{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:09:21Z","timestamp":1793650161100,"version":"4.5.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019092","name":"Natural Science Foundation for Distinguished Young Scholars of Hunan Province","doi-asserted-by":"publisher","award":["2021JJ10078"],"award-info":[{"award-number":["2021JJ10078"]}],"id":[{"id":"10.13039\/501100019092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019081","name":"Science and Technology Program of Hunan Province","doi-asserted-by":"publisher","award":["2022RC3056"],"award-info":[{"award-number":["2022RC3056"]}],"id":[{"id":"10.13039\/501100019081","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFF1100203"],"award-info":[{"award-number":["2022YFF1100203"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82104846"],"award-info":[{"award-number":["82104846"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Diabetic foot ulcer (DFU) is a break in the skin of the foot caused by diabetes. It is one of the most serious and debilitating complications of diabetes. The previous study suggested that dominant M1 polarization during DFU could be the leading reason behind impaired wound healing. This study concluded that macrophage M1 polarization predominates in DFU skin tissue. iNOS was increased in HG-induced M1-polarized macrophages; conversely, Arg-1 was decreased. Macrophage pellets after HG stimulation can impair endothelial cell (EC) function by inhibiting cell viability, tube formation and cell migration, indicating M1 macrophage-derived small extracellular vesicles (sEVs) -mediated HUVEC dysfunction. sEVs miR-503 was significantly upregulated in response to HG stimulation, but inhibition of miR-503 in HG-stimulated macrophages attenuated M1 macrophage-induced HUVEC dysfunction. ACO1 interacted with miR-503 and mediated the miR-503 package into sEVs. Under HG stimulation, sEVs miR-503 taken in by HUVECs targeted IGF1R in HUVECs and inhibited IGF1R expression. In HUVECs, miR-503 inhibition improved HG-caused HUVEC dysfunction, whereas IGF1R knockdown aggravated HUVEC dysfunction; IGF1R knockdown partially attenuated miR-503 inhibition effects on HUVECs. In the skin wound model in control or STZ-induced diabetic mice, miR-503-inhibited sEVs improved, whereas IGF1R knockdown further hindered wound healing. Therefore, it can be inferred from the results that the M1 macrophage-derived sEVs miR-503 targets IGF1R in HUVECs, inhibits IGF1R expression, leads to HUVEC dysfunction, and impedes wound healing in diabetic patients, while packaging miR-503 as an M1 macrophage-derived sEVs may be mediated by ACO1.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1104890","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T01:03:06Z","timestamp":1684803786000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":27,"title":["Diabetic macrophage small extracellular vesicles-associated miR-503\/IGF1R axis regulates endothelial cell function and affects wound healing"],"prefix":"10.3389","volume":"14","author":[{"given":"Jianqiang","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanshan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liuhuan","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfei","family":"Mu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1177\/0141076816688346","article-title":"Prevention and treatment of diabetic foot ulcers","volume":"110","author":"Lim","year":"2017","journal-title":"J R Soc Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-012-9619-x","article-title":"Diagnostics and treatment of the diabetic foot","volume":"41","author":"Apelqvist","year":"2012","journal-title":"Endocrine"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.3272","article-title":"Diabetic foot ulcer classifications: a critical review","author":"Monteiro-Soares","year":"2020","journal-title":"Diabetes Metab Res Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67698-2","article-title":"The global burden of diabetic foot disease","volume":"366","author":"Boulton","year":"2005","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2015.0676","article-title":"Diabetic wounds exhibit decreased Ym1 and arginase expression with increased expression of IL-17 and IL-20","volume":"5","author":"Finley","year":"2016","journal-title":"Adv Wound Care (New Rochelle)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/stem.503","article-title":"Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing","volume":"28","author":"Zhang","year":"2010","journal-title":"Stem Cells"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700701","article-title":"Inflammation in wound repair: molecular and cellular mechanisms","volume":"127","author":"Eming","year":"2007","journal-title":"J Invest Dermatol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: in vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.ajpath.2010.08.003","article-title":"Wound macrophages as key regulators of repair: origin, phenotype, and function","volume":"178","author":"Brancato","year":"2011","journal-title":"Am J Pathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.081002","article-title":"A transgenic mouse model of inducible macrophage depletion: effects of diphtheria toxin-driven lysozyme m-specific cell lineage ablation on wound inflammatory, angiogenic, and contractive processes","volume":"175","author":"Goren","year":"2009","journal-title":"Am J Pathol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in tissue repair, regeneration, and fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2011.0307","article-title":"Regulation