Skin Extracellular Matrix Research Articles

Photo-crosslinked hyaluronic acid hydrogels designed for simultaneous delivery of mesenchymal stem cells and tannic acid: Advancing towards scarless wound healing

The quest for scarless wound healing is imperative in healthcare, aiming to diminish the challenges of conventional wound treatment. Hyaluronic acid (HA), a key component of the skin's extracellular matrix, plays a pivotal role in wound healing and skin rejuvenation. Leveraging the advantages of HA hydrogels, this research focuses first on tuning the physicochemical and mechanical properties of photo-crosslinkable methacrylated HA (MAHA) by varying the methacrylation degree, polymer concentration, photo-crosslinker concentration, and UV exposure time. The optimized hydrogel, featuring suitable porosity, swelling ratio, degradability, and mechanical properties, was then used for the combined delivery of tannic acid (TA), known for its hemostatic, antibacterial, and antioxidant properties, and Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) cultured on the MAHA-TA hydrogel to enhance skin regeneration. The composite MAHA-TA-MSC hydrogel demonstrated favorable pores and biocompatibility, evidenced by cell viability, and promoted cell proliferation. When applied to dorsal wounds in rats, this composite hydrogel accelerated wound healing and reduced scarring. Additionally, molecular and histopathological analyses revealed increased expression of IL-10, the TGF-β3/TGF-β1 ratio, and the Collagen III/Collagen I ratio. These findings suggest that the MAHA-TA-MSC hydrogel is a promising candidate for scarless acute wound healing.

Skin senescence-from basic research to clinical practice.

The most recognizable implications of tissue aging manifest themselves on the skin. Skin laxity, roughness, pigmentation disorders, age spots, wrinkles, telangiectasia or hair graying are symptoms of physiological aging. Development of the senescent phenotype depends on the interaction between aging cells and remodeling of the skin's extracellular matrix (ECM) that contains collagen and elastic fiber. Aging changes occur due to the combination of both endogenous (gene mutation, cellular metabolism or hormonal agents) and exogenous factors (ultraviolet light, environmental pollutants, and unsuitable diet). However, overproduction of mitochondrial reactive oxygen species (ROS) is a key factor driving cellular senescence. Aging theories have disclosed a range of diverse molecular mechanisms that are associated with cellular senescence of the body. Theories best supported by evidence include protein glycation, oxidative stress, telomere shortening, cell cycle arrest, and a limited number of cell divisions. Accumulation of the ECM damage is suggested to be a key factor in skin aging. Every cell indicates a functional and morphological change that may be used as a biomarker of senescence. Senescence-associated β-galactosidase (SA-β-gal), cell cycle inhibitors (p16INK4a, p21CIP1, p27, p53), DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), senescence-associated heterochromatin foci (SAHF), shortening of telomeres or downregulation of lamina B1 constitute just an example of aging biomarkers known so far. Aging may also be assessed non-invasively through measuring the skin fluorescence of advanced glycation end-products (AGEs). This review summarizes the recent knowledge on the pathogenesis and clinical conditions of skin aging as well as biomarkers of skin senescence.

ECM-mimetic glucomannan hydrogel promotes pressure ulcer healing by scavenging ROS, promoting angiogenesis and regulating macrophages

Pressure ulcers (PUs) have emerged as a significant burden on both individuals and society. Effective treatment of PUs is a significant clinical challenge due to the compromised tissue microenvironment characterized by extracellular matrix (ECM) depletion, increased levels of reactive oxygen species (ROS), excessive inflammation and impaired angiogenesis. To this end, we have developed a glucomannan hydrogel (GM-Pgel) that mimics the skin's extracellular matrix to accelerate wound healing by regulating chronic inflammation in the PUs. This hydrogel not only faithfully replicates the components and nanofibrous architecture of ECM-like glycoproteins but also exhibits remarkable capabilities in enhancing neovascularization, scavenging ROS, and promoting macrophage polarization toward the M2 phenotype. In summary, this ECM-mimetic multifunctional hydrogel emerges as a promising dressing with diverse functionalities, capable of reshaping the compromised tissue environment without the need for additional drugs, exogenous cytokines, or cells. This presents a compelling and effective strategy for the repair and regeneration of chronic cutaneous wounds.

