Migration Of Dermal Fibroblasts Research Articles

GelMA loaded with platelet lysate promotes skin regeneration and angiogenesis in pressure ulcers by activating STAT3

Pressure ulcers (PU) are caused by persistent long-term pressure, which compromises the integrity of the epidermis, dermis, and subcutaneous adipose tissue layer by layer, making it difficult to heal. Platelet products such as platelet lysate (PL) can promote tissue regeneration by secreting numerous growth factors based on clinical studies on skin wound healing. However, the components of PL are difficult to retain in wounds. Gelatin methacrylate (GelMA) is a photopolymerizable hydrogel that has lately emerged as a promising material for tissue engineering and regenerative medicine. The PL liquid was extracted, flow cytometrically detected for CD41a markers, and evenly dispersed in the GelMA hydrogel to produce a surplus growth factor hydrogel system (PL@GM). The microstructure of the hydrogel system was observed under a scanning electron microscope, and its sustained release efficiency and biological safety were tested in vitro. Cell viability and migration of human dermal fibroblasts, and tube formation assays of human umbilical vein endothelial cells were applied to evaluate the ability of PL to promote wound healing and regeneration in vitro. Real-time polymerase chain reaction (PCR) and western blot analyses were performed to elucidate the skin regeneration mechanism of PL. We verified PL’s therapeutic effectiveness and histological analysis on the PU model. PL promoted cell viability, migration, wound healing and angiogenesis in vitro. Real-time PCR and western blot indicated PL suppressed inflammation and promoted collagen I synthesis by activating STAT3. PL@GM hydrogel system demonstrated optimal biocompatibility and favorable effects on essential cells for wound healing. PL@GM also significantly stimulated PU healing, skin regeneration, and the formation of subcutaneous collagen and blood vessels. PL@GM could accelerate PU healing by promoting fibroblasts to migrate and secrete collagen and endothelial cells to vascularize. PL@GM promises to be an effective and convenient treatment modality for PU, like chronic wound treatment.

Enhanced skin regeneration and therapeutic delivery using novel diamond-augmented zinc oxide.

Recent advancements in dermatological therapeutics have highlighted the need for treatments that enhance skin regeneration and healing. Diamond-Augmented Zinc Oxide (ND-ZnO) technology combines zinc oxide with diamond particles in a unique core-shell structure, offering a multifaceted approach to overall skin health. This study evaluates the efficacy of ND-ZnO in promoting human dermal fibroblast migration and growth, enhancing total collagen synthesis, and improving transdermal delivery of active ingredients as a daily comprehensive skin regeneration topical therapy. In vitro assays assessed wound healing, collagen production, and skin absorption. Human Dermal Fibroblasts (HDFs) were used in scratch wound assays. Collagen synthesis was quantified using enzyme-linked immunosorbent assays (ELISA). Permeation tests were performed on reconstructed human epidermal tissues to evaluate niacinamide absorption. Clinical case studies validated ND-ZnO efficacy in post-CO₂ laser treatments and Actinic Keratosis removal recovery. ND-ZnO increased HDF migration by 198% compared to controls. Collagen synthesis assays showed a 71.3% restoration of collagen production in aged HDFs. Skin permeation studies revealed a 203% increase in niacinamide skin absorption with ND-ZnO. Clinical case studies demonstrated faster and more effective healing post-ablative CO₂ laser and significant improvements in Actinic Keratosis recovery. ND-ZnO technology enhances wound healing, collagen synthesis, and active ingredient delivery, offering substantial benefits for daily skin regeneration and other dermatological applications. This innovative approach holds promise for advancing dermatological therapeutics, providing comprehensive skin care solutions that address both protective and regenerative needs.

Extracellular Vesicles Derived from Opuntia ficus-indica Fruit (OFI-EVs) Speed Up the Normal Wound Healing Processes by Modulating Cellular Responses.

