The role of small extracellular vesicles in cerebral and myocardial ischemia-Molecular signals, treatment targets, and future clinical translation.

The heart and the brain mutually interact with each other, forming a functional axis that is disturbed under conditions of ischemia. 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. ©2021 The Authors. Stem Cells published by Wiley Periodicals LLC on behalf of AlphaMed Press 2021.