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Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function.

ABSTRACT: Background:Diabetic wounds are one of the most common and serious complications of diabetes mellitus, characterized by the dysfunction of wound-healing-related cells in quantity and quality. Our previous studies revealed that human amniotic epithelial cells (hAECs) could promote diabetic wound healing by paracrine action. Interestingly, numerous studies demonstrated that exosomes derived from stem cells are the critical paracrine vehicles for stem cell therapy. However, whether exosomes derived from hAECs (hAECs-Exos) mediate the effects of hAECs on diabetic wound healing remains unclear. This study aimed to investigate the biological effects of hAECs-Exos on diabetic wound healing and preliminarily elucidate the underlying mechanism. Methods:hAECs-Exos were isolated by ultracentrifugation and identified by transmission electron microscopy, dynamic light scattering and flow cytometry. A series of in vitro functional analyses were performed to assess the regulatory effects of hAECs-Exos on human fibroblasts (HFBs) and human umbilical vein endothelial cells (HUVECs) in a high-glycemic microenvironment. High-throughput sequencing and bioinformatics analyses were conducted to speculate the related mechanisms of actions of hAECs-Exos on HFBs and HUVECs. Subsequently, the role of the candidate signaling pathway of hAECs-Exos in regulating the function of HUVECs and HFBs, as well as in diabetic wound healing, was assessed. Results:hAECs-Exos presented a cup- or sphere-shaped morphology with a mean diameter of 105.89?±?10.36 nm, were positive for CD63 and TSG101 and could be internalized by HFBs and HUVECs. After that, hAECs-Exos not only significantly promoted the proliferation and migration of HFBs, but also facilitated the angiogenic activity of HUVECs in vitro. High-throughput sequencing revealed enriched miRNAs of hAECs-Exos involved in wound healing. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses have shown that the target genes of the top 15 miRNAs were highly enriched in the PI3K-AKT pathway. Further functional studies demonstrated that the PI3K-AKT-mTOR pathway was necessary for the induced biological effects of hAECs-Exos on HFBs and HUVECs, as well as on wound healing, in diabetic mice. Conclusions:Our findings demonstrated that hAECs-Exos represent a promising, novel strategy for diabetic wound healing by promoting angiogenesis and fibroblast function via activation of the PI3K-AKT-mTOR pathway.

SUBMITTER: Wei P

PROVIDER: S-EPMC7476545 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function.

Wei Pei P Zhong Chenjian C Yang Xiaolan X Shu Futing F Xiao Shichu S Gong Teng T Luo Pengfei P Li Li L Chen Zhaohong Z Zheng Yongjun Y Xia Zhaofan Z

Burns & trauma 20200907

<h4>Background</h4>Diabetic wounds are one of the most common and serious complications of diabetes mellitus, characterized by the dysfunction of wound-healing-related cells in quantity and quality. Our previous studies revealed that human amniotic epithelial cells (hAECs) could promote diabetic wound healing by paracrine action. Interestingly, numerous studies demonstrated that exosomes derived from stem cells are the critical paracrine vehicles for stem cell therapy. However, whether exosomes ...[more]

PMID: 32923490

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Project description:The application of blood plasma for soft tissue wound healing is receiving much more attention recently. Exosomes are critical paracrine mediators that can be obtained from biological fluids including plasma and be able to induce regenerative effects by transferring bioactive molecules such as microRNAs (miRNAs). This study aimed to investigate the effects of exosomes from human umbilical cord blood plasma (UCB-Exos) on wound healing and to elucidate the underlying mechanism. Methods: UCB-Exos were isolated by ultracentrifugation and subcutaneously injected into full-thickness skin wounds in mice. The efficacy of UCB-Exos on wound healing was evaluated by measuring wound closure rates, histological analysis and immunofluorescence examinations. In vitro, quantitative real-time PCR (qRT-PCR) analysis was performed to detect the expression levels of a class of miRNAs that have positive roles in regulating wound healing. The scratch wound assay, transwell assay and cell counting kit-8 analysis were conducted to assess the effects of UCB-Exos on migration and proliferation of human skin fibroblasts and endothelial cells. Tube formation assay was carried out to test the impact of UCB-Exos on angiogenic tube formation ability of endothelial cells. Meanwhile, by using specific RNA inhibitors or siRNAs, the roles of the candidate miRNA and its target genes in UCB-Exos-induced regulation of function of fibroblasts and endothelial cells were assessed. Results: The local transplantation of UCB-Exos into mouse skin wounds resulted in accelerated re-epithelialization, reduced scar widths, and enhanced angiogenesis. In vitro, UCB-Exos could promote the proliferation and migration of fibroblasts, and enhance the angiogenic activities of endothelial cells. Notably, miR-21-3p was found to be highly enriched in UCB-Exos and served as a critical mediator in UCB-Exos -induced regulatory effects through inhibition of phosphatase and tensin homolog (PTEN) and sprouty homolog 1 (SPRY1). Conclusion: Our results suggest that UCB-Exos are important effectors of plasma activity and can be used as a novel promising strategy for soft tissue wound healing.

Project description:Skin wound healing is a common challenging clinical issue which requires advanced treatment strategies. The present study investigated the therapeutic effects of exosomes derived from dental pulp stem cells (DPSC‑Exos) on cutaneous wound healing and the underlying mechanisms. The effects of DPSC‑Exos on cutaneous wound healing in mice were examined by measuring wound closure rates, and using histological and immunohistochemical analysis. A series of functional assays were performed to evaluate the effects of DPSC‑Exos on the angiogenic activities of human umbilical vein endothelial cells (HUVECs) in vitro. Tandem mass tag‑based quantitative proteomics analysis of DPSCs and DPSC‑Exos was performed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to evaluate the biological functions and pathways for the differentially expressed proteins in DPSC‑Exos. Western blot analysis was used to assess the protein levels of cell division control protein 42 (Cdc42) and p38 in DPSC‑Exos and in HUVECs subjected to DPSC‑Exos‑induced angiogenesis. SB203580, a p38 mitogen‑activated protein kinase (MAPK) signaling pathway inhibitor, was employed to verify the role of the p38 MAPK pathway in vitro and in vivo. Histological and immunohistochemical staining revealed that the DPSC‑Exos accelerated wound healing by promoting neovascularization. The DPSC‑Exos promoted the migration, proliferation and capillary formation capacity of HUVECs. Proteomics data demonstrated that proteins contained in DPSC‑Exos regulated vasculature development and angiogenesis. Pathway analysis revealed that proteins expressed in DPSC‑Exos were involved in several pathways, including MAPK pathway. Western blot analysis demonstrated that the DPSC‑Exos increased the protein levels of Cdc42 and phosphorylation of p38 in HUVECs. SB203580 suppressed the angiogenesis induced by DPSC‑Exos. On the whole, the present study demonstrates that DPSC‑Exos accelerate cutaneous wound healing by enhancing the angiogenic properties of HUVECs via the Cdc42/p38 MAPK signaling pathway.

Dataset Information

Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function.

Publications

Exosomes derived from human amniotic epithelial cells accelerate diabetic wound healing via PI3K-AKT-mTOR-mediated promotion in angiogenesis and fibroblast function.

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