Plant-derived extracellular vesicles (EVs) have been recognized as important mediators of intercellular communication able to transfer active biomolecules across the plant and animal kingdoms. EVs have demonstrated an impressive array of biological activities, displaying preventive and therapeutic potential in mitigating various pathological processes. Indeed, the simplicity of delivering exogenous and endogenous bioactive molecules to mammalian cells with their low cytotoxicity makes EVs suitable agents for new therapeutic strategies for a variety of pathologies. In this study, EVs were isolated from Opuntia ficus-indica fruit (OFI-EVs) and characterized by particle size distribution, concentration, and bioactive molecule composition. OFI-EVs had no obvious toxicity and demonstrated a protective role in the inflammatory process and oxidative stress in vitro model of chronic skin wounds. The results demonstrated that pretreatment with OFI-EVs decreased the activity and gene expression of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α) in the LPS-stimulated human leukemia monocytic cell line (THP-1). Furthermore, OFI-EVs promote the migration of human dermal fibroblasts (HDFs), speeding up the normal wound healing processes. This study sheds light, for the first time, on the role of OFI-EVs in modulating important biological processes such as inflammation and oxidation, thereby identifying EVs as potential candidates for healing chronic cutaneous wounds.

Investigating the impact of botulinum toxin type a on the migration of normal human dermal fibroblasts: An invitro wound healing assay.

Botulinum toxin A (BoNT-A) is widely utilized in the management of hypertrophic and keloid scars. One proposed mechanism for scar prevention involves the inhibition of fibroblast migration in scars by BoNT-A. However, the data regarding the effect of BoNT-A on the migration of normal human dermal fibroblasts (NHDF) is limited. The aim of this study was to investigate the inhibitory effect of different types and dilutions of BoNT-A on the migration of NHDF. In vitro scratch wound assay, NHDF cells were cultured, incubated, and subjected to scratching using a sterile tip. Subsequently, the scratched NHDF monolayer was treated with different types of BoNT-A, including onabotulinumtoxinA (ONA), incobotulinumtoxinA (INCO), prabotulinumtoxinA (PRABO), or letibotulinumtoxinA (LETI), at varying concentrations of 10, 20, 25, 40, 50, and 100 units/milliliter (U/mL). Additionally, abobotulinumtoxinA (ABO) was administered at concentrations of 33, 50, 66, 71, 100, 150, 300, and 500 U/mL. Normal saline solution (NSS) served as a negative control. The extent of NHDF migration was evaluated by comparing each dilution of BoNT-A with the controls using high-content imaging at the 48-h time point. Furthermore, the viability of the of NHDF was assessed. The concentrations of 25, 40, and 50 U/mL of ONA (p < 0.001) and 25 U/mL of LETI (p < 0.05) demonstrated significantly inhibited NHDF migration in comparison to the control group. Conversely, all dilutions of PRABO, INCO, and ABO exhibited comparable NHDF migration to that of the control group. Regarding NHDF viability, no significant decrease was observed across any of the BoNT-A types and dilutions. Different types and dilutions of BoNT-A demonstrated variable inhibitory effects on NHDF migration invitro. The selection of BoNT-A formulation may significantly impact the clinical outcome of scar prevention related to fibroblast migration.

GHK-Cu/Pionin-loaded in situ electrospun PVB/PVP smart dressing promotes wound healing via anti-oxidant, anti-inflammatory, antimicrobial, and tissue regenerative effects

