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The dysfunction of endothelial cells caused by hyperglycemia is observed as a decrease in neovascularization in diabetic wound healing. Studies have found that epidermal stem cells (EpiSCs) can promote the angiogenesis of full-thickness wounds. To further explain the therapeutic effect of EpiSCs, EpiSC-derived exosomes (EpiSC-EXOs) are considered the main substance contributing to stem cell effectivity. In our study, EpiSCs and EpiSC-EXOs were supplied to the dorsal wounds of db/db mice. Results showed that EpiSCs could colonize in the wound area and both EpiSCs and EpiSC-EXOs could accelerate diabetic wound healing by promoting angiogenesis. In vitro, persistent high glucose led to the malfunction and apoptosis of endothelial cells. The apoptosis induced by high glucose is due to excessive autophagy and was alleviated by EpiSC-EXOs. RNA sequencing of EpiSC-EXOs showed that miR200b-3p was enriched in EpiSC-EXOs and alleviated the apoptosis of endothelial cells. Synapse defective rho GTPase homolog 1 was identified the target of miR200b-3p and affected the phosphorylation of ERK to regulate intracellular autophagy and apoptosis. Furthermore, animal experiments validated the angiogenic effect of miR200b-3p. Collectively, our results verified the effect of EpiSC-EXOs on apoptosis caused by hyperglycemia in endothelial cells through the miR200b-3p/synapse defective rho GTPase homolog 1 /RAS/ERK/autophagy pathway, providing a theoretical basis for EpiSC in treating diabetic wounds., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chronic diabetic wounds remain a globally recognized clinical challenge, which occurs mainly due to the disturbances of wound microenvironmental induced by high concentrations of reactive oxygen species (ROS). Impairments in angiogenesis and inflammation in the wound microenvironment ultimately impede the normal healing process. Therefore, targeting macrophage and vascular endothelial cell dysfunction is a promising therapeutic strategy. In our study, we fabricated artificial composite scaffolds composed of naringin/carboxymethyl chitosan/sodium hyaluronate/silk fibroin (NG/CMCS/HA/SF) to promote wound healing. The NG/CMCS/HA/SF scaffold demonstrated favorable anti-inflammatory, anti-oxidative, and pro-angiogenic properties in both in vitro and in vivo experiments, effectively promoting the healing of diabetic wounds. The positive therapeutic effects observed indicate that the composite scaffolds have great potential in clinical wound healing applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Diabetic foot ulceration is a major diabetic complication with unmet needs. We investigated the efficacy of epidermal stem cells and epidermal stem cells-derived exosomes (ESCs-Exo) in improving impaired diabetic wound healing and their mechanisms of action. In vitro experiments showed that ESCs-Exo enhanced the proliferation and migration of diabetic fibroblasts and macrophages and promoted alternative or M2 macrophage polarization. In wounds of db/db mice, treatment with both epidermal stem cells and ESCs-Exo, when compared with fibroblast exosomes and PBS control, accelerated wound healing by decreasing inflammation, augmenting wound cell proliferation, stimulating angiogenesis, and inducing M2 macrophage polarization. Multiplex protein quantification of wound lysates revealed TGFβ signaling influenced by ESCs-Exo. High-throughput sequencing of small RNAs contained in the ESCs-Exo showed higher proportions of microRNAs than those contained in fibroblast exosomes. In silico functional analysis showed that the ESCs-Exo microRNAs‒target genes were primarily involved in homeostatic processes and cell differentiation and highlighted regulatory control of phosphatidylinositol-3 kinase/protein kinase B and TGFβ signaling pathways. This was also validated in vitro. Collectively, our results indicate that epidermal stem cells and ESCs-Exo are equally effective in promoting impaired diabetic wound healing and that ESCs-Exo treatment may be a promising and technically advantageous alternative to stem cell therapies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Excessive inflammation and reduced angiogenesis are two major obstacles in burn wound healing and skin regeneration. Here we report the fabrication and application of a sophisticated hydrogel from chemically modified hyaluronic acid (HA), dextran (Dex), and β-cyclodextrin (β-CD) integrating resveratrol (Res) and vascular endothelial growth factor (VEGF) plasmid as the anti-inflammatory and pro-angiogenic components for burn wounds. Firstly, covalent alterations were conducted to obtain methacrylic acid anhydride modified HA (HAMA), N-hydroxyethylacrylamide (HEAA) modified Dex (Dex-HEAA), and poly(ethylene glycol) methyl acrylate (526) modified β-CD (526-β-CD), respectively. Secondly, anti-inflammatory substance Res was embedded into the lipophilic central cavity of 526-β-CD to achieve a complex of 526-β-CD-Res. Then hydrogels with different HAMA, Dex-HEAA, and 526-β-CD-Res ratios were generated via UV irradiation. Lastly, plasmid DNA encoded with vascular endothelial growth factor (pDNA-VEGF) conjugating with polyethylenimine was loaded into the hydrogel scaffold. Combining the benefits of all components of the scaffold, the hydrogel embedded with Res and VEGF (Gel-Res/pDNA-VEGF) accelerated the splinted excisional burn wound healing, particularly by inhibiting inflammation response and promoting microvascular formation while being biocompatible. The Res and VEGF gene loaded hydrogel system can be considered as a promising wound dressing for the treatment of various types of wounds. STATEMENT OF SIGNIFICANCE: Combining the benefits of all components of the scaffold, the hydrogel embedded with Res and VEGF (Gel-Res/pDNA-VEGF) accelerated the splinted excisional burn wound healing, particularly by inhibiting inflammation response and promoting microvascular formation while being biocompatible. The Res and VEGF gene loaded hydrogel system can be considered as a promising wound dressing for the treatment of various types of wounds., (Copyright © 2019. Published by Elsevier Ltd.)

Hypertrophic scarring (HS) is a fibrotic skin condition characterized by aberrant fibroblast phenotypes and excessive deposition of extracellular matrix components. 2-Amino-2-[2-(4-octylphenyl)]-1, 3-propanediol hydrochloride (FTY720), an immunomodulator approved for treating multiple sclerosis, is reported to attenuate fibrosis in multiple disease models. Here we found that FTY720 could significantly attenuate the proliferation and fibrosis in HS fibroblasts (HSFs) and in an animal HS model. Upon treating HSFs or normal dermal fibroblasts with FTY720 at different concentrations for different time periods, we found that FTY720 presented a pleiotropic effect specifically on HSFs but not NFs, including reducing cell viability, arresting cell cycle progression at the G0/G1 phase, promoting apoptosis, inhibiting migration and contraction, and suppressing the expressions of α-smooth muscle actin, collagen I, and collagen III. Mechanistic studies showed that the antifibrotic activities of FTY720 were potentially mediated through sphingosine 1-phosphate receptor 5 to inhibit the protein kinase B/mTOR/p70S6K, but not the Smad, signaling pathway. The in vitro actions of FTY720 also translated into a rabbit ear HS model, stimulating the healing of HS. These findings collectively suggest that FTY720 targets multiple phenotypes of HSFs and is a promising therapeutic agent for HS., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)