Optimizing Cell Therapy by Sorting Cells with High Extracellular Vesicle Secretion
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE240981 | GEO | 2024/01/07
REPOSITORIES: GEO
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Project description:Critical challenges remain in clinical translation of extracellular vesicle (EV)-based therapeutics due to the absence of methods to enrich cells with high EV secretion. Current cell sorting methods are limited to surface markers that are uncorrelated to EV secretion or therapeutic potential. We developed a nanovial technology for enrichment of millions of single cells based on EV secretion. This approach was applied to select mesenchymal stem cells (MSCs) with high EV secretion as therapeutic cells for improving treatment. The selected MSCs exhibited distinct transcriptional profiles associated with EV biogenesis and vascular regeneration and maintained high levels of EV secretion after sorting and regrowth. In a mouse model of myocardial infarction, treatment with high-secreting MSCs improved heart functions compared to treatment with low-secreting MSCs. These findings highlight the therapeutic importance of EV secretion in regenerative cell therapies and suggest that selecting cells based on EV secretion could enhance therapeutic efficacy.
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Project description:Optimizing Cell Therapy by Sorting Cells with High Extracellular Vesicle Secretion
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Project description:Human macrophages secrete extracellular vesicles loaded with numerous immunoregulatory proteins. Here we employed high throughput quantitative proteomics to characterize the modulation of vesicle-mediated protein secretion during non-canonical caspase-4/5-dependent inflammasome activation. We show that human macrophages activate robust caspase-4- dependent extracellular vesicle secretion upon transfection of LPS, and this process is also partially dependent on NLRP-3 and caspase-5. Similar effect occurs with delivery of the LPS with E. coli-derived outer membrane vesicles. Moreover, sensitization of the macrophages through TLR4 prior to LPS transfection dramatically augments the EV-mediated protein secretion. Our data demonstrate that this process differs significantly from ATP-induced vesiculation, and is dependent on autocrine interferon signal associated with TLR4 activation. TLR4 activation preceding the non-canonical inflammasome activation significantly enhances vesicle-mediated secretion of inflammasome components caspase-1, ASC and lytic cell death effectors GSDMD, MLKL and NINJ1, suggesting that inflammatory EV transfer may exert paracrine effects in recipient cells. Moreover, using bioinformatic methods, we identify 15-deoxy-delta-12,14-prostaglandin J2 and parthenolide as inhibitors of caspase-4-mediated inflammation and vesicle secretion, indicating potential new therapeutic potential of these anti-inflammatory drugs.
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Project description:Bacteria actively secrete extracellular vesicles (EVs), spherical nano-sized proteolipids into the extracellular milieu. Bacterial EVs have gained wide interests as non-living complex vaccines or delivery vehicles. However, no studies have used bacterial EVs in treating cancer so far. Our results showed remarkable capability of EVs derived from Escherichia coli W3110 msbB-deficient mutant to effectively induce long-term anti-tumor immune responses that can fully eradicate established tumors without notable adverse effects. This anti-tumor effect was IFN-γ-dependent, and we present a comprehensive proteome of E. coli W3110 msbB-deficient EVs to investigate which vesicular components induce the anti-tumor effects.
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Project description:Type 2 diabetes mellitus is a chronic age-associated degenerative metabolic disease that reflects relative insulin deficiency and resistance. Extracellular vesicles (EVs; exosomes, microvesicles and apoptotic bodies) are small (50-400 nM) lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids as part of intercellular communication systems. Recent studies in mouse models and in cell culture suggest that EVs may modulate insulin signaling. We designed a longitudinal and cross-sectional cohort of euglycemic, pre-diabetic and diabetic participants. Diabetic individuals had significantly higher levels of EVs in their circulation than euglycemic controls. We found that insulin resistance increases EV secretion through an autophagy-dependent mechanism. Furthermore, the levels of several proteins involved in insulin signaling were altered in EVs from individuals with high levels of insulin resistance and β-cell dysfunction. Moreover, EVs from diabetic individuals were preferentially internalized by circulating leukocytes. Microarray of these leukocytes revealed altered gene expression pathways related to cell survival, oxidative stress and immune function. Collectively, these results suggest that insulin resistance increases the secretion of EVs, which are preferential internalized by leukocytes and whose gene expression is subsequently altered by the internalized EVs.
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Project description:Extracellular Vesicles were isolated from primary cultures of neural stem cells (NSCs) and astrocytes by performing serial centrifugation and a 100,000 x g ultracentrifugation step. The goal of this experiment is to compare EV small RNAs from two cell types.
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Project description:Extracellular α-Synuclein has been implicated in interneuronal propagation of disease pathology in Parkinson's Disease. How α-Synuclein is released into the extracellular space is still unclear. Here, we show that α-Synuclein is present in extracellular vesicles in the central nervous system. We find that sorting of α-Synuclein in extracellular vesicles is regulated by sumoylation and that sumoylation acts as a sorting factor for targeting of both, cytosolic and transmembrane proteins, to extracellular vesicles. We provide evidence that the SUMO-dependent sorting utilizes the endosomal sorting complex required for transport (ESCRT) by interaction with phosphoinositols. Ubiquitination of cargo proteins is so far the only known determinant for ESCRT-dependent sorting into the extracellular vesicle pathway. Our study reveals a function of SUMO protein modification as a Ubiquitin-independent ESCRT sorting signal, regulating the extracellular vesicle release of α-Synuclein. We deciphered in detail the molecular mechanism which directs α-Synuclein into extracellular vesicles which is of highest relevance for the understanding of Parkinson's disease pathogenesis and progression at the molecular level. We furthermore propose that sumo-dependent sorting constitutes a mechanism with more general implications for cell biology.
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