Hyaluronan and proteoglycan link protein 1 – A novel signaling molecule for rejuvenating aged skin

The skin seems to rejuvenate upon exposure to factors within the circulation of young organisms. Intrinsic factors that modulate skin aging are poorly understood. We used heterochronic parabiosis and aptamer-based proteomics to identify serum-derived rejuvenating factors. We discovered a novel extracellular function of hyaluronan and proteoglycan link protein 1 (HAPLN1). Its serum levels decreased with age, disturbing the integrity of the skin extracellular matrix, which is predominantly composed of collagen I and hyaluronan; levels of various markers, which decrease in aged skin, were significantly restored in vivo and in vitro by the administration of recombinant human HAPLN1 (rhHAPLN1). rhHAPLN1 protected transforming growth factor beta receptor 2 on the cell surface from endocytic degradation via mechanisms such as regulation of viscoelasticity, CD44 clustering. Moreover, rhHAPLN1 regulated the levels of nuclear factor erythroid 2–related factor 2, phosphorylated nuclear factor kappa B, and some cyclin-dependent kinase inhibitors such as p16 and p21. Therefore, rhHAPLN1 may act as a novel biomechanical signaling protein to rejuvenate aged skin.

Development of carboxymethyl cellulose/gelatin hydrogel loaded with Omega-3 for skin regeneration.

Hydrogels have several characteristics, including biocompatibility, physical similarity with the skin's extracellular matrix, and regeneration capacity. Cell migration and proliferation are facilitated by natural polymers such as gelatin (Gel) and carboxymethyl cellulose (CMC). Gelatin dressing acts as a structural framework for cell migration into the wound area, stimulating cell division and promoting granulation tissue formation. Omega-3 fatty acids from fish oil may prevent wound infection and improve the healing of wounds in the early stages. We studied the preparation of wound dressing containing Omega-3 and its ability to heal wounds. In this study, CMC-Gel hydrogels containing different concentrations of Omega-3 were investigated in full-thickness wounds. After the fabrication of the hydrogels by using surfactant (tween 20) and microemulsion method (oil in water), various tests such as SEM, Water uptake evaluation, weight loss, cell viability, blood compatibility, and in vivo study in rat cutaneous modeling during 14 days were performed to evaluate the properties of the fabricated hydrogels. The analysis of the hydrogels revealed that they possess porous structures with interconnected pores, with an average size of 83.23 ± 6.43μm. The hydrogels exhibited a swelling capacity of up to 60% of their initial weight within 24h, as indicated by the weight loss and swelling measurements. Cell viability study with the MTT technique showed that no cytotoxicity was observed at the recommended dosage, however, increasing the amount of omega-3 caused hemolysis, cell death, and inhibition of coagulation activity. An in vivo study in adult male rats with a full-thickness model showed greater than 91% improvement of the primary wound region after 2 weeks of treatment. Histological analysis demonstrated Omega-3 in hydrogels, which is a promising approach for topical skin treatment to prevent scar, and has shown efficacy as wound dressing by improving the repair process at the defect site.

Apple Pomace Extract Induces Cell Proliferation and Increases Type I Collagen and Hyaluronan Production in Human Skin Fibroblasts In Vitro.

Apple pomace is the residue left after apples are squeezed. The majority of pomace produced worldwide is produced by the apple manufacturing industry, however, most of the pomace produced by the industry is discarded. Apple pomace contains functional ingredients, such as polyphenols and triterpenoids, and exerts several beneficial effects on human health; however, studies on its cosmetic effects on the skin are lacking. Therefore, herein, we investigated the effects of apple pomace extract (APE) on human skin fibroblasts (HSFs) in vitro. When HSFs were cultured with the extract for 72h, the number of HSFs increased at concentrations of 10 and 20µg/mL. Transcriptome analysis and reverse transcription-quantitative PCR results revealed that the extract upregulated the expression of hyaluronan synthase (HAS) 1, HAS2, and HAS3 and downregulated the expression of HYAL1, a gene encoding the hyaluronan-degrading enzyme, in HSFs. Additionally, enzyme-linked immunosorbent assay revealed increased amounts of factors related to skin extracellular matrix, such as type I collagen and hyaluronic acid, secreted in the culture supernatant. The western blotting results suggested that the extract induced extracellular signal-regulated kinase and protein kinase B phosphorylation in HSFs. Additionally, several GO_Terms related to mitosis were detected in the Gene Ontology analysis. This is the first study to show that APE induces the proliferation of HSFs and production of factors related to skin anti-aging.

