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Several signaling pathways involved in cell proliferation, differentiation and survival during newt tissue regeneration have been elucidated, however the factors that coordinate signaling between cells, as well as the conservation of these factors in other animals, are not well defined. Here we report that media conditioned by newt limb explant cells (A1 cells) protect mammalian cardiomyocytes from oxidative stress\u2010induced apoptosis. The cytoprotective effect of A1\u2010conditioned media was negated by exposing A1 cells to GW4869, which suppresses the generation of extracellular vesicles (EVs). A1\u2010EVs are similar in diameter (~100\u2013150\u00a0nm), structure, and share several membrane surface and cargo proteins with mammalian exosomes. However, isolated A1\u2010EVs contain significantly higher levels of both RNA and protein per particle than mammalian EVs. Additionally, numerous cargo RNAs and proteins are unique to A1\u2010EVs. Of particular note, A1\u2010EVs contain numerous mRNAs encoding nuclear receptors, membrane ligands, as well as transcription factors. Mammalian cardiomyocytes treated with A1\u2010EVs showed increased expression of genes in the PI3K\/AKT pathway, a pivotal player in survival signaling. We conclude that newt cells secrete EVs with diverse, distinctive RNA and protein contents. Despite ~300\u00a0million years of evolutionary divergence between newts and mammals, newt EVs confer cytoprotective effects on mammalian cardiomyocytes.<\/jats:p>","DOI":"10.1080\/20013078.2018.1456888","type":"journal-article","created":{"date-parts":[[2018,4,15]],"date-time":"2018-04-15T11:47:01Z","timestamp":1523792821000},"update-policy":"https:\/\/doi.org\/10.1080\/tandf_crossmark_01","source":"Crossref","is-referenced-by-count":37,"title":["Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes"],"prefix":"10.1002","volume":"7","author":[{"given":"Ryan C.","family":"Middleton","sequence":"first","affiliation":[{"name":"Smidt Heart Institute Cedars\u2010Sinai Medical Center Los Angeles CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell G.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute Cedars\u2010Sinai Medical Center Los Angeles CA 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