Journal
NATURE CELL BIOLOGY
Volume 20, Issue 3, Pages 332-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-018-0040-4
Keywords
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Categories
Funding
- National Cancer Institute [U01-CA169538]
- National Institutes of Health (NIH) [R01-CA169416, R01-CA218513]
- US Department of Defense [W81XWH-13-10249, W81XWH-13-1-0425]
- Sohn Conference Foundation
- Children's Cancer and Blood Foundation
- Manning Foundation
- Hartwell Foundation
- Nancy C. and Daniel P. Paduano Foundation
- Starr Cancer Consortium
- Pediatric Oncology Experimental Therapeutic Investigator Consortium (POETIC)
- James Paduano Foundation
- NIH/WCM CTSC [NIH/NCATS: UL1TR00457, UL1TR002384]
- Malcolm Hewitt Wiener Foundation
- Champalimaud Foundation
- Thompson Family Foundation
- Beth Tortolani Foundation
- Charles and Marjorie Holloway Foundation
- Sussman Family Fund
- Lerner Foundation
- Breast Cancer Alliance
- Manhasset Women's Coalition Against Breast Cancer
- National Institute on Minority Health and Health Disparities (NIMHD) of the NIH [MD007599]
- NIH/NCATS [UL1TR00457]
- FEDER (Fundo Europeu de Desenvolvimento Regional funds through COMPETE) POCI, Portugal [NORTE-01-0145-FEDER-000029]
- FCT - Fundacao para a Ciencia e a Tecnologia [POCI-01-0145-FEDER-007274]
- FCT [POCI-01-0145-FEDER-016585 (PTDC/BBB-EBI/0567/2014), SFRH/BPD/75871/2011, SFRH/BPD/111048/2015, SFRH/BD/110636/2015]
- BiotechHealth PhD Programme [PD/0016/2012]
- American Portuguese Biomedical Research Fund
- [U01-CA210240]
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/111048/2015, SFRH/BD/110636/2015] Funding Source: FCT
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The heterogeneity of exosomal populations has hindered our understanding of their biogenesis, molecular composition, biodistribution and functions. By employing asymmetric flow field-flow fractionation (AF4), we identified two exosome subpopulations (large exosome vesicles, Exo-L, 90-120 nm; small exosome vesicles, Exo-S, 60-80 nm) and discovered an abundant population of non-membranous nanoparticles termed 'exomeres' (similar to 35 nm). Exomere proteomic profiling revealed an enrichment in metabolic enzymes and hypoxia, microtubule and coagulation proteins as well as specific pathways, such as glycolysis and mTOR signalling. Exo-S and Exo-L contained proteins involved in endosomal function and secretion pathways, and mitotic spindle and IL-2/STAT5 signalling pathways, respectively. Exo-S, Exo-L and exomeres each had unique N-glycosylation, protein, lipid, DNA and RNA profiles and biophysical properties. These three nanoparticle subsets demonstrated diverse organ biodistribution patterns, suggesting distinct biological functions. This study demonstrates that AF4 can serve as an improved analytical tool for isolating extracellular vesicles and addressing the complexities of heterogeneous nanoparticle subpopulations.
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