Thermo-assisted fabrication of a novel shape-memory hyaluronic acid sponge for non-compressible hemorrhage control

Hyaluronic acid (HA), a major component of skin extracellular matrix, provides an excellent framework for hemostatic design; however, there still lacks HA materials tailored with superior mechanical properties to address non-compressible hemorrhages. Here, we present a solvent-free thermal approach for constructing a shape-memory HA sponge for this application. Following facile thermal incubation around 130 °C, HA underwent cross-linking via esterification with poly(acrylic acid) within the sponge pre-shaped through a prior freeze-drying process. The resulting sponge system exhibited extensively interconnected macropores with a high fluid absorption capacity, excellent shape-memory property, and robust mechanical elasticity. When introduced to whole blood in vitro, the HA sponges demonstrated remarkable hemostatic properties, yielding a shorter coagulation time and lower blood clotting index compared to the commercial gelatin sponge (GS). Furthermore, in vivo hemostatic studies involving two non-compressible hemorrhage models (rat liver volume defect injury or femoral artery injury) achieved a significant reduction of approximately 64% (or 56%) and 73% (or 70%) in bleeding time and blood loss, respectively, which also outperformed GS. Additionally, comprehensive in vitro and in vivo evaluations suggested the good biocompatibility and biodegradability of HA sponges. This study highlights the substantial potential for utilizing the designed HA sponges in massive bleeding management.

Physical Properties and Biochemical Composition of Extracellular Matrix-Derived Hydrogels Dictate Vascularization Potential in an Organ-Dependent Fashion.

The inherent extracellular matrix (ECM) originating from a specific tissue impacts the process of vascularization, specifically vascular network formation (VNF) orchestrated by endothelial cells (ECs). The specific contribution toward these processes of ECM from highly disparate organs such as the skin and lungs remains a relatively unexplored area. In this study, we compared VNF and ECM remodeling mediated by microvascular ECs within gel, lung, and combinations thereof (hybrid) ECM hydrogels. Irrespective of the EC source, the skin-derived ECM hydrogel exhibited a higher propensity to drive and support VNF compared to both lung and hybrid ECM hydrogels. There were distinct disparities in the physical properties of the three types of hydrogels, including viscoelastic properties and complex architectural configurations, including fiber diameter, pore area, and numbers among the fibers. The hybrid ECM hydrogel properties were unique and not the sum of the component ECM parts. Furthermore, cellular ECM remodeling responses varied with skin ECM hydrogels promoting matrix metalloproteinase 1 (MMP1) secretion, while hybrid ECM hydrogels exhibited increased MMP9, fibronectin, and collagen IV deposition. Principal component analysis (PCA) indicated that the influence of a gel's mechanical properties on VNF was stronger than the biochemical composition. These data indicate that the organ-specific properties of an ECM dictate its capacity to support VNF, while intriguingly showing that ECs respond to more than just the biochemical constituents of an ECM. The study suggests potential applications in regenerative medicine by strategically selecting ECM origin or combinations to manipulate vascularization, offering promising prospects for enhancing wound healing through pro-regenerative interventions.

Lapagyl mitigates UV-induced inflammation and immunosuppression via Foxp3+ Tregs and CCL pathway: A single-cell transcriptomics study

