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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 -
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 -
Frontiers in Immunology 2022Fibrotic scars are common in both human and mouse skin wounds. However, wound-induced hair neogenesis in the murine wounding models often results in regenerative repair...
BACKGROUND
Fibrotic scars are common in both human and mouse skin wounds. However, wound-induced hair neogenesis in the murine wounding models often results in regenerative repair response. Herein, we aimed to uncover cellular functional heterogeneity in dermis between fibrotic and regenerative wound healing fates.
METHODS
The expression matrix of single-cell RNA sequencing (scRNA-seq) data of fibrotic and regenerative wound dermal cells was filtered, normalized, and scaled; underwent principal components analysis; and further analyzed by Uniform Manifold Approximation and Projection (UMAP) for dimension reduction with the Seurat package. Cell types were annotated, and cell-cell communications were analyzed. The core cell population myofibroblast was identified and the biological functions of ligand and receptor genes between myofibroblast and macrophage were evaluated. Specific genes between fibrotic and regenerative myofibroblast and macrophage were identified. Temporal dynamics of myofibroblast and macrophage were reconstructed with the Monocle tool.
RESULTS
Across dermal cells, there were six cell types, namely, EN1-negative myofibroblasts, EN1-positive myofibroblasts, hematopoietic cells, macrophages, pericytes, and endothelial cells. Ligand and receptor genes between myofibroblasts and macrophages mainly modulated cell proliferation and migration, tube development, and the TGF-β pathway. Specific genes that were differentially expressed in fibrotic compared to regenerative myofibroblasts or macrophages were separately identified. Specific genes between fibrotic and regenerative myofibroblasts were involved in the mRNA metabolic process and organelle organization. Specific genes between fibrotic and regenerative macrophages participated in regulating immunity and phagocytosis. We then observed the underlying evolution of myofibroblasts or macrophages.
CONCLUSION
Collectively, our findings reveal that myofibroblasts and macrophages may alter the skin wound healing fate through modulating critical signaling pathways.
Topics: Animals; Dermis; Endothelial Cells; Fibrosis; Ligands; Mice; Sequence Analysis, RNA; Wound Healing
PubMed: 35664010
DOI: 10.3389/fimmu.2022.875407 -
Anais Brasileiros de Dermatologia 2018
Topics: Adult; Axilla; Biopsy; Dermis; Female; Fox-Fordyce Disease; Hair Follicle; Humans; Vulva
PubMed: 29641729
DOI: 10.1590/abd1806-4841.20187348 -
Frontiers in Immunology 2019Juvenile-onset systemic sclerosis (jSSc) is a rare and severe autoimmune disease with associated life-threatening organ inflammation and evidence of fibrosis. The organ... (Review)
Review
Juvenile-onset systemic sclerosis (jSSc) is a rare and severe autoimmune disease with associated life-threatening organ inflammation and evidence of fibrosis. The organ manifestations of jSSc resemble adult SSc, but with better outcomes and survival. The etiology of jSSc appears to reflect adult-onset SSc, with similar inflammatory mediators and autoantibodies, but with a significant population of children with uncharacterized anti-nuclear antibodies. The genetics of patients with jSSc differ from women with SSc, resembling instead the genes of adult males with SSc, with additional HLA genes uniquely associated with childhood-onset disease. Current treatments are aimed at inhibiting the inflammatory aspect of disease, but important mechanisms of fibrosis regulated by dermal white adipose tissue dendritic cells may provide an avenue for targeting and potentially reversing the fibrotic stage.
Topics: Adult; Antibodies, Antinuclear; Child; Dendritic Cells; Dermis; Female; Humans; Scleroderma, Systemic; Subcutaneous Fat
PubMed: 31293569
DOI: 10.3389/fimmu.2019.01352 -
Frontiers in Immunology 2019Pemphigoid diseases are a subgroup of autoimmune skin diseases characterized by widespread tense blisters. Standard of care typically involves immunosuppressive... (Review)
Review
Pemphigoid diseases are a subgroup of autoimmune skin diseases characterized by widespread tense blisters. Standard of care typically involves immunosuppressive treatments, which may be insufficient and are often associated with significant adverse events. As such, a deeper understanding of the pathomechanism(s) of pemphigoid diseases is necessary in order to identify improved therapeutic approaches. A major initiator of pemphigoid diseases is the accumulation of autoantibodies against proteins at the dermal-epidermal junction (DEJ), followed by protease activation at the lesion. The contribution of proteases to pemphigoid disease pathogenesis has been investigated using a combination of and models. These studies suggest proteolytic degradation of anchoring proteins proximal to the DEJ is crucial for dermal-epidermal separation and blister formation. In addition, proteases can also augment inflammation, expose autoantigenic cryptic epitopes, and/or provoke autoantigen spreading, which are all important in pemphigoid disease pathology. The present review summarizes and critically evaluates the current understanding with respect to the role of proteases in pemphigoid diseases.
