Therapeutics development and pathway discovery: The multifaced role of extracellular vesicles

Extracellular vesicles (EVs), or exosomes, have emerged as pivotal players in cardiac physiopathological events. These nanoscale vesicles, rich in proteins, lipids, and nucleic acids, stand at the forefront of innovative research., with various objectives.

The primary aim is to  develop novel therapeutics for cardiac repair.For instance, Aggrawal's recent study (1) highlighted that exosomes derived from porcine mesenchymal stromal cells restored the mitochondrial respiratory function of hypoxic cells in culture. The authors further demonstrated the recovery of myocardial systolic and diastolic function in a porcine model of chronically ischemic myocardium using the EVs embedded within a collagen sponge applied during Coronary Artery Bypass Grafting. The combined treatment led to reduced fibrosis and inflammation, coupled with an increase in mitochondrial size and aspect ratio.

Second, Chen et al. (2) creating a novel therapeutic agent by encapsulating EVs derived from cardiac resident macrophages with thymosin β4 into monocyte membranes. The loaded EVs demonstrated the ability to target the heart specifically, evaded the immune system, and promoted cardiac cell proliferation and angiogenesis.
Thirdly, EVs have also become an essential tool in uncovering new targets and pathways as demonstrated in the ground-breaking study by Roefs et al. (3). EV are part of a highly dynamic and responsive system, constantly adapting to the changing physiological landscape. A comprehensive understanding of EV’s precise composition is essential to fully harness their potential and unravel their specific roles in cellular signalling. This study underscored the contribution of both cardiac progenitor cell (CPC)-derived EVs and their co-isolated proteins to the mechanism of action of EVs, emphasizing the importance of identifying the proteomic composition of EV preparations.

Specifically, the research explored the proteomic composition of functional CPC-EVs and associated proteins as well as and their role in human microvascular endothelial cell activation and migration. Among the identified proteins, the role of PAPP-A was sophisticatedly elucidated. By creating PAPP-A knockout CPCs using CRISPR/Cas9 technology, along with IGF-R inhibitor and phosphoproteome analysis, the authors revealed that PAPP-A, bound to the EV membrane, facilitates the release of IGF-1, activating intracellular signalling pathways involved in endothelial cell activation.