Biocompatible, antibacterial, anti-inflammatory, and tissue regenerative smart dressings are in urgent need for infected skin wound repair in clinics. Portable in situ 3D-electrospun technology has the great advantage of direct deposition of required smart dressing on wound surfaces. Here, we fabricated a copper peptide (GHK-Cu) and quaternium-73 (Pionin) dual-drug-loaded polyvinyl butyral (PVB)/polyvinylpyrrolidone (PVP) smart nanofibers dressing using in-situ electrospinning technology for skin wound repair. The physicochemical properties and biological activities of smart dressing were extensively analyzed. In vivo biocompatibility, anti-oxidant, anti-inflammatory, and antimicrobial activities of smart dressing were analyzed during wound healing. Stable and homogeneous PVB/PVP nanofiber smart dressing with uniformly distributed GHK-Cu and Pionin and anabolic biological activities was obtained. Biocompatible smart dressing gave a sustained release of GHK-Cu and Pionin, promoted the migration and adhesion of dermal fibroblasts and keratinocytes, and showed anti-oxidant and anti-apoptotic effects in vitro and in vivo. Smart dressing exerted anti-inflammatory properties via M1 to M2 macrophage phenotype switching and effectively promoted wound healing. Pionin released from smart dressing not only killed but also inhibited the expression and delivery of virulence factor expression and bacteria adhesion. During wound healing, smart dressing promoted the proliferation of cells in the epidermal tissue, epithelial tissue remodeling, granulation tissue growth, neovascularization, and M2 macrophage polarization. Moreover, this smart dressing scavenged excess reactive oxygen species, increased SOD3 and SIRT1 expression, and repaired peroxidized tissue, consequently promoting wound healing. In summary, our results indicate that GHK-Cu/Pionin-loaded in situ electrospun PVB/PVP smart dressing promotes wound healing via anti-oxidant, anti-inflammatory, antimicrobial, and tissue regenerative effects, suggesting clinical application of this smart dressing for complicated skin wound healing.

CircCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models

Chronic wounds are a major complication in patients with diabetes. Here, we identify a therapeutic circRNA and load it into small extracellular vesicles (sEVs) to treat diabetic wounds in preclinical models. We show that circCDK13 can stimulate the proliferation and migration of human dermal fibroblasts and human epidermal keratinocytes by interacting with insulin-like growth factor 2 mRNA binding protein 3 in an N6-Methyladenosine-dependent manner to enhance CD44 and c-MYC expression. We engineered sEVs that overexpress circCDK13 and show that local subcutaneous injection into male db/db diabetic mouse wounds and wounds of streptozotocin-induced type I male diabetic rats could accelerate wound healing and skin appendage regeneration. Our study demonstrates that the delivery of circCDK13 in sEVs may present an option for diabetic wound treatment.

Mesenchymal stem cell-secretome laden photopolymerizable hydrogels for wound healing.

Mesenchymal stem cell-derived secretome represents an emerging acellular therapeutic which possess significant opportunity for clinical applications due to its anti-inflammatory, immunomodulatory, and wound healing properties. However, maintaining therapeutic efficacy and ensuring stability of cell-based products is challenging, requiring a robust delivery method. Therefore, we designed a hydrogel-based scaffold loaded with CK Cell Technologies' proprietary Mesenchymal stem cell-secretome for controlled release treatment of acute and chronic wounds. We incorporated both conditioned media (CM) and extracellular vesicles (EVs) into gelatin methacryloyl (GelMA) hydrogels and demonstrated how we can tune the diffusive release of the EVs from them. To demonstrate viability of the approach, we developed a wound healing scratch assay where we see in situ release of CM and EVs promote enhanced migration of human dermal fibroblasts (hDFs). We see the colocalization of these EVs in the fibroblasts using fluorescent microscopy. Finally, as a surrogate for in vivo neovascularization, we conducted an in vitro tube formation assay for the MSC-secretome using matrigel-embedded human microvascular endothelial cells. By adding CM and EVs, we observe an increase in tubulogenesis. Collectively, our data demonstrates by tuning the GelMA properties, we can influence the controlled release of the MSC-secretome for a wound dressing and bandage application for chronic and acute wounds.

Fe-Porphyrin Cross-Linked Hydrogel for Reactive Oxygen Species Scavenging and Oxygen Generation in Diabetic Wounds.