of macrophage polarization and wound healing","volume":"1","author":"Ferrante","year":"2012","journal-title":"Adv Wound Care (New Rochelle)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1177\/0022034509359125","article-title":"Factors affecting wound healing","volume":"89","author":"Guo","year":"2010","journal-title":"J Dent Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.preteyeres.2015.07.002","article-title":"Progress in corneal wound healing","volume":"49","author":"Ljubimov","year":"2015","journal-title":"Prog Retin Eye Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1046\/j.1087-0024.2000.00014.x","article-title":"Angiogenesis in wound healing","volume":"5","author":"Tonnesen","year":"2000","journal-title":"J Investig Dermatol Symp Proc"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2228","DOI":"10.3390\/cells9102228","article-title":"Mechanistic actions of microRNAs in diabetic wound healing","volume":"9","author":"Petkovic","year":"2020","journal-title":"Cells"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI79052","article-title":"MicroRNA-132 enhances transition from inflammation to proliferation during wound healing","volume":"125","author":"Li","year":"2015","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/wrr.12470","article-title":"Integrative analysis of miRNA and mRNA paired expression profiling of primary fibroblast derived from diabetic foot ulcers reveals multiple impaired cellular functions","volume":"24","author":"Liang","year":"2016","journal-title":"Wound Repair regenerat"},{"key":"B20","doi-asserted-by":"publisher","first-page":"5836","DOI":"10.1038\/s41598-019-42309-4","article-title":"microRNA-155 inhibition restores fibroblast growth factor 7 expression in diabetic skin and decreases wound inflammation","volume":"9","author":"Moura","year":"2019","journal-title":"Sci Rep"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201211138","article-title":"Extracellular vesicles: exosomes, microvesicles, and friends","volume":"200","author":"Raposo","year":"2013","journal-title":"J Cell Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00442","article-title":"Tetraspanins in extracellular vesicle formation and function","volume":"5","author":"Andreu","year":"2014","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"D89","DOI":"10.1093\/nar\/gky985","article-title":"EVmiRNA: a database of miRNA profiling in extracellular vesicles","volume":"47","author":"Liu","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/s41556-019-0299-0","article-title":"Extracellular vesicle-packaged HIF-1\u03b1-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells","volume":"21","author":"Chen","year":"2019","journal-title":"Nat Cell Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/1476-4598-10-117","article-title":"Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells","volume":"10","author":"Yang","year":"2011","journal-title":"Mol Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.07.003","article-title":"Peripheral circulating exosome-mediated delivery of miR-155 as a novel mechanism for acute lung inflammation","volume":"27","author":"Jiang","year":"2019","journal-title":"Mol Ther"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201802427RRR","article-title":"Exosomes from high glucose-treated macrophages activate glomerular mesangial cells via TGF-\u03b21\/Smad3 pathway in vivo and in vitro","volume":"33","author":"Zhu","year":"2019","journal-title":"FASEB J Off Publ Fed Am Soc. Exp Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1161\/01.RES.0000124920.09738.26","article-title":"Glucose enhances human macrophage LOX-1 expression: role for LOX-1 in glucose-induced macrophage foam cell formation","volume":"94","author":"Li","year":"2004","journal-title":"Circ Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2012.256","article-title":"Comparison of protein, microRNA, and mRNA yields using different methods of urinary exosome isolation for the discovery of kidney disease biomarkers","volume":"82","author":"Alvarez","year":"2012","journal-title":"Kidney Int"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3892\/or.2012.1967","article-title":"Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines","volume":"28","author":"Chiba","year":"2012","journal-title":"Oncol Rep"},{"key":"B31","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13059-018-1604-0","article-title":"Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5","volume":"20","author":"Qin","year":"2019","journal-title":"Genome Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1069","article-title":"RBPDB: a database of RNA-binding specificities","volume":"39","author":"Cook","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"bqab104","DOI":"10.1210\/endocr\/bqab104","article-title":"Endothelial insulin receptors promote VEGF-a signaling via ERK1\/2 and sprouting angiogenesis","volume":"162","author":"Walker","year":"2021","journal-title":"Endocrinol 162"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.01.021","article-title":"Cellular and molecular biology of aging endothelial cells","volume":"89","author":"Donato","year":"2015","journal-title":"J Mol Cell Cardiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00049","article-title":"Role of hippo pathway-YAP\/TAZ signaling in angiogenesis","volume":"7","author":"Boopathy","year":"2019","journal-title":"Front Cell Dev Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s12964-019-0376-9","article-title":"Elevated kallikrein-binding protein in diabetes impairs wound