Transfer of Functional Cargo in Exomeres

Abstract

SUMMARY Exomeres are a recently discovered type of extracellular nanoparticle with no known biological function. Herein, we describe a simple ultracentrifugation-based method for separation of exomeres from exosomes. Exomeres are enriched in Argonaute 1–3 and amyloid precursor protein. We identify distinct functions of exomeres mediated by two of their cargo, the β-galactoside α2,6-sialyltransferase 1 (ST6Gal-I) that α2,6- sialylates N-glycans, and the EGFR ligand, amphiregulin (AREG). Functional ST6Gal-I in exomeres can be transferred to cells, resulting in hypersialylation of recipient cell-surface proteins including β1-integrin. AREG-containing exomeres elicit prolonged EGFR and downstream signaling in recipient cells, modulate EGFR trafficking in normal intestinal organoids, and dramatically enhance the growth of colonic tumor organoids. This study provides a simplified method of exomere isolation and demonstrates that exomeres contain and can transfer functional cargo. These findings underscore the heterogeneity of nanoparticles and should accelerate advances in determining the composition and biological functions of exomeres.

Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche

“…31 The presence of the fulllength amphiregulin on different EV subpopulations has been confirmed by other reports as well. [32][33][34] However, all these studies used cancer cell lines and some of them only analyzed the molecular cargo of EVs. To our knowledge, this is the first report to prove the role of fibroblast-derived EVs in the transmission of EGF activity, such as amphiregulin, among non-cancer cells in an organoid system, modeling the ISC niche.…”

Exosomes: Revisiting their role as “garbage bags”

“…It has been found to accumulate in multivesicular bodies in AD brains and to be released in association with exosomes . APP has been reported to be part of a subset of exosomes specifically endocytosed by neurons rather than glial cells, though these data might be tempered because APP and BACE‐1 were recently found to be enriched in exomeres rather than exosomes . Interestingly, neuronal exosomes can even trap monomeric Aβ peptides released in the extracellular space through their binding to glycosphingolipids such as GM1, while promoting amyloid‐β clearance after exosome uptake by brain‐resident phagocyte microglia .…”

“…139 APP has been reported to be part of a subset of exosomes specifically endocytosed by neurons rather than glial cells, 140 though these data might be tempered because APP and BACE-1 were recently found to be enriched in exomeres rather than exosomes. 141 Interestingly, neuronal exosomes can even trap monomeric Aβ peptides released in the extracellular space through their binding to glycosphingolipids such as GM1, while promoting amyloid-β clearance after exosome uptake by brain-resident phagocyte microglia. 142 Microglia uptake of exosomes was shown to occur through macropinocytosis, without inducing a concomitant inflammatory response, 143 which is reminiscent of what we suggested for reticulocyte exosomes and their lysoPC eat-me signal.…”

Fragmentation of extracellular ribosomes and tRNAs shapes the extracellular RNAome

“…However, extracellular soluble ribonucleoproteins remain the least studied exRNA carriers 15 , with most attention thus far placed at the level of EVs. A new extracellular nanoparticle was recently discovered 16,17 , but the exact identity and RNA content of these complexes termed “exomers” needs further characterization.…”