BackgroundAs the largest organ of the body, the skin is constantly subjected to ultraviolet radiation (UVR), leading to inflammations and changes that mirror those seen in chronological aging. Although various small molecule drugs have been explored for treating skin photoaging, they typically suffer from low stability and a high incidence of adverse reactions. Consequently, the continued investigation of photoaging treatments, particularly those utilizing herbal products, remains a critical clinical endeavor. One such herbal product, Lapagyl, is derived from the bark of the lapacho tree and possesses antioxidant efficacies that could be beneficial in combating skin photoaging. PurposeThis research aimed to evaluate the efficacy of the herbal product Lapagyl in combating UVR-induced skin photoaging. Additionally, it sought to unravel the mechanisms by which Lapagyl promotes the regeneration of the skin extracellular matrix. MethodsTo investigate whether Lapagyl can alleviate skin aging and damage, a UVR radiation model was established using SKH-1 hairless mice. The dorsal skins of these mice were evaluated for wrinkle formation, texture, moisture, transepidermal water loss (TEWL), and elasticity. Pathological assessments were conducted to determine Lapagyl's efficacy. Additionally, single-cell sequencing and spectrum analysis were employed to elucidate the working mechanisms and primary components of Lapagyl in addressing UVR-induced skin aging and injury. ResultsLapagyl markedly reduced UVR-induced wrinkles, moisture loss, and elasticity decrease in SKH-1 mice. Single-cell sequencing demonstrated that Lapagyl corrected the imbalance in cell proportions caused by UVR, decreased UVR-induced ROS expression, and protected basal and spinous cells from skin damage. Additionally, Lapagyl effectively prevented the entry of inflammatory cells into the skin by reducing CCL8 expression and curtailed the UVR-induced formation of Foxp3+ regulatory T cells (Tregs) in the skin. Both pathological assessments and ex vivo skin model results demonstrated that Lapagyl effectively reduced UVR-induced damage to collagen and elastin. Spectrum analysis identified Salidroside as the primary compound remaining in the skin following Lapagyl treatment. Taken together, our study elucidated the skin protection mechanism of the herbal product Lapagyl against UVR damage at the cellular level, revealing its immunomodulatory effects, with salidroside identified as the primary active compound for skin. ConclusionOur study provided a thorough evaluation of Lapagyl's protective effects on skin against UVR damage, delving into the mechanisms at the cellular level. We discovered that Lapagyl mitigates skin inflammation and immunosuppression by regulating Foxp3+ Tregs and the CCL pathway. These insights indicate that Lapagyl has potential as a novel therapeutic option for addressing skin photoaging.

Smart Tissue Carriers for Innovative Cosmeceuticals and Nutraceuticals

The present review was conducted to investigate the possibilities in realizing novel nanostructured tissues containing functional molecules that can be commercialized as solid products (without using emulsifiers and preservatives) for cosmeceutical and nutraceutical applications. After considering the principal concepts regarding skin and mucous features and physiologies, the possibilities in using bio-based, biodegradable and biocompatible materials was explored by investigating the correlations between their structures and morphologies with respect to the characteristics of the skin extracellular matrix (ECM). Regarding the new smart type of biodegradable tissues, their possible composition was reviewed in relation to the skin aging process and to the current contest for novel, innovative cosmeceuticals and nutraceuticals that consider the “beauty from within” concept. The barriers to the development of these new tissues were mainly identified due the necessity in defining the claim regarding green products. Moreover, the market growth data regarding these novel products were highlighted to support the idea that the diffusion of smart tissue-based cosmeceuticals and nutraceuticals is an opportunity for new sustainable industrial chains in the development of bioeconomies.

Biomimetic aligned nanofibrous dressings containing cell-selective polymer enhance diabetic wound regeneration

Diabetic ulcers remain a significant challenge in wound care due to loss of epithelial cell migration. Aligned nanofibrous scaffolds mimicking the skin's extracellular matrix (ECM) are promising candidates for diabetic wound healing. In this study, a composition of poly(ε-caprolactone), gelatin, and dopamine-containing varying amounts of ε-polylysine (ε-PL) was electrospun to prepare aligned nanofiber wound dressings (ANFDs). We then investigated the morphological, physicochemical, mechanical, and biological properties of fabricated ANDFs. The presence of ε-PL confers bactericidal properties while promoting epithelial and fibroblast adhesion, proliferation, and migration, confirming its cell selectivity. The clinical importance of the ANFDs was then demonstrated in a mice model of full-thickness diabetic wounds. The results confirm that ANFD treatment resulted in a higher rate of wound closure in the linear range of wound closure than wounds treated with silver dressings. Taken together, these results suggest the potential of antimicrobial ANFDs for the treatment of diabetic wounds.

Suppression of UVB-Induced MMP-1 Expression in Human Skin Fibroblasts Using Lysate of Lactobacillus iners Derived from Korean Women's Skin in Their Twenties.

