Regulation of Mesenchymal Progenitor Cell-Induced Neo-Vascularization by Endothelial Progenitor Cell-Derived Exosomes

Despite advances in the application of autologous mesenchymal stem/progenitor cells (MSPCs) and endothelial colony forming cells (ECFCs) for novel regenerative therapies, our understanding of the basic mechanisms involved in therapeutic neovascularization remains incomplete. Specifically, the individual contribution of the cell types to vessel formation and maintenance is poorly understood. Here we investigate if MSPC-derived exosomes (small vesicles that are secreted into the extracellular space and fuse with other cells to deliver mRNAs, regulatory miRNAs and proteins) can promote ECFC proliferation, migration and differentiation.

We have generated exosome-enriched fractions from conditioned culture media of human umbilical cord or bone marrow-derived MSCPs propagated in human platelet lysate. These purified fractions were added to the culture media of ECFCs for 48 – 72 hours. Employing FACS analysis, microscopy, and the automated xCELLigence system (ROCHE) we uncovered that MSPC exosomes significantly alter the morphology and the proliferative index of ECFCs, as well as their specific marker profile. Moreover we identified that exosome enriched fractions are sufficient for modifying the expression pattern of the collagen sensor DDR1 at the mRNA level and also influence the levels of the DDR1 regulatory miRNA 199. Significantly, exosome-enriched fractions from ECFCs did not elicit any detectable alterations in ECFCs themselves, whereas we could see changes in morphology, migratory potential, proliferative activity and marker expression in MSPCs.

Taken together our data suggest that progenitor cell-derived exosomes contribute to the neo-vascularization process induced by pairwise injection of ECFCs and MSPCs, and that at least part of the role executed by MSPCs could be delivered in a cell-free manner through exosome-enriched preparations.

No relevant conflicts of interest to declare.