Healing chronic diabetic wounds is challenging because of excessive reactive oxygen species (ROS) and hypoxia in the wound microenvironment. To address this issue, we propose a hydrogel wound dressing composed of polyethylene glycol (PEG) cross-linked with a biomimetic catalase, Fe-containing porphyrin (FeP) (i.e., FeP hydrogel). The immobilized FeP can serve as a catalyst for both ROS scavenging and O2 generation. The properties of the hydrogels were optimized by varying the composition ratios of the two constituent materials based on their mechanical properties and catalytic activity. Our in vitro cell experiments revealed that the FeP-80 hydrogel enhanced the proliferation and migration of keratinocytes and dermal fibroblasts and promoted the expression of angiogenic growth factors in keratinocytes. When tested with an in vivo diabetic chronic wound model, the FeP-80 hydrogel promoted wound healing by facilitating re-epithelialization, promoting angiogenesis, and suppressing inflammation, compared with other control groups.

Yeast-Derived Nucleotides Enhance Fibroblast Migration and Proliferation and Provide Clinical Benefits in Atopic Dermatitis.

Nucleotides, glycosaminoglycans, and omega-3 essential fatty acids (O3s) could be used for improving skin health, although their modes of action, alone or in combination, are not yet fully understood. To gain some insight into these mechanisms, we performed two in vitro tests and one in vivo pilot trial. The effects on human dermal fibroblast proliferation and migration were evaluated with the following compounds and combinations: 0.156 mg/mL O3s, 0.0017 mg/mL hyaluronic acid (HA), 0.0004 mg/mL dermatan sulfate (DS), 0.0818 mg/mL nucleotides, and [O3s + HA + DS] and [O3s + HA + DS + nucleotides] at the same concentrations. In both in vitro assays, adding nucleotides to [O3s + HA + DS] provided significant improvements. The resulting combination [O3s + HA + DS + nucleotides] was then tested in vivo in dogs with atopic dermatitis by oral administration of a supplement providing a daily amount of 40 mg/kg nucleotides, 0.9 mg/kg HA, 0.18 mg/kg DS, 53.4 mg/kg EPA, and 7.6 mg/kg DHA. After 30 days, the pruritus visual analog scale (pVAS) score was significantly reduced, and no adverse effects were observed. In conclusion, the combination of nucleotides plus glycosaminoglycans and O3s could serve as a useful therapeutic alternative in skin health applications.

Effectiveness of Ya-Samarn-Phlae in diabetic wound healing: Evidence from in vitro studies and a multicenter randomized controlled clinical trial

Ethnopharmacological relevanceYa-Samarn-Phlae (YaSP) has traditionally been widely used in southern Thailand for treating chronic and infected wounds, including diabetic foot ulcers. However, there are only a limited number of clinical studies supporting the use of this polyherbal formulation. Therefore, the present work aims to provide clinical evidence to support the application of YaSP, prepared according to a standardized traditional procedure (T-YaSP). Additionally, its potential chemical markers and wound healing-related biological activities were examined. Materials and methodsThe in vitro wound healing-related biological activities of YaSP ethanol extract and T-YaSP, including antibacterial activity against Staphylococcus epidermidis, inhibition and eradication of staphylococcal biofilm, anti-inflammatory effects, and enhancement of human dermal fibroblast migration in scratch wounds, were examined using well-established protocols. The chemical profiles of the ethanol extract of YaSP and T-YaSP were compared, and with promising chemical markers, arecoline, alpha-mangostin, and curcumin were selected and quantified using the HPLC method. A prospective, multicenter, randomized, controlled, parallel-group study was conducted over 12 weeks to evaluate the efficacy of the YaSP solution as an adjunct therapy, combined with standard wound care, for diabetic ulcers compared to standard treatment. ResultsThe YaSP extract reduces NO production and can scavenge NO radicals in LPS-induced RAW 264.7 macrophage cells. Additionally, in a scratch assay, this extract and one of its herbal components, Curcuma longa, enhance the migration of human dermal fibroblasts. T-YaSP, containing 2.412 ± 0.002 mg/g of arecoline, 2.399 ± 0.005 mg/g of curcumin, and 0.017 ± 0.000 mg/g of α-mangostin, has shown the ability to inhibit the development and eradicate the mature biofilm of S. epidermidis. The use of T-YaSP as an adjunct therapy led to a significantly higher proportion of patients achieving healing within six weeks compared to the standard treatment group (36%/9 patients vs. 4%/1 patient; p = 0.013). After 12 weeks, 19 out of 25 patients in the T-YaSP group experienced complete healing, whereas only four patients in the standard treatment group achieved complete wound healing (76% in the T-YaSP group vs. 16% in the control group; p < 0.001). ConclusionThe results presented here represent the first randomized controlled trial to demonstrate the effectiveness of the traditional polyherbal solution, T-YaSP, which exhibits a wide range of wound healing-related activities. Utilizing T-YaSP as an adjunctive treatment resulted in a significant improvement in the number of type 2 diabetic patients achieving complete healing. However, to explore and utilize YaSP further, conducting a double-blind, randomized controlled trial with a larger population is necessary.

