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A schematic model of epidermal stem cell competition for skin homeostasis and ageing Top, homeostatic epidermis. COL17A1⁺ stem cells undergo parallel cell divisions that spread horizontally on the basement membrane and naturally generate the mechanical driving force for cell competition to eliminate COL17A1low/− stressed stem cells in the basal layer because of spatial constraints. Bottom, aged epidermis. Thin, atrophic and fragile skin with basal cells of COL17A1⁻MCM2⁻ exhausted/quiescent state resulting from repetitive stem cell competition and clonal expansion processes in homeostatic epidermis.
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Stem cells underlie tissue homeostasis, but their dynamics during ageing—and the relevance of these dynamics to organ ageing—remain unknown. Here we report that the expression of the hemidesmosome component collagen XVII (COL17A1) by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis, and that the r...
Citations
... Skin morphology illustrates observable time passing by epidermal atrophy and fragility, leading to wrinkles, diminished dermal thickness and content, and pigmentary defects [6,20]. Intrinsic factors associated with cell senescence impair the skin's physiological functions, including DNA damage, telomeres shortening, and reactive oxygen species (ROS) production [6]. ...
... The decline in the number of epithelial cells, including DF, Langerhans cells, and melanocytes, combined with ECM degradation, results in an impairment of skin integrity and youthful guise [6]. Ageing skin loses its thickness, rete ridges, melanocytes and functional dermal fibroblasts [20]. Cutaneous fragility has been partly attributed to changes in hemidesmosomes, structures that connect keratinocytes to the basement membrane [20]. ...
... Ageing skin loses its thickness, rete ridges, melanocytes and functional dermal fibroblasts [20]. Cutaneous fragility has been partly attributed to changes in hemidesmosomes, structures that connect keratinocytes to the basement membrane [20]. Epidermal cells and DF and their interaction with each other are critical in defining skin architecture and function [6]. ...
Stem cells are a group of undifferentiated cells capable of increasing to enkindle differentiated cells. Mesenchymal stem cells are versatile multilineage stromal-derived non-hematopoietic progenitor cells that play an essential role in regenerative medicine. They have the aptitude to execute tissue regeneration by triggering inflammation, angiogenesis, and recruiting tissue-specific progenitors. Mesenchymal stem cells possess excellent qualities like stemness potency, ease of isolation, low risk of malignancy, and therapeutic versatility. The predilection of skin mesenchymal stem cells includes hair follicle stem cells, sebaceous gland stem cells, melanocyte stem cells, interfollicular epidermis stem cells, and dermal stem cells. Exosomes are nano-sized membranous extracellular lipidic vesicles. Exosomes deliver cell-free therapeutics. The task of mesenchymal stem cells in dermatologic therapeutics is establishing order in function and integrity. They refine the skin and appearance and restore previous structural foundations in aesthetics.
... Type XVII collagen (COL17) is a type II transmembrane protein expressed in the epidermal basement membrane that influences differentiation of hair follicle stem cells (HFSCs) [11,12]. Expression of COL17 is strictly regulated, the downregulation of COL17 can lead to skin aging, atrophy, fragility, discoloration, and alopecia [13,14]. Similar to other types of collagen, COL17 assembles into a triple-helix structure relied on conserved G-X-Y repeats, where X and Y are mostly proline and hydroxyproline residues [12]. ...
... The major contributions of COL17 are maintenance of hair follicle stem cells (HFSCs) and stabilization of epidermal patterns [14]. Overexpression of COL17 is related to the expression of nestin and SSEA1, which are critical for hair health [31]. ...
... Comparing with previous COL sequential design strategies [7,24], this study focused on extracting fragments from native human COL. Even though the function of COL17 was long been reported [11,14], but the functional fragment search was firstly applied. Moreover, our result showed that the identified variant could benefit HFSCs differentiation mimicking the whole length of COL17 [31]. ...
