Role of Phosphatidylserine-Derived Negative Surface Charges in the Recognition and Uptake of Intravenously Injected B16BL6-Derived Exosomes by Macrophages

Matsumoto, Akira; Takahashi, Yuki; Nishikawa, Makiya; Sano, Kohei; Morishita, Masaki; Charoenviriyakul, Chonlada; Saji, Hideo; Takakura, Yoshinobu

doi:10.1016/j.xphs.2016.07.022

Cited by 171 publications

(151 citation statements)

References 33 publications

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“…Tumor depleted mesenchymal tumor stroma by exosomes from CD8 + T cells cannot acquire the invasive and metastatic properties as in progressive tumors 6 SEO ET AL. | 3001 (TIM)-1, -3, and -4 on hepatic macrophages seem to be ligands for PS-derived negative surface charge on EV 47,48. However, in our study regarding intratumoral administration of CD8 + T-cell exosomes, even though a large number of F4/80 + CD11b + macrophages were present in tumor lesions, no exosome uptake was seen at 2 hours after intratumoral treatment.…”

contrasting

confidence: 67%

“…When exosomes are given systemically, most of them are engulfed by hepatic macrophages and digested in their lysosomes . In the presence of calcium ion, scavenger receptors such as SR‐A (scavenger receptor class A), annexins, and T‐cell immunoglobulin and mucin domain containing (TIM)‐1, ‐3, and ‐4 on hepatic macrophages seem to be ligands for PS‐derived negative surface charge on EV . However, in our study regarding intratumoral administration of CD8 + T‐cell exosomes, even though a large number of F4/80 + CD11b + macrophages were present in tumor lesions, no exosome uptake was seen at 2 hours after intratumoral treatment.…”

Section: Phosphatidylserine‐derived Negative Charges Of Exosome Surfacesmentioning

confidence: 68%

“…Consistent with membranes of dead cells, membranes of extracellular vesicles including MV, apoptotic bodies, and exosomes expose negatively charged PS on the outer leaflet in contrast with localization at the inner leaflet of the plasma membrane of viable cells, which is the main reason that EV are negatively charged . When exosomes are given systemically, most of them are engulfed by hepatic macrophages and digested in their lysosomes . In the presence of calcium ion, scavenger receptors such as SR‐A (scavenger receptor class A), annexins, and T‐cell immunoglobulin and mucin domain containing (TIM)‐1, ‐3, and ‐4 on hepatic macrophages seem to be ligands for PS‐derived negative surface charge on EV .…”

Section: Phosphatidylserine‐derived Negative Charges Of Exosome Surfacesmentioning

confidence: 99%

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Exosome‐mediated regulation of tumor immunology

2018

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Exosomes are representative extracellular vesicles (EV) derived from multivesicular endosomes (MVE) and have been described as new particles in the communication of neighborhood and/or distant cells by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and nucleotides including micro (mi) RNAs. Exosomes from immune cells and tumor cells act in part as a regulator in tumor immunology. CD8+ T cells that show potent cytotoxic activity against tumor cells reside as an inactive naïve form in the T‐cell zone of secondary lymphoid organs. Once receiving tumor‐specific antigenic stimulation by dendritic cells (DC), CD8+ T cells are activated and differentiated into effector CTL. Subsequently, CTL circulate systemically, infiltrate into tumor lesions through the stromal neovasculature where mesenchymal stromal cells, for example, mesenchymal stem cells (MSC) and cancer‐associated fibroblasts (CAF), abundantly exist, destroy mesenchymal tumor stroma in an exosome‐mediated way, go into tumor parenchyma, and attack tumor cells by specific interaction. DC‐derived and regulatory T (Treg) cell‐derived exosomes, respectively, promote and inhibit CTL generation in this setting. In this review, we describe the roles of exosomes from immune cells and tumor cells on the regulation of tumor progression.

