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The Phenotypic Effects of Exosomes Secreted from Distinct Cellular Sources: a Comparative Study Based on miRNA Composition

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  • Theme: Pioneering Pharmaceutical Science by Emerging Investigators
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Abstract

Exosomes are nano-sized vesicles composed of lipids, proteins, and nucleic acids. Their molecular landscape is diverse, and exosomes derived from different cell types have distinct biological activities. Since exosomes are now being utilized as delivery vehicles for exogenous therapeutic cargoes, their intrinsic properties and biological effects must be understood. We performed miRNA profiling and found substantial differences in the miRNA landscape of prostate cancer (PC3) and human embryonic kidney (HEK) 293 exosomes with little correlation in abundance of common miRNAs (R2 = 0.16). Using a systems-level bioinformatics approach, the most abundant miRNAs in PC3 exosomes but not HEK exosomes were predicted to significantly modulate integrin signaling, with integrin-β3 loss inducing macrophage M2 polarization. PC3 but not HEK exosomes downregulated integrin-β3 expression levels by 70%. There was a dose-dependent polarization of RAW 264.7 macrophages toward an M2 phenotype when treated with PC3-derived exosomes but not HEK-derived exosomes. Conversely, HEK exosomes, widely utilized as delivery vehicles, were predicted to target cadherin signaling, with experimental validation showing a significant increase in the migratory potential of MCF7 breast cancer cells treated with HEK exosomes. Even widely utilized exosomes are unlikely to be inert, and their intrinsic activity ought to be assessed before therapeutic deployment.

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Acknowledgements

We acknowledge support by the NIH through awards R01EB023262 and R21EB021454. We thank Dr. Prashant Singh for performing the miRNA profiling for HEK and PC3 cells and exosomes. The authors declare no competing financial interests.

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  1. Scott Ferguson and Sera Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University at Buffalo, The State University of New York, Buffalo, New York, 14214, USA

    Scott Ferguson, Sera Kim, Christine Lee, Michael Deci & Juliane Nguyen

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  1. Scott Ferguson
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  2. Sera Kim
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  3. Christine Lee
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  5. Juliane Nguyen
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Contributions

J.N. and S.F. conceived and designed the experiments. S.F. carried out the exosomal characterization, and cellular uptake experiment. S.K. carried out the bioinformatics analysis and MTS assay. C.J.L. performed the macrophage polarization study. M.D. provided M2 polarization insights and reviewed the manuscript. J.N. and S.F. analyzed the data. S.F., and J.N. wrote, reviewed and edited the manuscript. J.N supervised the project. All authors approved the final manuscript.

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Correspondence to Juliane Nguyen.

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Theme Editor: Ho-Leung Fung

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Ferguson, S., Kim, S., Lee, C. et al. The Phenotypic Effects of Exosomes Secreted from Distinct Cellular Sources: a Comparative Study Based on miRNA Composition. AAPS J 20, 67 (2018). https://doi.org/10.1208/s12248-018-0227-4

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