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The biodistribution of either intravenous or intramyocardial injection of MSC\u2010EV in the presence of myocardial injury is uncharacterized at this time. We hypothesized that intramyocardial injection will ensure delivery of MSC\u2010EV to the ischemic myocardium, while intravenous injection will not. Human bone marrow mesenchymal stem cells were cultured and the MSC\u2010EV were isolated and characterized. The MSC\u2010EVs were then labeled with DiD lipid dye. FVB mice with normal cardiac function underwent left coronary artery ligation followed by either peri\u2010infarct intramyocardial or tail vein injection of 3*10<jats:sup>6<\/jats:sup> or 2*10<jats:sup>9<\/jats:sup> particles of DiD\u2010labeled MSC\u2010EV or a DiD\u2010saline control. The heart, lungs, liver, spleen and kidneys were harvested 2\u00a0h post\u2010injection and were submitted for fluorescent molecular tomography imaging. Myocardial uptake of MSC\u2010EV was only visualized after intramyocardial injection of 2*10<jats:sup>9<\/jats:sup> MSC\u2010EV particles (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.01) compared to control, and there were no differences in cardiac fluorescence after tail vein injection of MSC\u2010EV (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.5). There was no significantly detectable MSC\u2010EV uptake in other organs after intramyocardial injection. After tail vein injection of 2*10<jats:sup>9<\/jats:sup> particles of MSC\u2010EV, the liver (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.02) and spleen (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.04) appeared to have diffuse MSC\u2010EV uptake compared to controls. Even in the presence of myocardial injury, only intramyocardial but not intravenous administration resulted in detectable levels of MSC\u2010EV in the ischemic myocardium. This study confirms the role for intramyocardial injection in maximal and effective delivery of MSC\u2010EV. Our ongoing studies aimed at developing bioengineered MSC\u2010EV for targeted delivery to the heart may render MSC\u2010EV clinically applicable for cardiovascular disease.<\/jats:p>","DOI":"10.14814\/phy2.15568","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T02:50:21Z","timestamp":1679885421000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Visualization of cardiac uptake of bone marrow mesenchymal stem cell\u2010derived extracellular vesicles after intramyocardial or intravenous injection in murine myocardial infarction"],"prefix":"10.14814","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2191-3066","authenticated-orcid":false,"given":"Cynthia M.","family":"Xu","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center Rhode Island Hospital  Providence Rhode Island USA"},{"name":"Division of Cardiothoracic Surgery Alpert Medical School of Brown University and Rhode Island Hospital Providence  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharif A.","family":"Sabe","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center Rhode Island Hospital  Providence Rhode Island USA"},{"name":"Division of Cardiothoracic Surgery Alpert Medical School of Brown University and Rhode Island Hospital Providence  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayane","family":"Brinck\u2010Teixeira","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center Rhode Island Hospital  Providence Rhode Island USA"},{"name":"Division of Cardiothoracic Surgery Alpert Medical School of Brown University and Rhode Island Hospital Providence  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Sabra","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center Rhode Island Hospital  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank W.","family":"Sellke","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center Rhode Island Hospital  Providence Rhode Island USA"},{"name":"Division of Cardiothoracic Surgery Alpert Medical School of Brown University and Rhode Island Hospital Providence  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2981-2638","authenticated-orcid":false,"given":"M. Ruhul","family":"Abid","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center Rhode Island Hospital  Providence Rhode Island USA"},{"name":"Division of Cardiothoracic Surgery Alpert Medical School of Brown University and Rhode Island Hospital Providence  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,3,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.51571"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.591065"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-020-00305-y"},{"key":"e_1_2_10_5_1","first-page":"201","article-title":"Exosomes secreted by cardiosphere\u2010derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction","volume":"38","author":"Gallet R.","year":"2017","journal-title":"European Heart Journal"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2014.1663"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951-022-01529-z"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12085"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2016.01.009"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ani12060749"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-019-09926-y"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-46407-1"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3402\/jev.v3.24641"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2021.01.001"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.008344"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3791\/55353"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0238879"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.012617"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10101392"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201601109"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2018.1535750"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/960926"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.121.17574"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20215468"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/09636897221102898"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.3329"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21682-7"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.15568","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T04:21:23Z","timestamp":1704946883000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.15568"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3]]},"references-count":26,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,3]]}},"alternative-id":["10.14814\/phy2.15568"],"URL":"https:\/\/doi.org\/10.14814\/phy2.15568","archive":["Portico"],"relation":{},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3]]},"assertion":[{"value":"2022-10-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e15568"}}