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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.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Human pancreatic islets of Langerhans contain five distinct endocrine cell types, each producing a characteristic hormone. The dysfunction or loss of the insulin-producing β cells causes diabetes mellitus, a disease that harms millions. Until now, β cells were generally regarded as a single, homogenous cell population. Here we identify four antigenically distinct subtypes of human β cells, which we refer to as β1-4, and which are distinguished by differential expression of ST8SIA1 and CD9. These subpopulations are always present in normal adult islets and have diverse gene expression profiles and distinct basal and glucose-stimulated insulin secretion. Importantly, the β cell subtype distribution is profoundly altered in type 2 diabetes. These data suggest that this antigenically defined β cell heterogeneity is functionally and likely medically relevant.
Gangliosides have been shown to be necessary for beta-amyloid (Abeta) binding and aggregation. GD3 synthase (GD3S) is responsible for biosynthesis of the b- and c-series gangliosides, including two of the four major brain gangliosides. We examined Abeta-ganglioside interactions in neural tissue from mice lacking the gene coding for GD3S (St8sia1), and in a double-transgenic (APP/PSEN1) mouse model of Alzheimer's disease cross-bred with GD3S-/- mice. In primary neurons and astrocytes lacking GD3S, Abeta-induced cell death and Abeta aggregation were inhibited. Like GD3S-/- and APP/PSEN1 double-transgenic mice, APP/PSEN1/GD3S-/- "triple-mutant" mice are indistinguishable from wild-type mice on casual examination. APP/PSEN1 double-transgenics exhibit robust impairments on a number of reference-memory tasks. In contrast, APP/PSEN1/GD3S-/- triple-mutant mice performed as well as wild-type control and GD3S-/- mice. Consistent with the behavioral improvements, both aggregated and unaggregated Abeta and associated neuropathology were almost completely eliminated in triple-mutant mice. These results suggest that GD3 synthase may be a novel therapeutic target to combat the cognitive deficits, amyloid plaque formation, and neurodegeneration that afflict Alzheimer's patients.
Target inactivation analysis was used to measure the functional size of uridine diphosphogalactose: N-acetylglucosamine beta(1,4)galactosyltransferase (galactosyltransferase), cytidine monophospho-N-acetyl-neuraminic acid: beta-galactoside alpha(2,6) sialytransferase (sialyltransferase), and uridine diphosphatase (UDPase) in Golgi membranes isolated from rat liver. The size of nucleoside diphosphatase (NDPase), an enzyme similar to UDPase but localized in rat liver endoplasmic reticulum, was also estimated by target inactivation analysis. The related enzymes, UDPase and NDPase, have target sizes of 96 +/- 4 and 77 +/- 3 kDa, while galactosyltransferase and sialyltransferase have target sizes of 97 +/- 10 and 130 +/- 20 kDa, respectively. The target inactivation sizes of galactosyltransferase and of sialyltransferase are about twice the monomer molecular weights of these enzymes obtained from sedimentation studies of the solubilized membranes as well as those predicted from previously reported cDNA sequences. We conclude from our studies that galactosyltransferase and sialyltransferase probably function as dimers in the Golgi membrane.