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confidence: 67%

Section: Phosphatidylserine‐derived Negative Charges Of Exosome Surfacesmentioning

confidence: 68%

Section: Phosphatidylserine‐derived Negative Charges Of Exosome Surfacesmentioning

confidence: 99%

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Exosome‐mediated regulation of tumor immunology

2018

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“…Lactadherin has been shown to bind to phosphatidylserine-containing vesicles via its C1C2 domain [19]. As an example, a streptavidin/lactadherin construct was expressed on B16BL6 cell-derived EV and was able to stably bind an 125 I-labelled biotin derivative for effective quantitative assessment of EV biodistribution [20]. …”

Section: Introductionmentioning

confidence: 99%

Scalable, cGMP‐compatible purification of extracellular vesicles carrying bioactive human heterodimeric IL‐15/lactadherin complexes

Watson

Yung

Bergamaschi

et al. 2018

J of Extracellular Vesicle

128

102

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The development of extracellular vesicles (EV) for therapeutic applications is contingent upon the establishment of reproducible, scalable, and high-throughput methods for the production and purification of clinical grade EV. Methods including ultracentrifugation (U/C), ultrafiltration, immunoprecipitation, and size-exclusion chromatography (SEC) have been employed to isolate EV, each facing limitations such as efficiency, particle purity, lengthy processing time, and/or sample volume. We developed a cGMP-compatible method for the scalable production, concentration, and isolation of EV through a strategy involving bioreactor culture, tangential flow filtration (TFF), and preparative SEC. We applied this purification method for the isolation of engineered EV carrying multiple complexes of a novel human immunostimulatory cytokine-fusion protein, heterodimeric IL-15 (hetIL-15)/lactadherin. HEK293 cells stably expressing the fusion cytokine were cultured in a hollow-fibre bioreactor. Conditioned medium was collected and EV were isolated comparing three procedures: U/C, SEC, or TFF + SEC. SEC demonstrated comparable particle recovery, size distribution, and hetIL-15 density as U/C purification. Relative to U/C, SEC preparations achieved a 100-fold reduction in ferritin concentration, a major protein-complex contaminant. Comparative proteomics suggested that SEC additionally decreased the abundance of cytoplasmic proteins not associated with EV. Combination of TFF and SEC allowed for bulk processing of large starting volumes, and resulted in bioactive EV, without significant loss in particle yield or changes in size, morphology, and hetIL-15/lactadherin density. Taken together, the combination of bioreactor culture with TFF + SEC comprises a scalable, efficient method for the production of highly purified, bioactive EV carrying hetIL-15/lactadherin, which may be useful in targeted cancer immunotherapy approaches.

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“…Scavenger receptors such as SR-A (Scavenger receptor class A) on hepatic macrophages seem to be a ligand for phosphatidylserine-derived negative surface charge on exosomes [17,18] . In liver metastasis of pancreatic cancer, pancreatic cancer cell-released exosomes participate in the formation of pre-metastasis niche by promotion of TGF-β and fibronectin production of hepatic stellate cells after kupffer cell activation [19] , showing close relationship between exosomes and liver macrophages.…”

Section: Relationship Among B Cells Macrophage and Exosomesmentioning

confidence: 99%

Exosome-mediated immune regulation and its clinical application

Seo

2018

Trends Immunother

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Immune system is a precise mechanism for maintenance of homeostasis by lymphocyte-mediated elimination of extracellular and intercellular pathogens, and abnormal cells in cytokine-, chemokine-, antibody-, and cytotoxic granuledependent manners. Extracellular vesicles, e.g. exosomes, released from multivesicular endosome in immune cells have been known to be a part of the immune system. Exosomes released by antigen-presenting cells (APCs)

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Role of Phosphatidylserine-Derived Negative Surface Charges in the Recognition and Uptake of Intravenously Injected B16BL6-Derived Exosomes by Macrophages

Cited by 171 publications

References 33 publications

Exosome‐mediated regulation of tumor immunology

Exosome‐mediated regulation of tumor immunology

Scalable, cGMP‐compatible purification of extracellular vesicles carrying bioactive human heterodimeric IL‐15/lactadherin complexes

Exosome-mediated immune regulation and its clinical application

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