P024 Synergistic effect of phytochemicals combination including ginsenosides and curcumin on recovery from radiation-induced toxicity

Abstract Background Radiotherapy is commonly used to treat solid cancers located in the pelvis. A considerable number of patients experience proctitis of varying severity, even for a considerable period after radiotherapy. These side effects are often long-lasting or progressively worsen despite multiple therapeutic efforts and are a primary cause of an unexpectedly low quality of life, even after successful cancer treatment. Therefore, this in vitro study, as an initial trial, evaluated the single and combined efficacy of ginsenoside, curcumin, butyric acid, and sucralfate compounds in treating radiation-induced proctitis. Methods Cell viability and migration assay, endothelial cell tube formation assay were performed using human colon cancer cell lines, dermal fibroblasts, keratinocytes, and human umbilical vein endothelial cells, which were exposed to radiation. In addition, Inflammatory cytokine assay for CXCL10, CCL2, CCL8, IFN-γ, IL-4, IL-12, and IL-21 is performed using human monocytes treated with LPS (lipopolysaccharide). In all assay, the single and combined efficacy of ginsenoside, curcumin, butyric acid, and sucralfate were analyzed. Results While the candidate compounds did not affect the proliferation and migration of cancer cells, they promoted the recovery of cell activity, including motility. They exhibited anti-inflammatory effects on human dermal fibroblasts or human umbilical vein endothelial cells within in vitro disease models. When each compound was tested, curcumin and ginsenoside were the most effective in cell recovery and promoted the migration of human dermal fibroblasts and cell restoration of human umbilical vein endothelial cells. The combination of ginsenoside and curcumin resulted in cell migration recovery of approximately 54%. In addition, there was a significant improvement in the length of the endothelial tube, with an increase of approximately 25%, suggesting that the ginsenoside-curcumin-containing combination was the most effective against radiation-induced damage. Furthermore, it was shown that the combination could alleviate radiation-induced inflammation by reducing the concentrations of IFN-γ and IL-12, associated with activated macrophages among LPS-induced inflammatory cytokines, by approximately 20% and 45%, respectively. Conclusion Our study provides valuable insights into using curcumin and ginsenoside as potential compounds for the effective treatment of radiation-induced injuries and highlights the promising therapeutic benefits of combining these two compounds.

Combination of phytochemicals, including ginsenoside and curcumin, shows a synergistic effect on the recovery of radiation-induced toxicity.

Radiotherapy is commonly used to treat solid cancers located in the pelvis. A considerable number of patients experience proctitis of varying severity, even for a considerable period after radiotherapy. These side effects are often long-lasting or progressively worsen despite multiple therapeutic efforts and are a primary cause of an unexpectedly low quality of life, even after successful cancer treatment. Therefore, this study evaluated the individual and combined efficacy of ginsenoside, curcumin, butyric acid, and sucralfate compounds in treating radiation-induced proctitis. While the candidate compounds did not affect the proliferation and migration of cancer cells, they promoted the recovery of cell activity, including motility. They exhibited anti-inflammatory effects on human dermal fibroblasts or human umbilical vein endothelial cells within in vitro disease models. When each compound was tested, curcumin and ginsenoside were the most effective in cell recovery and promoted the migration of human dermal fibroblasts and cell restoration of human umbilical vein endothelial cells. The combination of ginsenoside and curcumin resulted in cell migration recovery of approximately 54%. In addition, there was a significant improvement in the length of the endothelial tube, with an increase of approximately 25%, suggesting that the ginsenoside-curcumin-containing combination was the most effective against radiation-induced damage. Furthermore, studies evaluating the effects of combined treatments on activated macrophages indicated that the compounds effectively reduced the secretion of inflammatory cytokines, including chemokines, and alleviated radiation-induced inflammation. In conclusion, our study provides valuable insights into using curcumin and ginsenoside as potential compounds for the effective treatment of radiation-induced injuries and highlights the promising therapeutic benefits of combining these two compounds.

