The microRNA regulatory landscape of MSC-derived exosomes: a systems view

Abstract

Mesenchymal stem cell (MSC)-derived exosomes mediate tissue regeneration in a variety of diseases including ischemic heart injury, liver fibrosis, and cerebrovascular disease. Despite an increasing number of studies reporting the therapeutic effects of MSC exosomes, the underlying molecular mechanisms and their miRNA complement are poorly characterized. Here we microRNA (miRNA)-profiled MSC exosomes and conducted a network analysis to identify the dominant biological processes and pathways modulated by exosomal miRNAs. At a system level, miRNA-targeted genes were enriched for (cardio)vascular and angiogenesis processes in line with observed cardiovascular regenerative effects. Targeted pathways were related to Wnt signaling, pro-fibrotic signaling via TGF-β and PDGF, proliferation, and apoptosis. When tested, MSC exosomes reduced collagen production by cardiac fibroblasts, protected cardiomyocytes from apoptosis, and increased angiogenesis in HUVECs. The intrinsic beneficial effects were further improved by virus-free enrichment of MSC exosomes with network-informed regenerative miRNAs capable of promoting angiogenesis and cardiomyocyte proliferation. The data presented here help define the miRNA landscape of MSC exosomes, establish their biological functions through network analyses at a system level, and provide a platform for modulating the overall phenotypic effects of exosomes.

Boosting the biogenesis and secretion of mesenchymal stem cell-derived exosomes

“…Exosomes derived from MSCs are known to have intrinsic tissue regenerative effects; that is, they induce angiogenesis and cellular proliferation and inhibit fibrosis [2]. However, their widespread therapeutic use as drug carriers is currently hampered by their limited cellular secretion [18].…”

“…We chose three representative assays to assess if the small molecule modulators affected the intrinsic regenerative effects of MSC exosomes [8]. Exosomes derived from MSCs treated with small molecule modulators retained their antifibrotic effects and showed similar inhibition of collagen in cardiac fibroblasts as the exosomes derived from unmodified MSCs.…”

“…The size distribution and concentration of exosomes were characterized by nanoparticle tracking analysis (NTA) as previously described [7,8]. Briefly, exosomes were diluted in PBS and measured three times in three different areas for each sample, with the average used to determine exosome concentration.…”

“…Exosomes have emerged as promising carriers for cancer vaccines and drugs, as vehicles and mediators of cardiac regeneration, and as possible alternatives to cell-based therapies [1]. For example, mesenchymal stem cell (MSC)-derived exosomes have been shown to mediate tissue regeneration in a variety of diseases including ischemic heart disease, lung injury, liver fibrosis, and cerebrovascular disease [2]. This is mainly due to their intrinsic regenerative capacity, in that they are able to induce angiogenesis, promote proliferation, prevent apoptosis, and inhibit inflammatory reactions [2].…”

“…For example, mesenchymal stem cell (MSC)-derived exosomes have been shown to mediate tissue regeneration in a variety of diseases including ischemic heart disease, lung injury, liver fibrosis, and cerebrovascular disease [2]. This is mainly due to their intrinsic regenerative capacity, in that they are able to induce angiogenesis, promote proliferation, prevent apoptosis, and inhibit inflammatory reactions [2]. In addition to their intrinsic biological functions, exosomes are also promising drug carriers due to their small size, excellent biocompatibility, and capacity to load specific and diverse therapeutic molecules including proteins, nucleic acids, and small molecules.…”