healing through inducing macrophage M1 polarization","volume":"17","author":"Feng","year":"2019","journal-title":"Cell Commun Signal"},{"key":"B37","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1038\/s41392-021-00765-3","article-title":"Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a\/Src","volume":"6","author":"Xiao","year":"2021","journal-title":"Signal Transduct. Target Ther"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15958","article-title":"Inhibition of exosomal miR-24-3p in diabetes restores angiogenesis and facilitates wound repair via targeting PIK3R3","volume":"24","author":"Xu","year":"2020","journal-title":"J Cell Mol Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.3390\/biomedicines10061252","article-title":"Macrophage-derived extracellular vesicles: a promising tool for personalized cancer therapy","volume":"10","author":"Barone","year":"2022","journal-title":"Biomedicines"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.7150\/thno.52843","article-title":"CircUbe3a from M2 macrophage-derived small extracellular vesicles mediates myocardial fibrosis after acute myocardial infarction","volume":"11","author":"Wang","year":"2021","journal-title":"Theranostics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1186\/s12951-021-00964-8","article-title":"MiR-144-5p, an exosomal miRNA from bone marrow-derived macrophage in type 2 diabetes, impairs bone fracture healing via targeting Smad1","volume":"19","author":"Zhang","year":"2021","journal-title":"J Nanobiotechnol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"108223","DOI":"10.1016\/j.intimp.2021.108223","article-title":"M2 macrophage-derived exosomal miR-501 contributes to pubococcygeal muscle regeneration","volume":"101","author":"Zhou","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/s41419-019-1667-1","article-title":"Exosomes derived from M1 macrophages aggravate neointimal hyperplasia following carotid artery injuries in mice through miR-222\/CDKN1B\/CDKN1C pathway","volume":"10","author":"Wang","year":"2019","journal-title":"Cell Death Dis"},{"key":"B44","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.peptides.2018.05.008","article-title":"MiR-503 suppresses hypoxia-induced proliferation, migration and angiogenesis of endothelial progenitor cells by targeting apelin","volume":"105","author":"Wen","year":"2018","journal-title":"Peptides"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.reth.2019.12.002","article-title":"miR-503\/Apelin-12 mediates high glucose-induced microvascular endothelial cells injury via JNK and p38MAPK signaling pathway","volume":"14","author":"Chen","year":"2020","journal-title":"Regener Ther"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03425-6","article-title":"hnRNPA2B1 inhibits the exosomal export of miR-503 in endothelial cells","volume":"77","author":"Perez-Boza","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0195969","article-title":"Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes","volume":"13","author":"Statello","year":"2018","journal-title":"PloS One"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2980","DOI":"10.1038\/ncomms3980","article-title":"Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs","volume":"4","author":"Villarroya-Beltri","year":"2013","journal-title":"Nat Commun"},{"key":"B49","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.celrep.2016.09.031","article-title":"The RNA-binding protein SYNCRIP is a component of the hepatocyte exosomal machinery controlling MicroRNA sorting","volume":"17","author":"Santangelo","year":"2016","journal-title":"Cell Rep"},{"key":"B50","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.phrs.2019.04.021","article-title":"Ginsenoside F1 promotes angiogenesis by activating the IGF-1\/IGF1R pathway","volume":"144","author":"Zhang","year":"2019","journal-title":"Pharmacol Res"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1494","article-title":"Novel role of the IGF-1 receptor in endothelial function and repair: studies in endothelium-targeted IGF-1 receptor transgenic mice","volume":"61","author":"Imrie","year":"2012","journal-title":"Diabetes"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_201806_15178","article-title":"Up-regulation of microRNA-503 by high glucose reduces the migration and proliferation but promotes the apoptosis of human umbilical vein endothelial cells by inhibiting the expression of insulin-like growth factor-1 receptor","volume":"22","author":"Hou","year":"2018","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1692401","DOI":"10.1080\/20013078.2019.1692401","article-title":"Purity and yield of melanoma exosomes are dependent on isolation method","volume":"9","author":"Shu","year":"2020","journal-title":"J extracell. vesicles"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1697028","DOI":"10.1080\/20013078.2019.1697028","article-title":"Quality and efficiency assessment of six extracellular vesicle isolation methods by nano-flow cytometry","volume":"9","author":"Tian","year":"2020","journal-title":"J extracell. vesicles"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1104890\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T01:03:15Z","timestamp":1684803795000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1104890\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,23]]},"references-count":54,"alternative-id":["10.3389\/fimmu.2023.1104890"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1104890","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,23]]},"article-number":"1104890"}}