Antioxidative bioactive glass reinforced injectable hydrogel with reactive oxygen species scavenging capacity for diabetic wounds treatment

Diabetic wound healing remains a critical challenge due to its special hyperglycemic environment and disorder in wound healing process. The hyperglycemic microenvironment of diabetic wounds causes inhibitive angiogenesis and overproduction of reactive oxygen species (ROS), which leads to oxidative stress damage to biological macromolecules and cells, and hindrance of wound healing. Herein, an injectable thermo-sensitive methyl cellulose hydrogel with capacities of improving angiogenesis, scavenging ROS and antibiosis is developed to overcome the obstacles of diabetic wound healing. Through loading antioxidative cerium-doped bioactive glass nanoparticles (CeBG), the hydrogel demonstrates efficient ROS scavenging to protect cells from oxidative stress harm, as well as stimulation of dermal fibroblast proliferation and migration. Moreover, addition of quaternary chitosan (QCS) endows the hydrogel with antibacterial ability against E. coli and S. aureus. The hydrogel effectively accelerates diabetic wound healing in a mice model, and more importantly, the wound area presents improved angiogenesis, diminished inflammation and decreased ROS level. These data demonstrate that the hydrogel is a promising biomaterial for the clinical treatment of diabetic wounds, as well as facilitating the therapy of oxidative stress related diseases.

α-Catenin promotes dermal fibroblasts proliferation and migration during wound healing via FAK/YAP activation.

Skin wound healing is a complex and organized biological process, and the dermal fibroblasts play a crucial role. α-Catenin is known to be involved in regulating various cellular signals, and its role in wound healing remains unclear. Here, we have identified the pivotal role of the α-catenin/FAK/YAP signaling axis in the proliferation and migration of dermal fibroblasts, which contributes to the process of skin wound healing. Briefly, when α-catenin was knocked down specifically in dermal fibroblasts, the wound healing rate is significantly delayed. Moreover, interfering with α-catenin can impede the proliferation and migration of dermal fibroblasts both invitro and invivo. Mechanistically, the overexpression of α-catenin upregulates the nuclear accumulation of YAP and transcription of downstream target genes, resulting in enhanced the proliferation and migration of dermal fibroblasts. Furthermore, the FAK Tyr397 phosphorylation inhibitor blocked the promoting effects of α-catenin on YAP activation. Importantly, the continuous phosphorylation mutation of FAK Tyr397 reversed the retardatory effects of α-catenin knockdown on wound healing, by increasing the vitality of fibroblasts. Likewise, α-catenin/FAK was validated as a therapeutic target for wound healing in the db/db chronic trauma model. In summary, our findings have revealed a novel mechanism by which α-catenin facilitates the function of fibroblasts through the activity of the FAK/YAP signaling axis. These findings define a promising therapeutic strategy for accelerating the wound healing process.

KRT17 From Keratinocytes With High Glucose Stimulation Inhibit Dermal Fibroblasts Migration Through Integrin α11.

