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Developmental Cell Feb 2021Skin undergoes constant self-renewal, and its functional decline is a visible consequence of aging. Understanding human skin aging requires in-depth knowledge of the...
Skin undergoes constant self-renewal, and its functional decline is a visible consequence of aging. Understanding human skin aging requires in-depth knowledge of the molecular and functional properties of various skin cell types. We performed single-cell RNA sequencing of human eyelid skin from healthy individuals across different ages and identified eleven canonical cell types, as well as six subpopulations of basal cells. Further analysis revealed progressive accumulation of photoaging-related changes and increased chronic inflammation with age. Transcriptional factors involved in the developmental process underwent early-onset decline during aging. Furthermore, inhibition of key transcription factors HES1 in fibroblasts and KLF6 in keratinocytes not only compromised cell proliferation, but also increased inflammation and cellular senescence during aging. Lastly, we found that genetic activation of HES1 or pharmacological treatment with quercetin alleviated cellular senescence of dermal fibroblasts. These findings provide a single-cell molecular framework of human skin aging, providing a rich resource for developing therapeutic strategies against aging-related skin disorders.
Topics: Adolescent; Adult; Aged; Dermis; Epidermis; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; Humans; Middle Aged; Single-Cell Analysis; Skin Aging; Transcription Factor HES-1; Transcriptome; Young Adult
PubMed: 33238152
DOI: 10.1016/j.devcel.2020.11.002 -
International Dental Journal Jun 2021Gingival recession is a common finding in daily clinical practice. Several issues may be associated with the apical shift of the gingival margin such as dentine... (Review)
Review
Gingival recession is a common finding in daily clinical practice. Several issues may be associated with the apical shift of the gingival margin such as dentine hypersensitivity, root caries, non-carious cervical lesions (NCCLs), and compromised aesthetics. The first step in an effective management and prevention program is to identify susceptibility factors and modifiable conditions associated with gingival recession. Non-surgical treatment options for gingival recession defects include establishment of optimal plaque control, removal of overhanging subgingival restorations, behaviour change interventions, and use of desensitising agents. In cases where a surgical approach is indicated, coronally advanced flap and tunnelling procedures combined with a connective tissue graft are considered the most predictable treatment options for single and multiple recession defects. If there is a contraindication for harvesting a connective tissue graft from the palate or the patient wants to avoid a donor site surgery, adjunctive use of acellular dermal matrices, collagen matrices, and/or enamel matrix derivatives can be a valuable treatment alternative. For gingival recession defects associated with NCCLs a combined restorative-surgical approach can provide favourable clinical outcomes. If a patient refuses a surgical intervention or there are other contraindications for an invasive approach, gingival conditions should be maintained with preventive measures. This paper gives a concise review on when and how to treat gingival recession defects.
Topics: Acellular Dermis; Connective Tissue; Gingiva; Gingival Recession; Humans; Surgical Flaps; Treatment Outcome
PubMed: 34024328
DOI: 10.1111/idj.12617 -
Aging Cell Feb 2024Skin aging is characterized by changes in its structural, cellular, and molecular components in both the epidermis and dermis. Dermal aging is distinguished by reduced... (Review)
Review
Skin aging is characterized by changes in its structural, cellular, and molecular components in both the epidermis and dermis. Dermal aging is distinguished by reduced dermal thickness, increased wrinkles, and a sagging appearance. Due to intrinsic or extrinsic factors, accumulation of excessive reactive oxygen species (ROS) triggers a series of aging events, including imbalanced extracellular matrix (ECM) homeostasis, accumulation of senescent fibroblasts, loss of cell identity, and chronic inflammation mediated by senescence-associated secretory phenotype (SASP). These events are regulated by signaling pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), mechanistic target of rapamycin (mTOR), transforming growth factor beta (TGF-β), and insulin-like growth factor 1 (IGF-1). Senescent fibroblasts can induce and accelerate age-related dysfunction of other skin cells and may even cause systemic inflammation. In this review, we summarize the role of dermal fibroblasts in cutaneous aging and inflammation. Moreover, the underlying mechanisms by which dermal fibroblasts influence cutaneous aging and inflammation are also discussed.
Topics: Humans; Cellular Senescence; Fibroblasts; Dermis; Inflammation; Skin Aging
PubMed: 38040661
DOI: 10.1111/acel.14054 -
American Journal of Clinical Dermatology May 2021Dermatitis herpetiformis (DH), presenting with an intense itch and blistering symmetrical rash, typically on the elbows, knees, and buttocks, is a cutaneous... (Review)
Review
Dermatitis herpetiformis (DH), presenting with an intense itch and blistering symmetrical rash, typically on the elbows, knees, and buttocks, is a cutaneous manifestation of celiac disease. Though overt gastrointestinal symptoms are rare, three-fourths of patients with DH have villous atrophy in the small bowel, and the rest have celiac-type inflammatory changes. DH affects mostly adults and slightly more males than females. The mean age at onset is about 50 years. DH diagnosis is confirmed by showing granular immunoglobulin A deposits in the papillary dermis. The DH autoantigen, transglutaminase 3, is deposited at the same site in tightly bound immune complexes. At present, the DH-to-celiac disease prevalence is 1:8. The incidence of DH is decreasing, whereas that of celiac disease is increasing, probably because of improved diagnostics. In DH, the treatment of choice for all patients is a gluten-free diet (GFD) in which uncontaminated oats are allowed. At onset, most patients need additional dapsone to rapidly control the rash and itching. Dapsone can be stopped after a mean of 2 years, and a strict lifelong GFD alone is required. Dietary adherence offers an excellent long-term prognosis for patients with DH, with a normal quality of life and all-cause mortality.
