Dominant and recessive imprinting of exosomes from parent cells

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 microenvironment^7,8. 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.