To investigate the effects of overexpressed keratin 17 (KRT17) on the biology of human dermal fibroblasts (HDFs) and to explore the mechanism of KRT17 in diabetic wound healing. KRT17 expression was tested in diabetic keratinocytes, animal models, and patient skin tissues (Huazhong University of Science and Technology Ethics Committee, [2022] No. 3110). Subsequently, HDFs were stimulated with different concentrations of KRT17 in vitro. Changes in the proliferation and migration of HDFs were observed. Then, identification of KRT17-induced changes in dermal fibroblast of RNA sequencing-based transcriptome analysis was performed. KRT17 expression was upregulated under pathological conditions. In vitro stimulation of HDFs with different concentrations of KRT17 inhibited cell migration. RNA-seq data showed that enriched GO terms were extracellular matrix components and their regulation. KEGG analysis revealed that the highest number of enriched genes was PI3K-Akt, in which integrin alpha-11 (ITGA11) mRNA, a key molecule that regulates cell migration, was significantly downregulated. Decreased ITGA11 expression was observed after stimulation of HDFs with KRT17 in vitro. Increased expression of KRT17 in diabetic pathological surroundings inhibits fibroblast migration by downregulating the expression of ITGA11. Thus, KRT17 may be a molecular target for the treatment of diabetic wounds.

CaO2-Cu2O micromotors accelerate infected wound healing through antibacterial functions, hemostasis, improved cell migration, and inflammatory regulation.

During the wound tissue healing process, the relatively weak driving forces of tissue barriers and concentration gradients lead to a slow and inefficient penetration of bioactive substances into the wound area, consequently showing an impact on the effectiveness of deep wound healing. To overcome these challenges, we constructed biocompatible CaO2-Cu2O "micromotors". These micromotors reacted with the fluids at the wound site, releasing oxygen bubbles and propelling particles deep into the wound tissue. In vitro experimental results revealed that these micromotors not only exhibited antibacterial and hemostatic functions but also facilitated the migration of dermal fibroblasts and vascular endothelial cells, while modulating the inflammatory microenvironment. A methicillin-resistant Staphylococcus aureus infected full-thickness-wound model was created in rats, in which CaO2-Cu2O micromotors markedly expedited the wound healing process. Specifically, CaO2-Cu2O provided a sterile microenvironment for wounds and increased the amounts of M1-type macrophages during infection and inflammation. During the proliferation and remodeling stages, the amount of M1 macrophages gradually decreased, while the amount of M2 macrophages increased, and CaO2-Cu2O did not prolong the inflammatory period. Furthermore, the introduction of a regenerated silk fibroin (RSF) film on the wound surface successfully enhanced the therapeutic effects of CaO2-Cu2O against the infected wound. The combined application of oxygen-producing CaO2-Cu2O micromotors and a RSF film demonstrates significant therapeutic potential and emerges as a promising candidate for the treatment of infected wounds.

Effect of Elaeagnus Angustifolia extract on in vitro wound healing of human dermal fibroblast cells

AimThe purpose of this study was to determine the impact of Elaeagnus Angustifolia extract (EA) on human dermal fibroblast (HDF) survival, migration, and wound healing-related genes.MethodsAfter preparing the hydroalcoholic extract of EA, MTT and scratch tests were used to determine the effect of EA on the viability and migration of HDFs. In addition, the quantitative polymerase chain reaction (q-PCR) was conducted to evaluate the impact of EA on the expression of wound healing-related genes in HDFs.ResultAccording to the MTT test, a nontoxic concentration of EA (100 µg/ml) was obtained for further investigations. The scratch test results demonstrated that EA improved HDFs’ capacity to migrate when compared to the control group. Additionally, q-PCR results revealed that EA could significantly increase wound healing-related genes (VEGF-A, HLA-G5, and IL-6) in comparison with the control group.ConclusionsThe EA could have a significant impact on the viability and migration of HDFs. Also, EA increased the expression of wound healing-related genes.

MiR-21 Expressed by Dermal Fibroblasts Enhances Skin Wound Healing Through the Regulation of Inflammatory Cytokine Expression.