Topics: Autoantibodies; Autoantigens; Dermis; Epidermis; Humans; Pemphigoid, Bullous; Peptide Hydrolases
PubMed: 31297118
DOI: 10.3389/fimmu.2019.01454 -
Experimental Dermatology Sep 2014Here, we explore the evolution and development of skin-associated adipose tissue with the goal of establishing nomenclature for this tissue. Underlying the reticular... (Review)
Review
Here, we explore the evolution and development of skin-associated adipose tissue with the goal of establishing nomenclature for this tissue. Underlying the reticular dermis, a thick layer of adipocytes exists that encases mature hair follicles in rodents and humans. The association of lipid-filled cells with the skin is found in many invertebrate and vertebrate species. Historically, this layer of adipocytes has been termed subcutaneous adipose, hypodermis and subcutis. Recent data have revealed a common precursor for dermal fibroblasts and intradermal adipocytes during development. Furthermore, the development of adipocytes in the skin is independent from that of subcutaneous adipose tissue development. Finally, the role of adipocytes has been shown to be relevant for epidermal homoeostasis during hair follicle regeneration and wound healing. Thus, we propose a refined nomenclature for the cells and adipose tissue underlying the reticular dermis as intradermal adipocytes and dermal white adipose tissue, respectively.
Topics: Adipocytes, White; Adipose Tissue, White; Animals; Dermis; Hair Follicle; Humans; Mice; Regeneration; Species Specificity; Subcutaneous Fat; Terminology as Topic; Wound Healing
PubMed: 24841073
DOI: 10.1111/exd.12450 -
Journal of Anatomy Aug 2019The structure and function of the skin relies on the complex expression pattern and organisation of extracellular matrix macromolecules, of which collagens are a... (Review)
Review
The structure and function of the skin relies on the complex expression pattern and organisation of extracellular matrix macromolecules, of which collagens are a principal component. The fibrillar collagens, types I and III, constitute over 90% of the collagen content within the skin and are the major determinants of the strength and stiffness of the tissue. However, the minor collagens also play a crucial regulatory role in a variety of processes, including cell anchorage, matrix assembly, and growth factor signalling. In this article, we review the expression patterns, key functions and involvement in disease pathogenesis of the minor collagens found in the skin. While it is clear that the minor collagens are important mediators of normal tissue function, homeostasis and repair, further insight into the molecular level structure and activity of these proteins is required for translation into clinical therapies.
Topics: Animals; Basement Membrane; Collagen; Dermis; Humans
PubMed: 31318053
DOI: 10.1111/joa.12584 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Mar 2017As a novel population of neural crest-origin precursor cells, skin-derived precursor cells (SKPs) can be isolated from both embryonic and adult dermis. These cells have... (Review)
Review
As a novel population of neural crest-origin precursor cells, skin-derived precursor cells (SKPs) can be isolated from both embryonic and adult dermis. These cells have important values for research and potential clinical application in wound healing, organ regeneration and disease treatment for advantages in the abundance of cell sources, accessibility, potential of multipotent differentiation, and absence of ethical concerns. Here we review the developmental and anatomical origins of SKPs and their potential application in regenerative medicine. SKPs originate from the embryonic neural crest, and their sources may vary in different areas of the body. SKPs are widely found in the dermis, especially in the dermal papilla (DP), which was known as a niche of SKPs. The multipotent SKPs can used for autologous transplantation and are of vital importance in tissue repair.
Topics: Cell Differentiation; Cells, Cultured; Dermis; Humans; Neural Crest; Skin; Stem Cells; Wound Healing
PubMed: 28377365
DOI: 10.3969/j.issn.1673-4254.2017.03.26 -
International Journal of Molecular... Jul 2021We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other... (Review)
Review
We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis-e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey-Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)-vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).
Topics: Animals; Antigens, CD34; Dermatitis; Dermis; Humans; Neoplasm Proteins; Skin Neoplasms; Telocytes
PubMed: 34298962
DOI: 10.3390/ijms22147342