Topics: Adult; Age Factors; Celiac Disease; Combined Modality Therapy; Dapsone; Dermatitis Herpetiformis; Dermis; Diet, Gluten-Free; Female; Humans; Immunoglobulin A; Intestinal Mucosa; Intestine, Small; Male; Patient Compliance; Prevalence; Prognosis; Quality of Life; Risk Factors; Sex Factors; Treatment Outcome
PubMed: 33432477
DOI: 10.1007/s40257-020-00584-2 -
TheScientificWorldJournal 2020Intradermal therapy, known as mesotherapy, is a technique used to inject a drug into the surface layer of the skin. In particular, it involves the use of a short needle... (Review)
Review
Intradermal therapy, known as mesotherapy, is a technique used to inject a drug into the surface layer of the skin. In particular, it involves the use of a short needle to deposit the drug in the dermis. The intradermal microdeposit modulates the drug's kinetics, slowing absorption and prolonging the local mechanism of action. It is successfully applied in the treatment of some forms of localized pain syndromes and other local clinical conditions. It could be suggested when a systemic drug-sparing effect is useful, when other therapies have failed (or cannot be used), and when it can synergize with other pharmacological or nonpharmacological therapies. Despite the lack of randomized clinical trials in some fields of application, a general consensus is also reached in nonpharmacological mechanism of action, the technique execution modalities, the scientific rationale to apply it in some indications, and the usefulness of the informed consent. The Italian Mesotherapy Society proposes this position paper to apply intradermal therapy based on scientific evidence and no longer on personal bias.
Topics: Analgesics; Animals; Dermis; Forecasting; Humans; Injections, Intradermal; Italy; Mesotherapy; Pain; Practice Guidelines as Topic; Skin Absorption; Treatment Outcome
PubMed: 32577099
DOI: 10.1155/2020/3542848 -
Dermatology (Basel, Switzerland) 2020Hair is a defining feature of mammals and has critical functions, including protection, production of sebum, apocrine sweat and pheromones, social and sexual... (Review)
Review
Hair is a defining feature of mammals and has critical functions, including protection, production of sebum, apocrine sweat and pheromones, social and sexual interactions, thermoregulation, and provision of stem cells for skin homeostasis, regeneration, and repair. The hair follicle (HF) is considered a "mini-organ," consisting of intricate and well-organized structures which originate from HF stem and progenitor cells. Dermal papilla cells are the main components of the mesenchymal compartments in the hair bulb and are instrumental in generating signals to regulate the behavior of neighboring epithelial cells during the hair cycle. Mesenchymal-epithelial interactions within the dermal papilla niche drive HF embryonic development as well as the postnatal hair growth and regeneration cycle. This review summarizes the current understanding of HF development, repair, and regeneration, with special focus on cell signaling pathways governing these processes. In particular, we discuss emerging paradigms of molecular signaling governing the dermal papilla-epithelial cellular interactions during hair growth and maintenance and the recent progress made towards tissue engineering of human hair follicles.
Topics: Animals; Dermis; Hair Follicle; Humans; Mice; Regeneration; Skin; Stem Cells; Wound Healing
PubMed: 32163945
DOI: 10.1159/000506155 -
Cells Feb 2020Human skin dermis contains fibroblast subpopulations in which characterization is crucial due to their roles in extracellular matrix (ECM) biology. This study...
Fibroblasts from the Human Skin Dermo-Hypodermal Junction are Distinct from Dermal Papillary and Reticular Fibroblasts and from Mesenchymal Stem Cells and Exhibit a Specific Molecular Profile Related to Extracellular Matrix Organization and Modeling.
Human skin dermis contains fibroblast subpopulations in which characterization is crucial due to their roles in extracellular matrix (ECM) biology. This study investigates the properties of fibroblasts localized at the frontier of deep dermis and hypodermis, i.e., dermo-hypodermal junction fibroblasts (F-DHJ), which were compared to intermediate reticular dermis (Fr) and superficial papillary dermis (Fp) fibroblasts. F-DHJ differed from Fr and Fp cells in their wider potential for differentiation into mesodermal lineages and in their absence of contractility when integrated in a three-dimensional dermal equivalent. The transcriptomic profile of F-DHJ exhibited specificities in the expression of genes involved in ECM synthesis-processing and "tissue skeleton" organization. In accordance with transcriptome data, ECM proteins, notably Tenascin C, distributions differed between the reticular dermis and the dermo-hypodermal junction areas, which was documented in normal adult skin. Finally, genome-wide transcriptome profiling was used to evaluate the molecular proximity of F-DHJ with the two dermal fibroblast populations (Fp and Fr) and with the mesenchymal stem cells (MSCs) corresponding to five tissue origins (bone marrow, fat, amnion, chorion, and cord). This comparative analysis classified the three skin fibroblast types, including F-DHJ, as a clearly distinct group from the five MSC sample origins.