The management of skin wound healing is still a challenge. MicroRNA-21 (miR-21) has been reported to play important roles in wound repair; however, the underlying mechanism needs to be further clarified. The present study aimed to study the direct role of miR-21 in skin wound healing in miR-21 KO mice and to investigate the role of miR-21 in controlling the migration and proliferation of primary human skin cells and its underlying mechanism(s). miR-21 KO and wild-type (WT) mice were used for in vivo wound healing assays, while mouse and human primary skin cells were used for in vitro assays. miR-21 inhibitors or mimics or negative control small RNAs were transfected to either inhibit or enhance miR-21 expression in the human primary dermal fibroblasts or epidermal cells. RNA sequencing analysis was performed to identify the potential molecular pathways involved. We found that the loss of miR-21 resulted in slower wound healing in miR-21 KO mouse skin and especially delayed the healing of dermal tissue. In vitro assays demonstrated that the reduced expression of miR-21 caused by its inhibitor inhibited the migration of human primary dermal fibroblasts, which could be enhanced by increased miR-21 expression caused by miR-21 mimics. RNA-sequence analysis revealed that the inhibition of miR-21 expression downregulated the inflammatory response pathways associated with the decreased expression of inflammatory cytokines, and the addition of IL-1β into the culture medium enhanced the migration and proliferation of dermal fibroblasts in vitro. In conclusion, miR-21 in dermal fibroblasts can promote the migration and growth of epidermal and dermal cells to enhance skin wound healing through controlling the expression of inflammatory cytokines.

Hypoxic microenvironment promotes dermal fibroblast migration and proliferation via a BNIP3-autophagy pathway.

Upon injury, nearby cells, including fibroblasts at the wound edge, are often found in a hypoxic microenvironment. Nevertheless, the influence of hypoxia on skin fibroblasts is poorly understood. Using previously established mouse full-thickness wounds, we show that Bcl-2 and adenovirus E1B 19-kDa interacting protein 3 (BNIP3) expression was significantly elevated at the wound edge, and hypoxia treatment enhanced BNIP3 expression in fibroblasts. Interestingly, BNIP3 promoted the migration and proliferation, as well as the activation of autophagy, in fibroblasts under hypoxia. The hypoxia-induced autophagy was found to induce the migration and proliferation of fibroblasts, a process that could be reversed by knocking down the autophagy-related gene for autophagy protein 5, ATG5. Furthermore, hypoxia-inducible factor 1 subunit alpha (HIF-1α) was significantly upregulated in fibroblasts under hypoxia treatment, and HIF-1α knockdown attenuated the hypoxia-induced expression of BNIP3 and the migration and proliferation of fibroblasts. Altogether, our results establish the hypoxia-BNIP3-autophagy signaling axis as a newly identified regulatory mechanism of skin fibroblast migration and proliferation upon wounding. Autophagy intervening might thus represent a promising therapeutic strategy for patients with chronic refractory wounds.

Simulated microgravity attenuates skin wound healing by inhibiting dermal fibroblast migration via F-actin/YAP signaling pathway.

Skin and its cell components continuously subject to extrinsic and intrinsic mechanical forces and are mechanical sensitive. Disturbed mechanical homeostasis may lead to changes in skin functions. Gravity is the integral mechanical force on the earth, however, how gravity contributes to the maintenance of skin function and how microgravity in space affects the wound healing are poorly understood. Here, using microgravity analogs, we show that simulated microgravity (SMG) inhibits the healing of cutaneous wound and the accumulation of dermal fibroblasts in the wound bed. In vitro, SMG inhibits the migration of human foreskin fibroblast cells (HFF-1), and decreases the F-actin polymerization and YAP (yes-associated protein) activity. The SMG-inhibited migration can be recovered by activating YAP or F-actin polymerization using lysophosphatidic acid (LPA) or jasplakinolide (Jasp), suggesting the involvement of F-actin/YAP signaling pathway in this process. In SMG rats, LPA treatment improves the cutaneous healing with increased dermal fibroblasts in the wound bed. Together, our results demonstrate that SMG attenuates the cutaneous wound healing by inhibiting dermal fibroblast migration, and propose the crucial role of F-actin/YAP mechano-transduction in the maintenance of skin homeostasis under normal gravity, and YAP as a possible therapeutic target for the skin care of astronauts in space.