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Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway
BACKGROUND: Mesenchymal stem cell (MSC)-derived exosomes emerge as promising candidates for treating delayed wound healing in diabetes due to the promotion of angiogenesis. Preconditioned MSC with chemical or biological factors could possibly enhance the biological activities of MSC-derived exosomes...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425015/ https://www.ncbi.nlm.nih.gov/pubmed/32787917 http://dx.doi.org/10.1186/s13287-020-01824-2 |
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author | Yu, Muyu Liu, Wei Li, Junxian Lu, Junxi Lu, Huijuan Jia, Weiping Liu, Fang |
author_facet | Yu, Muyu Liu, Wei Li, Junxian Lu, Junxi Lu, Huijuan Jia, Weiping Liu, Fang |
author_sort | Yu, Muyu |
collection | PubMed |
description | BACKGROUND: Mesenchymal stem cell (MSC)-derived exosomes emerge as promising candidates for treating delayed wound healing in diabetes due to the promotion of angiogenesis. Preconditioned MSC with chemical or biological factors could possibly enhance the biological activities of MSC-derived exosomes. The purpose of this research focused on whether exosomes derived from the bone marrow MSC (BMSC) pretreated with atorvastatin (ATV), could exhibit better pro-angiogenic ability in diabetic wound healing or not and its underlying molecular mechanism. METHODS: We isolated exosomes from non-pretreated BMSC (Exos) and ATV pretreated BMSC (ATV-Exos) and evaluated their characterization by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blotting. In vivo, we made full-thickness skin defects in streptozotocin (STZ)-induced diabetic rats and the defects received multiple-point injection with PBS, Exos, or ATV-Exos. Two weeks later, histological analysis was conducted to evaluate the impact of different treatments on wound healing and the neovascularization was measured by micro-CT. In vitro, cell proliferation, migration, tube formation, and vascular endothelial growth factor (VEGF) secretion were measured in human umbilical vein endothelial cells (HUVEC). The role of miRNAs and AKT/eNOS signaling pathway in the promoted angiogenesis of ATV-Exos were assessed with their inhibitors. RESULTS: No significant difference in morphology, structure, and concentration was observed between ATV-Exos and Exos. In STZ-induced diabetic rats, ATV-Exos exhibited excellent abilities in facilitating the wound regeneration by promoting the formation of blood vessels compared with Exos without influencing liver and kidney function. Meanwhile, ATV-Exos promoted the proliferation, migration, tube formation, and VEGF level of endothelial cells in vitro. And AKT/eNOS pathway was activated by ATV-Exos and the pro-angiogenic effects of ATV-Exo were attenuated after the pathway being blocked. MiR-221-3p was upregulated by ATV-Exos stimulation, and miR-221-3p inhibitor suppressed the pro-angiogenesis effect of ATV-Exos. CONCLUSIONS: Exosomes originated from ATV-pretreated MSCs might serve as a potential strategy for the treatment of diabetic skin defects through enhancing the biological function of endothelial cells via AKT/eNOS pathway by upregulating the miR-221-3p. |
format | Online Article Text |
id | pubmed-7425015 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-74250152020-08-16 Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway Yu, Muyu Liu, Wei Li, Junxian Lu, Junxi Lu, Huijuan Jia, Weiping Liu, Fang Stem Cell Res Ther Research BACKGROUND: Mesenchymal stem cell (MSC)-derived exosomes emerge as promising candidates for treating delayed wound healing in diabetes due to the promotion of angiogenesis. Preconditioned MSC with chemical or biological factors could possibly enhance the biological activities of MSC-derived exosomes. The purpose of this research focused on whether exosomes derived from the bone marrow MSC (BMSC) pretreated with atorvastatin (ATV), could exhibit better pro-angiogenic ability in diabetic wound healing or not and its underlying molecular mechanism. METHODS: We isolated exosomes from non-pretreated BMSC (Exos) and ATV pretreated BMSC (ATV-Exos) and evaluated their characterization by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blotting. In vivo, we made full-thickness skin defects in streptozotocin (STZ)-induced diabetic rats and the defects received multiple-point injection with PBS, Exos, or ATV-Exos. Two weeks later, histological analysis was conducted to evaluate the impact of different treatments on wound healing and the neovascularization was measured by micro-CT. In vitro, cell proliferation, migration, tube formation, and vascular endothelial growth factor (VEGF) secretion were measured in human umbilical vein endothelial cells (HUVEC). The role of miRNAs and AKT/eNOS signaling pathway in the promoted angiogenesis of ATV-Exos were assessed with their inhibitors. RESULTS: No significant difference in morphology, structure, and concentration was observed between ATV-Exos and Exos. In STZ-induced diabetic rats, ATV-Exos exhibited excellent abilities in facilitating the wound regeneration by promoting the formation of blood vessels compared with Exos without influencing liver and kidney function. Meanwhile, ATV-Exos promoted the proliferation, migration, tube formation, and VEGF level of endothelial cells in vitro. And AKT/eNOS pathway was activated by ATV-Exos and the pro-angiogenic effects of ATV-Exo were attenuated after the pathway being blocked. MiR-221-3p was upregulated by ATV-Exos stimulation, and miR-221-3p inhibitor suppressed the pro-angiogenesis effect of ATV-Exos. CONCLUSIONS: Exosomes originated from ATV-pretreated MSCs might serve as a potential strategy for the treatment of diabetic skin defects through enhancing the biological function of endothelial cells via AKT/eNOS pathway by upregulating the miR-221-3p. BioMed Central 2020-08-12 /pmc/articles/PMC7425015/ /pubmed/32787917 http://dx.doi.org/10.1186/s13287-020-01824-2 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Yu, Muyu Liu, Wei Li, Junxian Lu, Junxi Lu, Huijuan Jia, Weiping Liu, Fang Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway |
title | Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway |
title_full | Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway |
title_fullStr | Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway |
title_full_unstemmed | Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway |
title_short | Exosomes derived from atorvastatin-pretreated MSC accelerate diabetic wound repair by enhancing angiogenesis via AKT/eNOS pathway |
title_sort | exosomes derived from atorvastatin-pretreated msc accelerate diabetic wound repair by enhancing angiogenesis via akt/enos pathway |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425015/ https://www.ncbi.nlm.nih.gov/pubmed/32787917 http://dx.doi.org/10.1186/s13287-020-01824-2 |
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