Topics: Adolescent; Adult; Aged; Aging; Biomarkers; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Shape; Dermis; Extracellular Matrix; Female; Fibroblasts; Humans; Mesenchymal Stem Cells; Middle Aged; Models, Biological; Phenotype; RNA, Messenger; Tenascin; Transcriptome; Young Adult
PubMed: 32033496
DOI: 10.3390/cells9020368 -
Theranostics 2021Vascular endothelial cells (ECs) are increasingly recognized as active players in intercellular crosstalk more than passive linings of a conduit for nutrition delivery.... (Comparative Study)
Comparative Study
Vascular endothelial cells (ECs) are increasingly recognized as active players in intercellular crosstalk more than passive linings of a conduit for nutrition delivery. Yet, their functional roles and heterogeneity in skin remain uncharacterized. We have used single-cell RNA sequencing (scRNA-seq) as a profiling strategy to investigate the tissue-specific features and intra-tissue heterogeneity in dermal ECs at single-cell level. Skin tissues collected from 10 donors were subjected to scRNA-seq. Human dermal EC atlas of over 23,000 single-cell transcriptomes was obtained and further analyzed. Arteriovenous markers discovered in scRNA-seq were validated in human skin samples via immunofluorescence. To illustrate tissue-specific characteristics of dermal ECs, ECs from other human tissues were extracted from previously reported data and compared with our transcriptomic data. In comparison with ECs from other human tissues, dermal ECs possess unique characteristics in metabolism, cytokine signaling, chemotaxis, and cell adhesions. Within dermal ECs, 5 major subtypes were identified, which varied in molecular signatures and biological activities. Metabolic transcriptome analysis revealed a preference for oxidative phosphorylation in arteriole ECs when compared to capillary and venule ECs. Capillary ECs abundantly expressed HLA-II molecules, suggesting its immune-surveillance role. Post-capillary venule ECs, with high levels of adhesion molecules, were equipped with the capacity in immune cell arrest, adhesion, and infiltration. Our study provides a comprehensive characterization of EC features and heterogeneity in human dermis and sets the stage for future research in identifying disease-specific alterations of dermal ECs in various dermatoses.
Topics: Base Sequence; Biomarkers; Capillaries; Cell Adhesion; Dermis; Endothelial Cells; Gene Expression; Humans; Phenotype; Single-Cell Analysis; Transcriptome; Venules
PubMed: 33995668
DOI: 10.7150/thno.54917 -
Proceedings of the National Academy of... Mar 2020Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked...
Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.
Topics: Animals; Dermis; Epidermal Cells; Epidermis; Hair Follicle; Mice; Mice, Inbred C57BL; Muscles; Re-Epithelialization; Regeneration; Sensory Receptor Cells; Skin Aging; Stem Cell Niche; Stem Cell Transplantation; Stem Cells; Transcriptome; Wound Healing
PubMed: 32094197
DOI: 10.1073/pnas.1901720117 -
Cell Stem Cell Sep 2020Dermal fibroblasts exhibit considerable heterogeneity during homeostasis and in response to injury. Defining lineage origins of reparative fibroblasts and regulatory...
Dermal fibroblasts exhibit considerable heterogeneity during homeostasis and in response to injury. Defining lineage origins of reparative fibroblasts and regulatory programs that drive fibrosis or, conversely, promote regeneration will be essential for improving healing outcomes. Using complementary fate-mapping approaches, we show that hair follicle mesenchymal progenitors make limited contributions to wound repair. In contrast, extrafollicular progenitors marked by the quiescence-associated factor Hic1 generated the bulk of reparative fibroblasts and exhibited functional divergence, mediating regeneration in the center of the wound neodermis and scar formation in the periphery. Single-cell RNA-seq revealed unique transcriptional, regulatory, and epithelial-mesenchymal crosstalk signatures that enabled mesenchymal competence for regeneration. Integration with scATAC-seq highlighted changes in chromatin accessibility within regeneration-associated loci. Finally, pharmacological modulation of RUNX1 and retinoic acid signaling or genetic deletion of Hic1 within wound-activated fibroblasts was sufficient to modulate healing outcomes, suggesting that reparative fibroblasts have latent but modifiable regenerative capacity.
Topics: Cicatrix; Dermis; Fibroblasts; Hair Follicle; Humans; Skin; Wound Healing
PubMed: 32755548
DOI: 10.1016/j.stem.2020.07.008