The process of skin aging is intricate, involving intrinsic aging, influenced by internal factors, and extrinsic aging, mainly caused by exposure to UV radiation, resulting in photoaging. Photoaging manifests as skin issues such as wrinkles and discoloration. The skin microbiome, a diverse community of microorganisms on the skin's surface, plays a crucial role in skin protection and can be affected by factors like humidity and pH. Probiotics, beneficial microorganisms, have been investigated for their potential to enhance skin health by regulating the skin microbiome. This can be accomplished through oral probiotics, impacting the gut-skin axis, or topical applications introducing live bacteria to the skin. Probiotics mitigate oxidative stress, suppress inflammation, and maintain the skin's extracellular matrix, ultimately averting skin aging. However, research on probiotics derived from human skin is limited, and there is no established product for preventing photoaging. The mechanism by which probiotics shield the skin microbiome and skin layers from UV radiation remains unclear. Recently, researchers have discovered Lactobacillus in the skin, with reports indicating a decrease in this microorganism with age. In a recent study, scientists isolated Lactobacillus iners KOLBM20 from the skin of individuals in their twenties and confirmed its effectiveness. A comparative analysis of genetic sequences revealed that strain KOLBM20 belongs to the Lactobacillus genus and closely relates to L. iners DSM13335(T) with a 99.20% similarity. Importantly, Lactobacillus iners KOLBM20 displayed anti-wrinkle properties by inhibiting MMP-1. This investigation demonstrated the inhibitory effect of KOLBM20 strain lysate on MMP-1 expression. Moreover, the data suggest that KOLBM20 strain lysate may prevent UVB-induced MMP-1 expression by inhibiting the activation of the ERK, JNK, and p38 signaling pathways induced by UVB. Consequently, KOLBM20 strain lysate holds promise as a potential therapeutic agent for preventing and treating skin photoaging.

Characterization of electrospun pluronic F68/polyvinyl alcohol nanofibers composites containing titanium dioxide, silver, and cobalt nanoparticles for biomedical applications

Nanoscale drug delivery systems and biomedical sensors are witnessing huge research interests. Polymeric nanoparticles, nanofibers, liposomes, and nano-emulsion are regarded as novel sensors and drug delivery systems including the various types of wound dressings formulated by micro/nanofibers, hydrogels, hydrocolloids, films, foams, and sponges. Consequently, the electro-spun nanofibrous mats received the most attention since the drugs and nanoparticles embedded nanofibers have been recognized as the potential candidates for sensors and wound dressing applications. These composite materials have superior surface area-to-volume ratio, high nano-porosity, distinct skin extracellular matrix structure, and ease of electro-spinning, which also supports a prolonged drug release. In this study the main advantages of the nano-fibrillary network and the active substances that can be incorporated in fabricating the composite nanofibers as sensors and wound dressing materials are discussed. The promising “Pluronic F68” and polyvinyl alcohol (PVA), materials are used including nanoparticles (NPs) of titanium dioxide (TiO2), silver, and cobalt. The difficulties that arise by converting the Pluronic into nanofibers via electrospinning due to its low melting point and beads formation and the blending of this material with polyvinyl alcohol (PVA) are discussed. The electro-spinability of the pure Pluronic, PVA and their blends are evaluated. The microstructures and morphologies of the fabricated composite nanofibers and structures are characterized using scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential thermal analysis (DSC), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). The fabricated blended nanofibers were found to be compact and entangled having a diameter from 50 nm to 80 nm and length ranging from 1 to 3 μm. Meanwhile, the pure Pluronic produced nano-beads with an average size of 40 nm. These nanocomposites can be used in biomedical applications such as biosensors by embedding nanoparticles of TiO2, silver, and cobalt and for antibacterial treatment in woundcare dressings.

Collagen study advances for photoaging skin.

Collagen dominates the skin's extracellular matrix (ECM). Type I collagen comprises 80%-90% of the skin's collagen, followed by type III (8%-12%) and type V (5%). Reactive oxygen species, matrix metalloproteinases, and collagen degradation all increase during photoaging, which disrupts the ECM's dynamic balance and lowers the amount of total collagen in the body. In recent years, domestic and foreign researchers have conducted multidimensional and multifaceted studies on collagen and skin photoaging. Collagen and the peptides that are derivates of it are currently being used more and more in biomedicine and medical esthetics. Offering new suggestions for both the avoidance and remedy of photoaging. This article reviews collagen and its potential connection to skin photoaging, illustrates the effects of collagen and peptide supplementation derivatives on photoaged skin, and briefly describes other compounds that can also be used to fight photoaging by increasing collagen synthesis in the skin. Both internal and external aging are inevitable, and as the main component of extracellular matrix, collagen plays a variety of functions in maintaining skin structure and fighting skin aging, and its role in photoaging is undeniable. Ultraviolet radiation can induce increased fragmentation and degradation of cutaneous collagen, while conversely, supplementation with collagen can effectively counteract photodamage-induced skin impairment. Collagen and its derived peptides are indispensable in photoaging skin, holding promising prospects for applications in skin aging.

