We read with great interest the Review by Boulanger et al. (Extracellular vesicles in coronary artery disease. Nat. Rev. Cardiol. 14, 259–272; 2017)1. The authors discuss the role of extracellular vesicles (including exosomes) as transporters of biological information between cells and tissues. Specifically, this Review provides an update on how exosomes released by stem cells might improve cardiac function after myocardial infarction. New studies suggest that many of the beneficial effects of exosome- based therapies are mediated by microRNAs2. In light of new exciting developments in exosome research, we wish to highlight some important additional points on how exosome functions are influenced by the imprinting of parent cells.
A study published in 2017 shows that exosomes derived from human CD34+ stem cells improved angiogenesis and motor function in mouse ischaemic limb, mimicking the effect of the parent cells, and that these effects were mediated by transferring the microRNA miR126-3p to endothelial cells3. By contrast, exosomes derived from CD34+-cell-depleted parent cells were ineffective3. These results suggest that CD34+ stem cells contain unique molecules that are delivered specifically to endothelial cells by exosomes. Another study published in 2017 demonstrates that the therapeutic effect of exosomes derived from human paediatric cardiac progenitor cells is influenced by both donor age and oxygen levels of the cell cultures2. These studies indicate that both the content and function of exosomes are determined by dominant imprinting of parent cells, which is regulated by the microenvironment surrounding the cells.
Moreover, exosomes also contain some mRNAs and microRNAs that are not functional in parent cells, but can be functional in recipient cells4. Similarly, a study in mice showed that exosomes derived from dendritic cells carry major histocompatibility complex class I and T cell co-stimulatory molecules that prime specific T cells to suppress the growth of tumours5. In some cases, exosomes can transfer antigens from tumours to dendritic cells, which in turn initiate a cytotoxic T cell-dependent immune response against tumour cells6. Therefore, exploring how recessive imprinting from parent cells might influence the therapeutic effects of exosomes is worthwhile.
In summary, emerging evidence demonstrates that exosomes not only mimic the effects of their parent cells, but also have great potential to overcome limitations associated with cell therapies, such as poor engraftment and survival under a hostile ischaemic microenvironment7,8. However, the molecular mechanisms of exosome dynamic generation, transport, and uptake remain poorly understood. Exploration of how dominant and recessive imprinting influence the molecular signature of exosomes and identification of cell type-specific receptors will enable targeted delivery of exosomes9. In this context, the Review by Boulanger et al.1 provides new insights into exosome-based therapies for cardiovascular diseases.
Y.L. and J.Z. contributed equally to this work. The authors were supported by Jiangsu Province Key Scientific and Technological Project (BE2016669), National Natural Science Foundation of China (81670358), Suzhou Science and Technology Project (SS201665), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Jiangsu Province's Key Discipline/Laboratory of Medicine (XK201118).
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Delivery of miR-675 by stem cell-derived exosomes encapsulated in silk fibroin hydrogel prevents aging-induced vascular dysfunction in mouse hindlimb
Materials Science and Engineering: C (2019)