Extracellular vesicle microRNA and protein cargo profiling in three clinical-grade stem cell products reveals key functional pathways

The cell origin-specific payloads within extracellular vesicles (EVs) mediate therapeutic bioactivity for a wide variety of stem cell types. In this study, we profiled the microRNA (miRNA) and protein cargos found within EVs produced by three clinical-grade stem cell products of different ontogenies being considered for clinical application, namely bone marrow-derived mesenchymal stromal cells (BM-MSCs), heart-derived cells (HDCs), and umbilical cord-derived MSCs (UC-MSCs). Although several miRNAs (757) and proteins (420) were found in common, each producer cell type expressed unique miRNA profiles when the most highly expressed transcripts were compared. Differential expression analysis revealed that BM-MSCs and HDCs were quite similar, while UC-MSCs had the greatest number of unique miRNAs and proteins. Despite these differences, all three EVs promoted cell adhesion/migration, immune response, platelet aggregation, protein translation/stabilization, and RNA processing. EVs from BM-MSCs were implicated in apoptosis, cell-cycle progression, collagen formation, heme pigment synthesis, and smooth muscle differentiation, while HDC and UC-MSC EVs were found to regulate complement activation, endopeptidase activity, and matrix metallopeptidases. Overall, miRNA and protein profiling reveal functional differences between three leading stem cell products. These findings provide a framework for mechanistic exploration of candidate therapeutic molecules driving the salutary effects of EVs.