Extracellular Matrix Remodeling in Atopic Dermatitis Harnesses the Onset of an Asthmatic Phenotype and Is a Potential Contributor to the Atopic March

The development of atopic dermatitis in infancy, and subsequent allergies, such as asthma in later childhood, is known as the atopic march. The mechanism is largely unknown, however the course of disease indicates an inter-epithelial crosstalk, through the onset of inflammation in the skin and progression to other mucosal epithelia. In this study, we investigated if and how skin-lung epithelial crosstalk contributes to the development of the atopic march. First, we emulated inter-epithelial crosstalk through indirect coculture of bioengineered atopic-like skin disease models and three-dimensional bronchial epithelial models triggering an asthma-like phenotype in the latter. A subsequent secretome analysis identified thrombospondin-1, CD44, complement factor C3, fibronectin, and syndecan-4 as potentially relevant skin-derived mediators. Because these mediators are extracellular matrix-related proteins, we then studied the involvement of the extracellular matrix, unveiling distinct proteomic, transcriptomic, and ultrastructural differences in atopic samples. The latter indicated extracellular matrix remodeling triggering the release of the above-mentioned mediators. Invivo mouse data showed that exposure to these mediators dysregulated activated circadian clock genes which are increasingly discussed in the context of atopic diseases and asthma development. Our data point toward the existence of a skin-lung axis that could contribute to the atopic march driven by skin extracellular matrix remodeling.

Effect of ellagic acid and retinoic acid on collagen and elastin production by human dermal fibroblasts.

Elastin is a fibrous protein key to the structure and support of skin as well as other organ tissues. Elastic fibers are located in the skin's dermal layer and make up approximately 2%-4% of the fat-free dry weight of the dermis in the skin of adults. Aging causes the progressive degradation of elastin fibers. Loss of these fibers can cause skin sagging and wrinkling, loss of healthy blood vessels and lung capacity, aneurysms, and Chronic Obstructive Pulmonary Disease (COPD). We hypothesized that ellagic acid, a polyphenol, will increase elastin in human dermal fibroblasts (HDF) due to polyphenols' elastin binding properties. We treated HDF's with 2μg/ml ellagic acid for 28 days to see the elastin deposition in HDF cell cultures. To test this, we treated HDFs with polyphenols ellagic acid for 3, 7, 14 and 21 days. For comparison purposes, we included a group of ellagic acid and retinoic acid since retinoic acid is already in the market for elastin regeneration purposes. When ellagic acid and retinoic acid were introduced together, insoluble elastin and collagen deposition were significantly higher in HDFs compared to other groups. Polyphenols and retinoic acid can improve skin extracellular matrix production of elastin and collagen and may improve skin fine wrinkles.

Fabrication and Characterization of an Electro-Compacted Collagen/Elastin/Hyaluronic Acid Sheet as a Potential Skin Scaffold.

The development of biomimetic structures with integrated extracellular matrix (ECM) components represents a promising approach to biomaterial fabrication. Here, an artificial ECM, comprising the structural protein collagen I and elastin (ELN), as well as the glycosaminoglycan hyaluronan (HA), is reported. Specifically, collagen and ELN areelectrochemically aligned to mimic the compositional characteristics of the dermal matrix. HA isincorporated into the electro-compacted collagen-ELN matrices via adsorption and chemical immobilization, to give a final composition of collagen/ELN/HA of 7:2:1. This produces a final collagen/ELN/hyaluronic acid scaffold (CEH) that recapitulates the compositional feature of the native skin ECM. This study analyzes the effect of CEH composition on the cultivation of human dermal fibroblast cells (HDFs) and immortalized human keratinocytes (HaCaTs). It is shown that the CEH scaffold supports dermal regeneration by promoting HDFs proliferation, ECM deposition, and differentiation into myofibroblasts. The CEH scaffolds arealso shown to support epidermis growth by supporting HaCaTs proliferation, differentiation, and stratification. A double-layered epidermal-dermal structure isconstructed on the CEH scaffold, further demonstrating its ability in supporting skin cell function and skin regeneration.

Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.

