{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T07:41:36Z","timestamp":1790494896626,"version":"4.1.0"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["CH\/11\/1\/28798"],"award-info":[{"award-number":["CH\/11\/1\/28798"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Leducq Transatlantic Network","award":["#14 CVD 04"],"award-info":[{"award-number":["#14 CVD 04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>After a myocardial infarction, the adult human heart lacks sufficient regenerative capacity to restore lost tissue, leading to heart failure progression. Finding novel ways to reprogram adult cardiomyocytes into a regenerative state is a major therapeutic goal. The epicardium, the outermost layer of the heart, contributes cardiovascular cell types to the forming heart and is a source of trophic signals to promote heart muscle growth during embryonic development. The epicardium is also essential for heart regeneration in zebrafish and neonatal mice and can be reactivated after injury in adult hearts to improve outcome. A recently identified mechanism of cell\u2013cell communication and signalling is that mediated by extracellular vesicles (EVs). Here, we aimed to investigate epicardial signalling via EV release in response to cardiac injury and as a means to optimize cardiac repair and regeneration.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We isolated epicardial EVs from mouse and human sources and targeted the cardiomyocyte population. Epicardial EVs enhanced proliferation in H9C2 cells and in primary neonatal murine cardiomyocytes in vitro and promoted cell cycle re-entry when injected into the injured area of infarcted neonatal hearts. These EVs also enhanced regeneration in cryoinjured engineered human myocardium (EHM) as a novel model of human myocardial injury. Deep RNA-sequencing of epicardial EV cargo revealed conserved microRNAs (miRs) between human and mouse epicardial-derived exosomes, and the effects on cell cycle re-entry were recapitulated by administration of cargo miR-30a, miR-100, miR-27a, and miR-30e to human stem cell-derived cardiomyocytes and cryoinjured EHM constructs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Here, we describe the first characterization of epicardial EV secretion, which can signal to promote proliferation of cardiomyocytes in infarcted mouse hearts and in a human model of myocardial injury, resulting in enhanced contractile function. Analysis of exosome cargo in mouse and human identified conserved pro-regenerative miRs, which in combination recapitulated the therapeutic effects of promoting cardiomyocyte proliferation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvab054","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T20:32:24Z","timestamp":1613161944000},"page":"597-611","source":"Crossref","is-referenced-by-count":76,"title":["Regenerative potential of epicardium-derived extracellular vesicles mediated by conserved miRNA transfer"],"prefix":"10.1093","volume":"118","author":[{"given":"Cristina Villa","family":"del Campo","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, British Heart Foundation, Oxbridge Centre of Regenerative Medicine, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7804-8133","authenticated-orcid":false,"given":"Norman Y","family":"Liaw","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, Robert-Koch-Str. 40, 37075 G\u00f6ttingen, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), partner site G\u00f6ttingen, Robert-Koch-Stra\u00dfe 42a, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mala","family":"Gunadasa-Rohling","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, British Heart Foundation, Oxbridge Centre of Regenerative Medicine, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Matthaei","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, Robert-Koch-Str. 40, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Braga","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Localit\u00e0 Padriciano, 99, 34149 Trieste TS, Italy"},{"name":"School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre, King's College London, Strand, London WC2R 2L, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5486-7289","authenticated-orcid":false,"given":"Tahnee","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, British Heart Foundation, Oxbridge Centre of Regenerative Medicine, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Salinas","sequence":"additional","affiliation":[{"name":"NGS- Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Centre G\u00f6ttingen (UMG), Robert-Koch-Str. 40, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8230-2341","authenticated-orcid":false,"given":"Niels","family":"Voigt","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, Robert-Koch-Str. 40, 37075 G\u00f6ttingen, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), partner site G\u00f6ttingen, Robert-Koch-Stra\u00dfe 42a, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2927-7225","authenticated-orcid":false,"given":"Mauro","family":"Giacca","sequence":"additional","affiliation":[{"name":"Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Localit\u00e0 Padriciano, 99, 34149 Trieste TS, Italy"},{"name":"School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre, King's College London, Strand, London WC2R 2L, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1190-4040","authenticated-orcid":false,"given":"Wolfram-Hubertus","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen, Robert-Koch-Str. 40, 37075 G\u00f6ttingen, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), partner site G\u00f6ttingen, Robert-Koch-Stra\u00dfe 42a, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9862-7332","authenticated-orcid":false,"given":"Paul Richard","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, British Heart Foundation, Oxbridge Centre of Regenerative Medicine, University of Oxford, Sherrington Building, Sherrington Rd, Oxford OX1 3PT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"2022013117275920800_cvab054-B1","first-page":"e28","article-title":"Heart disease and stroke statistics\u20132014 update: a report from the American Heart 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