Cell Line; Dose-Response Relationship, Drug; Epidermal Cells; Formins; Humans; Hydrogen Peroxide; Hypoxia-Inducible Factor 1, alpha Subunit; Microfilament Proteins; Oxidative Stress; Signal Transduction
PubMed: 30579254
DOI: 10.1016/j.biopha.2018.12.046 -
Plastic and Reconstructive Surgery Jul 2019The management of deep partial-thickness and full-thickness skin defects remains a significant challenge. Particularly with massive defects, the current standard...
BACKGROUND
The management of deep partial-thickness and full-thickness skin defects remains a significant challenge. Particularly with massive defects, the current standard treatment, split-thickness skin grafting, is fraught with donor-site limitations and unsatisfactory long-term outcomes. A novel, autologous, bioengineered skin substitute was developed to address this problem.
METHODS
To determine whether this skin substitute could safely provide permanent defect coverage, a phase I clinical trial was performed at the University Children's Hospital Zurich. Ten pediatric patients with acute or elective deep partial- or full-thickness skin defects were included. Skin grafts of 49 cm were bioengineered using autologous keratinocytes and fibroblasts isolated from a patient's small skin biopsy specimen (4 cm), incorporated in a collagen hydrogel.
RESULTS
Graft take, epithelialization, infection, adverse events, skin quality, and histology were analyzed. Median graft take at 21 days postoperatively was 78 percent (range, 0 to 100 percent). Healed skin substitutes were stable and skin quality was nearly normal. There were four cases of hematoma leading to partial graft loss. Histology at 3 months revealed a well-stratified epidermis and a dermal compartment comparable to native skin. Mean follow-up duration was 15 months.
CONCLUSIONS
In the first clinical application of this novel skin substitute, safe coverage of skin defects was achieved. Safety and efficacy phase II trials comparing the novel skin substitute to split-thickness skin grafts are ongoing.
CLINICAL QUESTION/LEVEL OF EVIDENCE
Therapeutic, IV.
Topics: Adolescent; Bioengineering; Burns; Cells, Cultured; Child; Child, Preschool; Dermis; Epidermal Cells; Epidermis; Female; Fibroblasts; Humans; Infant; Keratinocytes; Male; Prospective Studies; Skin; Skin Transplantation; Skin, Artificial; Transplantation, Autologous
PubMed: 31246829
DOI: 10.1097/PRS.0000000000005746 -
American Journal of Physiology. Cell... Dec 2022The epidermis is a specialized epithelium that constitutes the outermost layer of the skin, and it provides a protective barrier against environmental assaults.... (Review)
Review
The epidermis is a specialized epithelium that constitutes the outermost layer of the skin, and it provides a protective barrier against environmental assaults. Primarily consisting of multilayered keratinocytes, the epidermis is continuously renewed by proliferation of stem cells and the differentiation of their progeny, which undergo terminal differentiation as they leave the basal layer and move upward toward the surface, where they die and slough off. Basal keratinocytes rest on a basement membrane at the dermal-epidermal junction that is composed of specific extracellular matrix proteins organized into interactive and mechanically supportive networks. Firm attachment of basal keratinocytes, and their dynamic regulation via focal adhesions and hemidesmosomes, is essential for maintaining major skin processes, such as self-renewal, barrier function, and resistance to physical and chemical stresses. The adhesive integrin receptors expressed by epidermal cells serve structural, signaling, and mechanosensory roles that are critical for epidermal cell anchorage and tissue homeostasis. More specifically, the basement membrane components play key roles in preserving the stem cell pool, and establishing cell polarity cues enabling asymmetric cell divisions, which result in the transition from a proliferative basal cell layer to suprabasal cells committed to terminal differentiation. Finally, through a well-regulated sequence of synthesis and remodeling, the components of the dermal-epidermal junction play an essential role in regeneration of the epidermis during skin healing. Here too, they provide biological and mechanical signals that are essential to the restoration of barrier function.
Topics: Epidermis; Epidermal Cells; Basement Membrane; Keratinocytes; Dermis; Cell Differentiation
PubMed: 36374168
DOI: 10.1152/ajpcell.00069.2022