The chemotherapeutic agent paclitaxel causes peripheral neuropathy, a dose-limiting side effect, in up to 68% of cancer patients. In this study, we investigated the impact of paclitaxel therapy on the skin of breast cancer patients with chemotherapy-induced peripheral neuropathy (CIPN), building upon previous findings in zebrafish and rodents. Comprehensive assessments, including neurological examinations and quality of life questionnaires, were conducted, followed by intraepidermal nerve fiber (IENF) density evaluations using skin punch biopsies. Additionally, RNA sequencing, immunostaining for Matrix-Metalloproteinase 13 (MMP-13), and transmission electron microscopy provided insights into molecular and ultrastructural changes in this skin. The results showed no significant difference in IENF density between the control and CIPN patients despite the presence of patient-reported CIPN symptoms. Nevertheless, the RNA sequencing and immunostaining on the skin revealed significantly upregulated MMP-13, which is known to play a key role in CIPN caused by paclitaxel therapy. Additionally, various genes involved in the regulation of the extracellular matrix, microtubules, cell cycle, and nervous system were significantly and differentially expressed. An ultrastructural examination of the skin showed changes in collagen and basement membrane structures. These findings highlight the presence of CIPN in the absence of IENF density changes and support the role of skin remodeling as a major contributor to CIPN.

Collagen and Beyond: A Comprehensive Comparison of Human ECM Properties Derived from Various Tissue Sources for Regenerative Medicine Applications.

Collagen, along with proteoglycans, glycosaminoglycans, glycoproteins, and various growth factors, forms the extracellular matrix (ECM) and contributes to the complexity and diversity of different tissues. Herein, we compared the physicochemical and biological properties of ECM hydrogels derived from four different human tissues: skin, bone, fat, and birth. Pure human collagen type I hydrogels were used as control. Physical characterization of ECM hydrogels and assessment of cell response of cord-tissue mesenchymal stem cells (CMSCs) were performed. Decellularization efficiency was found to be >90% for all ECM. Hydroxyproline quantification assay showed that collagen content in birth ECM was comparable to collagen control and significantly greater than other sources of ECM. Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed the presence of γ, β, α1 and α2 collagen chains in all ECMs. Gelation kinetics of ECM hydrogels was significantly slower than collagen control. Compressive modulus of skin ECM was the highest and birth ECM was the lowest. Skin and birth ECM hydrogels were more stable than bone and fat ECM hydrogels. CMSCs encapsulated in birth ECM hydrogels exhibited the highest metabolic activity. Rheological characterization revealed that all ECM-derived inks exhibited shear thinning properties, and skin-derived ECM inks were most suitable for extrusion-based bioprinting for the concentration and printing conditions used in this study. Overall, results demonstrate that the physicochemical and biological properties of ECM hydrogels vary significantly depending on the tissue source. Therefore, careful selection of tissue source is important for development of ECM-based biomimetic tissue constructs for regenerative medicine applications.

Adipose Tissue-Derived Mesenchymal Stem Cell-Derived Exosomes Promote Wound Healing and Tissue Regeneration.

Wound healing is a complex process involving cell proliferation, migration, and extracellular matrix (ECM) remodeling. Extracellular vesicles (EVs) or exosomes derived from adipose tissue-derived stem cells (ASCs) are emerging as promising alternatives to cell therapy for advanced wound healing. Hyaluronic acid (HA), a major component of the skin ECM, is widely utilized in wound dressings and dermal fillers. This study aimed to investigate the effects of ASC-derived exosomes (ASC-EXOs) on human dermal fibroblasts (HDFs) and their potential combination with HA in in vivo wound healing and dermal filler models. In HDFs, ASC-EXOs increased cell proliferation and migration. ASC-EXOs also upregulated the expression of genes involved in cell proliferation and wound healing while stimulating collagen production in HDFs. In a porcine wound healing model, topical treatment with a combination of HA and ASC-EXOs led to higher wound closure rates compared to HA alone. Histological examination showed increased re-epithelialization and collagen type III deposition in wounds treated with the combination of HA and ASC-EXOs. In a mouse dermal filler model, tissues injected with the combination of HA and ASC-EXOs exhibited thicker tissue layers, increased vascularization, enhanced infiltration of myofibroblasts, and higher levels of collagen III and collagen fiber content compared to HA alone. These findings suggest that ASC-EXOs have beneficial effects on cell proliferation, migration, and gene expression related to wound healing, and they may accelerate wound closure and promote tissue regeneration. Furthermore, the combination of HA and ASC-EXOs may enhance wound healing and tissue remodeling, indicating its potential for both clinical and regenerative aesthetic applications in skin repair and regeneration.