Collagen XVII (COL17) is a transmembrane protein that mediates skin homeostasis. Due to expression of full length collagen was hard to achieve in microorganisms, arising the needs for selection of collagen fragments with desired functions for microbial biosynthesis. Here, COL17 fragments (27–33 amino acids) were extracted and replicated 16 times for recombinant expression in Escherichia coli. Five variants were soluble expressed, with the highest yield of 223 mg/L. The fusion tag was removed for biochemical and biophysical characterization. Circular dichroism results suggested one variant (sample-1707) with a triple-helix structure at >37 °C. Sample-1707 can assemble into nanofiber (width, 5.6 nm) and form hydrogel at 3 mg/mL. Sample-1707 was shown to induce blood clotting and promote osteoblast differentiation. Furthermore, sample-1707 exhibited high capacity to induce mouse hair follicle stem cells differentiation and osteoblast migration, demonstrating a high capacity to induce skin cell regeneration and promote wound healing. A strong hydrogel was prepared from a chitosan and sample-1707 complex with a swelling rate of >30 % higher than simply using chitosan. Fed-batch fermentation of sample-1707 with a 5-L bioreactor obtained a yield of 600 mg/L. These results support the large-scale production of sample-1707 as a biomaterial for use in the skin care industry.
... This reduction is primarily attributed to the increased activity of matrix-degrading proteases associated with aging. The decrease in COL17A1 levels impairs stem cells attachment to the basement membrane, leading to their elimination from the skin epidermal basal layer, results in decreased rates of keratinocyte renewal and the development of thinner epidermal layers 32,34 . COL17A1 deficiency also plays a significant role in hair aging, which is an inevitable part of the natural aging process 30,35 . ...
... When the epidermis forms a monolayer at the early stages of mouse skin development, the winner cells can kill and engulf the neighboring loser cells [22]. In case of an imbalance in skin homeostasis, cells with decreased COL17A1 expression can be cleared by cells with high COL17A1 expression [23,24]. During cancer progression, ongoing interactions between cancer and stromal cells lead to cellular metabolic competition [25]. ...
Rationale: Skin cells actively metabolize nutrients to ensure cell proliferation and differentiation. Psoriasis is an immune-disorder-related skin disease with hyperproliferation in epidermal keratinocytes and is increasingly recognized to be associated with metabolic disturbance. However, the metabolic adaptations and underlying mechanisms of epidermal hyperproliferation in psoriatic skin remain largely unknown. Here, we explored the role of metabolic competition in epidermal cell proliferation and differentiation in psoriatic skin. Methods: Bulk-and single-cell RNA-sequencing, spatial transcriptomics, and glucose uptake experiments were used to analyze the metabolic differences in epidermal cells in psoriasis. Functional validation in vivo and in vitro was done using imiquimod-like mouse models and inflammatory organoid models. Results: We observed the highly proliferative basal cells in psoriasis act as the winners of the metabolic competition to uptake glucose from suprabasal cells. Using single-cell metabolic analysis, we found that the "winner cells" promote OXPHOS pathway upregulation by COX7B and lead to increased ROS through glucose metabolism, thereby promoting the hyperproliferation of basal cells in psoriasis. Also, to prevent toxic damage from ROS, basal cells activate the glutathione metabolic pathway to increase their antioxidant capacity to assist in psoriasis progression. We further found that COX7B promotes psoriasis development by modulating the activity of the PPAR signaling pathway by bulk RNA-seq analysis. We also observed glucose starvation and high expression of SLC7A11 that causes suprabasal cell disulfide stress and affects the actin cytoskeleton, leading to immature differentiation of suprabasal cells in psoriatic skin. Conclusion: Our study demonstrates the essential role of cellular metabolic competition for skin tissue homeostasis.
... In aged animal skin, reductions in the number of hemidesmosomes and epidermal thickness are evident, correlating with reduced collagen XVII expression [24]. Beyond its structural role in the BM, collagen XVII is also involved in skin rejuvenation by enhancing skin stem cell renewal potential and facilitating structural recovery [24]. ...
