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Here, EV are isolated from key stages of the human induced pluripotent stem cell\u2010cardiomyocyte (hiPSC\u2010CM) differentiation and maturation, i.e., from hiPSC (hiPSC\u2010EV), cardiac progenitors, immature and mature cardiomyocytes, with the aim of identifying a promising cell biofactory for EV production, and pinpoint the genetic signatures of bioactive EV. EV secreted by hiPSC and cardiac derivatives show a typical size distribution profile and the expression of specific EV markers. Bioactivity assays show increased tube formation and migration in HUVEC treated with hiPSC\u2010EV compared to EV from committed cell populations. hiPSC\u2010EV also significantly increase cell cycle activity of hiPSC\u2010CM. Global miRNA expression profiles, obtained by small RNA\u2010seq analysis, corroborate an EV\u2010miRNA pattern indicative of stem cell to cardiomyocyte specification, confirming that hiPSC\u2010EV are enriched in pluripotency\u2010associated miRNA with higher in vitro pro\u2010angiogenic and pro\u2010proliferative properties. In particular, a stemness maintenance miRNA cluster upregulated in hiPSC\u2010EV targets the PTEN\/PI3K\/AKT pathway, involved in cell proliferation and survival. Overall, the findings validate hiPSC as cell biofactories for EV production for cardiac regenerative applications.<\/jats:p>","DOI":"10.1002\/advs.202104296","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T19:44:40Z","timestamp":1648151080000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Bioactivity and miRNome Profiling of Native Extracellular Vesicles in Human Induced Pluripotent Stem Cell\u2010Cardiomyocyte Differentiation"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3856-873X","authenticated-orcid":false,"given":"Ana F.","family":"Louro","sequence":"first","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2781\u2010901 Portugal"},{"name":"ITQB\u2010NOVA Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780\u2010157 Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2933-9895","authenticated-orcid":false,"given":"Marta A.","family":"Paiva","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2781\u2010901 Portugal"},{"name":"ITQB\u2010NOVA Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780\u2010157 Portugal"}]},{"given":"Marta R.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2781\u2010901 Portugal"},{"name":"ITQB\u2010NOVA Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780\u2010157 Portugal"}]},{"given":"Katharina A.","family":"Kasper","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2781\u2010901 Portugal"},{"name":"ITQB\u2010NOVA Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780\u2010157 Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1445-3556","authenticated-orcid":false,"given":"Paula M.","family":"Alves","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2781\u2010901 Portugal"},{"name":"ITQB\u2010NOVA Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780\u2010157 Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7245-6785","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Gomes\u2010Alves","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2781\u2010901 Portugal"},{"name":"ITQB\u2010NOVA Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780\u2010157 Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5013-6625","authenticated-orcid":false,"given":"Margarida","family":"Serra","sequence":"additional","affiliation":[{"name":"iBET Instituto de Biologia Experimental e Tecnol\u00f3gica  Apartado 12 Oeiras 2781\u2010901 Portugal"},{"name":"ITQB\u2010NOVA Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier Universidade Nova de Lisboa  Av. da Rep\u00fablica Oeiras 2780\u2010157 Portugal"}]}],"member":"311","published-online":{"date-parts":[[2022,3,24]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2012.12.002"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-018-0250-9"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.125"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2018.1535750"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvx211"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2018.01.006"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2017.1324730"},{"key":"e_1_2_9_8_1","first-page":"4791","volume":"15","author":"Ding Q.","year":"2018","journal-title":"Exp. 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