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Stem cell-derived extracellular vesicles (EVs) show great potential for the treatment of ischemic stroke and myocardial infarction. Due to heart-brain interactions, therapeutic actions of EVs in the brain and the heart cannot be regarded in an isolated way. Effects in each of the two organs reciprocally influence the outcome of the other. Stem cell-derived EVs modulate a large number of signaling pathways in both tissues. Upon ischemia, EVs prevent delayed injury, promote angiogenesis, enhance parenchymal remodeling, and enable functional tissue recovery. The therapeutic effects greatly depend on EV cargos, among which are noncoding RNAs like microRNAs (miRNAs) and proteins, which modulate cell signaling in a differential way that not always corresponds to each other in the two tissues. Interestingly, the same miRNA or protein localized in EVs can modulate different signaling pathways in the ischemic heart and brain, which may have diverse consequences for disease outcomes. Paying careful attention to unveiling these underlying mechanisms may provide new insights into tissue remodeling processes and identify targets for ischemic stroke and myocardial infarction therapies. Some of these mechanisms are discussed in this concise review, and consequences for the clinical translation of EVs are presented.<\/jats:p>","DOI":"10.1002\/stem.3329","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T06:16:50Z","timestamp":1621837010000},"page":"403-413","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The role of small extracellular vesicles in cerebral and myocardial ischemia\u2014Molecular signals, treatment targets, and future clinical translation"],"prefix":"10.1093","volume":"39","author":[{"given":"Xuan","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Neurology, University Medical Center Goettingen, Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk M.","family":"Hermann","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"B\u00e4hr","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Goettingen, Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1222-9211","authenticated-orcid":false,"given":"Thorsten R.","family":"Doeppner","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Goettingen, Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,12]]},"reference":[{"issue":"3","key":"2022022511041884600_stem3329-bib-0001","doi-asserted-by":"crossref","first-page":"138","DOI":"10.2174\/157340310791658785","article-title":"Epidemiology and risk factors of cerebral ischemia and ischemic heart diseases: similarities and differences","volume":"6","author":"Soler","year":"2010","journal-title":"Curr Cardiol Rev"},{"issue":"4","key":"2022022511041884600_stem3329-bib-0002","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1161\/CIRCRESAHA.117.311170","article-title":"Brain-heart interaction: cardiac complications after stroke","volume":"121","author":"Chen","year":"2017","journal-title":"Circ Res"},{"issue":"2067","key":"2022022511041884600_stem3329-bib-0003","first-page":"20150181","article-title":"Brain\u2013heart interactions: physiology and clinical implications","volume":"374","author":"Silvani","year":"2016","journal-title":"Philos Trans A Math Phys Eng Sci"},{"issue":"3","key":"2022022511041884600_stem3329-bib-0004","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1161\/CIRCRESAHA.116.308446","article-title":"Heart-brain axis: effects of neurologic injury on cardiovascular function","volume":"120","author":"Tahsili-Fahadan","year":"2017","journal-title":"Circ Res"},{"issue":"1","key":"2022022511041884600_stem3329-bib-0005","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1161\/STROKEAHA.117.019312","article-title":"Autonomic dysfunction predicts clinical outcomes after acute ischemic stroke: a prospective observational study","volume":"49","author":"Xiong","year":"2018","journal-title":"Stroke"},{"issue":"5","key":"2022022511041884600_stem3329-bib-0006","first-page":"289","article-title":"Cardiac arrhythmias in stroke unit patients. 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