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Sci Rep. 2018 Jan 23;8(1):1419. doi: 10.1038/s41598-018-19581-x.

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

Author information

1
Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA.
2
Department of Chemical and Biological Engineering, Department of Biomedical Engineering, Clinical and Translational Research Center of the University at Buffalo, The State University of New York, Buffalo, NY, 14260, USA.
3
Department of Medicine, Department of Physiology and Biophysics, Department of Biomedical Engineering, The Clinical and Translational Research Center of the University at Buffalo, Buffalo, New York and the VA Western New York Healthcare System, Buffalo, NY, 14214, USA.
4
Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA. julianen@buffalo.edu.

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.

PMID:
29362496
PMCID:
PMC5780426
DOI:
10.1038/s41598-018-19581-x
[Indexed for MEDLINE]
Free PMC Article

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