... In aged animal skin, reductions in the number of hemidesmosomes and epidermal thickness are evident, correlating with reduced collagen XVII expression [24]. Beyond its structural role in the BM, collagen XVII is also involved in skin rejuvenation by enhancing skin stem cell renewal potential and facilitating structural recovery [24]. Increased collagen XVII expression can attenuate epidermal thinning in aged mice [22,24]. ...
... Beyond its structural role in the BM, collagen XVII is also involved in skin rejuvenation by enhancing skin stem cell renewal potential and facilitating structural recovery [24]. Increased collagen XVII expression can attenuate epidermal thinning in aged mice [22,24]. Additionally, peptides that enhance BM components such as laminins and collagen XVII have shown promise in reducing skin wrinkles [25]. ...
The dermal–epidermal junction (DEJ) is essential for maintaining skin structural integrity and regulating cell survival and proliferation. Thus, DEJ rejuvenation is key for skin revitalization, particularly in age-related DEJ deterioration. Radiofrequency (RF) treatment, known for its ability to enhance collagen fiber production through thermal mechanisms and increase heat shock protein (HSP) expression, has emerged as a promising method for skin rejuvenation. Additionally, RF activates Piezo1, an ion channel implicated in macrophage polarization toward an M2 phenotype and enhanced TGF-β production. This study investigated the impact of RF treatment on HSP47 and HSP90 expression, known stimulators of DEJ protein expression. Furthermore, using in vitro and aged animal skin models, we assessed whether RF-induced Piezo1 activation and the subsequent M2 polarization could counter age-related DEJ changes. The RF treatment of H2O2-induced senescent keratinocytes upregulated the expression of HSP47, HSP90, TGF-β, and DEJ proteins, including collagen XVII. Similarly, the RF treatment of senescent macrophages increased Piezo1 and CD206 (M2 marker) expression. Conditioned media from RF-treated senescent macrophages enhanced the expression of TGF-β and DEJ proteins, such as nidogen and collagen IV, in senescent fibroblasts. In aged animal skin, RF treatment increased the expression of HSP47, HSP90, Piezo1, markers associated with M2 polarization, IL-10, and TGF-β. Additionally, RF treatment enhanced DEJ protein expression. Moreover, RF reduced lamina densa replication, disrupted lesions, promoted hemidesmosome formation, and increased epidermal thickness. Overall, RF treatment effectively enhanced DEJ protein expression and mitigated age-related DEJ structural changes by increasing HSP levels and activating Piezo1.
... Interestingly, niche encroachment uses a mechanism similar to the one proposed by Liu et al. They revealed a novel cell competition mechanism in aged mouse skin where senescent keratinocytes are eliminated due to a decreased cell-ECM adhesion arising from downregulation of COL17A1 24 . Here we demonstrate that in the absence of p63, most hemidesmosome-related genes, including Col17a1, are downregulated during embryogenesis thus allowing the opportunity for wild type PSC-derived cells to encroach the niche. ...
Autologous skin grafting is a standard treatment for skin defects such as burns. No artificial skin substitutes are functionally equivalent to autologous skin grafts. The cultured epidermis lacks the dermis and does not engraft deep wounds. Although reconstituted skin, which consists of cultured epidermal cells on a synthetic dermal substitute, can engraft deep wounds, it requires the wound bed to be well-vascularized and lacks skin appendages. In this study, we successfully generate complete skin grafts with pluripotent stem cell-derived epidermis with appendages on p63 knockout embryos’ dermis. Donor pluripotent stem cell-derived keratinocytes encroach the embryos’ dermis by eliminating p63 knockout keratinocytes based on cell-extracellular matrix adhesion mediated cell competition. Although the chimeric skin contains allogenic dermis, it is engraftable as long as autologous grafts. Furthermore, we could generate semi-humanized skin segments by human keratinocytes injection into the amnionic cavity of p63 knockout mice embryos. Niche encroachment opens the possibility of human skin graft production in livestock animals.
... HACAT, an immortalized human keratinocyte cell line derived from skin tissue and spontaneously transformed into immortalized human keratinocytes after long-term culture [15], was purchased from the National Collection of Authenticated Cell Cultures (Shanghai, China). Short tandem repeat (STR) profiling was employed to identify this cell line at nine different loci (Amelogenin: X; CSF1PO: 9; D13S317: 10; D16S539: 9; D5S818: 12; D7S820: 9; THO1: 9,3; TPOX: 11; vWA: 16). ...
Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na +) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na + transporters have been identified as a functional regulator of regeneration. However, the role of Na + in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na + ionophores that were employed to increase intracellular Na + content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na + decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na + ionophores replenish H + to the mito-chondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na + , which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na + ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.
... Particularly, several epigenetic factors that regulate skin fitness in normal conditions participate in the establishment of the senescent program, which comprises cell cycle arrest and the release of senescence-associated secretory phenotype (SASP) molecules [5][6][7][8]. Senescence has been indicated as one of the principal causes of aging not only in the skin but also in other systems, and the clearance of senescence species has been demonstrated to be an effective anti-aging strategy [9][10][11][12][13]. Along with epigenetic regulators, cellular cross-talk guarantees skin homeostasis, and it is also involved in the aging process due to its role in spreading senescence. ...
... Such impairment in wound healing contributes to disrupted wound healing process and the formation of chronic hard-to-heal wounds, posing significant healthcare challenges and economic burdens globally. The deterioration of normal epidermal structure, evidenced by the appearance of wrinkles, hyperpigmentation, and desquamation, may accelerate the degeneration of EpiSCs through the disruption of their natural niche [1]. ...
During skin aging, the degeneration of epidermal stem cells (EpiSCs) leads to diminished wound healing capabilities and epidermal disintegration. This study tackles this issue through a comprehensive analysis combining transcriptomics and untargeted metabolomics, revealing age-dependent alterations in the Gpx gene family and arachidonic acid (AA) metabolic networks, resulting in enhanced ferroptosis. Selenomethionine (Se-Met) could enhance GPX4 expression, thereby assisting EpiSCs in countering AA-induced mitochondrial damage and ferroptosis. Additionally, Se-Met demonstrates antioxidative characteristics and extensive ultraviolet absorption. For the sustained and controllable release of Se-Met, it was covalently grafted to UV-responsive GelMA hydrogels via AC-PEG-NHS tethers. The Se-Met@GelMA hydrogel effectively accelerated wound healing in a chronological aging mice model, by inhibiting lipid peroxidation and ferroptosis with augmented GPX4 expression. Moreover, in a photoaging model, this hydrogel significantly mitigated inflammatory responses, extracellular matrix remodeling, and ferroptosis in UV-exposed mice. These characteristics render Se-Met@GelMA hydrogel valuable in practical clinical applications.
... These specialized cells are distributed in the basal layer of the epidermis and hair follicles, endowed with an extraordinary capacity for proliferation, maintaining epidermal homeostasis [86]. The decline in tissue regeneration and function associated with aging is often linked to impaired epidermal stem cell function, as they struggle to effectively interact with other cell types or the extracellular matrix within the skin [87][88][89]. While genetic and epigenetic changes have been extensively documented in aging skin [90][91][92][93][94], recent studies are shedding light on the significant involvement of glycans in regulating epidermal stem cell behavior. ...
Glycosylation is a process where proteins or lipids are modified with glycans. The presence of glycans determines the structure, stability, and localization of glycoproteins, thereby impacting various biological processes, including embryogenesis, intercellular communication, and disease progression. Glycans can influence stem cell behavior by modulating signaling molecules that govern the critical aspects of self-renewal and differentiation. Furthermore, being located at the cell surface, glycans are utilized as markers for stem cell pluripotency and differentiation state determination. This review aims to provide a comprehensive overview of the current literature, focusing on the effect of glycans on stem cells with a reflection on the application of synthetic glycans in directing stem cell differentiation. Additionally, this review will serve as a primer for researchers seeking a deeper understanding of how synthetic glycans can be used to control stem cell differentiation, which may help establish new approaches to guide stem cell differentiation into specific lineages. Ultimately, this knowledge can facilitate the identification of efficient strategies for advancing stem cell-based therapeutic interventions.
