“…The EVs flotation density and hydrodynamic average size (determined by DLS) enabled the recovery of distinct fractions containing EVs with characteristic sizes and densities (S2 Fig). Considering the traditional classifications proposed for EVs, we found particles with density and size similar to exosomes, exosome-like particles and apoptotic bodies (S2 Fig) [32]. The process also enabled the recovery of small-sized RNAs in the EVs preparations that were protected from RNase treatment (S3 Fig).10.1080/20013078.2018.1541708-F0001Figure 1.EVs and VDE represent distinct aspects of the total EXO.…”
The use of secretion pathways for effector molecule delivery by microorganisms is a trademark of pathogenesis. Leishmania extracellular vesicles (EVs) were shown to have significant immunomodulatory potential. Still, they will act in conjunction with other released parasite-derived products that might modify the EVs effects. Notwithstanding, the immunomodulatory properties of these non-vesicular components and their influence in the infectious process remains unknown. To address this, we explored both in vitro and in vivo the immunomodulatory potential of promastigotes extracellular material (EXO), obtained as a whole or separated in two different fractions: EVs or vesicle depleted EXO (VDE). Using an air pouch model, we observed that EVs and VDE induced a dose-dependent cell recruitment profile different from the one obtained with parasites, attracting significantly fewer neutrophils and more dendritic cells (DCs). Additionally, when we co-inoculated parasites with extracellular products a drop in cell recruitment was observed. Moreover, in vitro, while VDE (but not EVs) downregulated the expression of DCs and macrophages activation markers, both products were able to diminish the responsiveness of these cells to LPS. Finally, the presence of Leishmania infantum extracellular products in the inoculum promoted a dose-dependent infection potentiation in vivo, highlighting their relevance for the infectious process. In conclusion, our data demonstrate that EVs are not the only relevant players among the parasite exogenous products. This, together with the dose-dependency observed, opens new avenues to the comprehension of Leishmania infectious process. The approach presented here should be exploited to revisit existing data and considered for future studies in other infection models.
“…The EVs flotation density and hydrodynamic average size (determined by DLS) enabled the recovery of distinct fractions containing EVs with characteristic sizes and densities (S2 Fig). Considering the traditional classifications proposed for EVs, we found particles with density and size similar to exosomes, exosome-like particles and apoptotic bodies (S2 Fig) [32]. The process also enabled the recovery of small-sized RNAs in the EVs preparations that were protected from RNase treatment (S3 Fig).10.1080/20013078.2018.1541708-F0001Figure 1.EVs and VDE represent distinct aspects of the total EXO.…”
The use of secretion pathways for effector molecule delivery by microorganisms is a trademark of pathogenesis. Leishmania extracellular vesicles (EVs) were shown to have significant immunomodulatory potential. Still, they will act in conjunction with other released parasite-derived products that might modify the EVs effects. Notwithstanding, the immunomodulatory properties of these non-vesicular components and their influence in the infectious process remains unknown. To address this, we explored both in vitro and in vivo the immunomodulatory potential of promastigotes extracellular material (EXO), obtained as a whole or separated in two different fractions: EVs or vesicle depleted EXO (VDE). Using an air pouch model, we observed that EVs and VDE induced a dose-dependent cell recruitment profile different from the one obtained with parasites, attracting significantly fewer neutrophils and more dendritic cells (DCs). Additionally, when we co-inoculated parasites with extracellular products a drop in cell recruitment was observed. Moreover, in vitro, while VDE (but not EVs) downregulated the expression of DCs and macrophages activation markers, both products were able to diminish the responsiveness of these cells to LPS. Finally, the presence of Leishmania infantum extracellular products in the inoculum promoted a dose-dependent infection potentiation in vivo, highlighting their relevance for the infectious process. In conclusion, our data demonstrate that EVs are not the only relevant players among the parasite exogenous products. This, together with the dose-dependency observed, opens new avenues to the comprehension of Leishmania infectious process. The approach presented here should be exploited to revisit existing data and considered for future studies in other infection models.
“…Exosomes are thus believed to have the potential to serve as shuttles for intercellular communication. 8,31 This may be highly relevant for carcinogenesis, and reported effects for tumor cell-derived exosomes range from inhibition of antitumor immune response 9,45 to the horizontal transfer of oncogenic factors, 11,15,50,51 induction of angiogenesis 11,48 and promotion of premetastatic niche formation. 52 Although these observations are potentially extremely important, one must be aware that most studies performed thus far used concentrated exosome preparations, and it is not clear how these experimental …”
The human papillomavirus (HPV) E6/E7 oncogenes play a crucial role in the HPV-induced carcinogenesis. In this study, the authors investigated whether silencing of endogenous HPV E6/E7 expression may influence the contents or amounts of extracellular microvesicles (eMVs) released from HPV-positive cancer cells. It was found that eMVs secreted from HeLa cells are enriched for Survivin protein. RNA interference studies revealed that maintenance of both intracellular and microvesicular Survivin amounts was strongly dependent on continuous E6/E7 expression. This indicates that intracellular HPV activities are translated into visible alterations of protein contents in eMVs. Besides Survivin, eMVs from HeLa cells contain additional members of the inhibitor of apoptosis protein (IAP) family (XIAP, c-IAP1 and Livin). In contrast, no evidence for the presence of the HPV E6 and E7 oncoproteins in eMVs was obtained. Moreover, it was found that silencing of HPV E6/E7 expression led to a significant increase of exosomes-representing eMVs of endocytic origin-released from HeLa cells. This effect was associated with the reinduction of p53, stimulation of the p53 target genes TSAP6 and CHMP4C that can enhance exosome production and induction of senescence. Taken together, these results show that silencing of HPV E6/E7 oncogene expression profoundly affects both the composition and amounts of eMVs secreted by HPV-positive cancer cells. This indicates that HPVs can induce molecular signatures in eMVs that may affect intercellular communication and could be explored for diagnostic purposes.Specific types of human papillomaviruses (HPVs), such as HPV16 and HPV18, cause cervical cancer and are closely linked to the development of additional human malignancies in the oropharyngeal and anogenital regions. 1 The viral E6 and E7 oncoproteins are crucial both for the HPV-associated induction of transformation and for the maintenance of the tumorigenic phenotype of HPV-positive cervical cancer cells. 2,3 E6 and E7 dysregulate intracellular pathways involved in the control of cellular proliferation, apoptosis and genetic stability. For example, E6 induces the proteolytic degradation of the p53 tumor suppressor protein 4 and stimulates telomerase activity, 5 whereas E7 interferes with the activity of the retinoblastoma tumor suppressor protein, pRb, and other pocket proteins. 6 In contrast to the increasing understanding of the intracellular activities of the viral E6/E7 oncogenes, surprisingly little is known about possible effects on the intercellular communication of HPV-positive cancer cells.Extracellular microvesicles (eMVs) include exosomes that are small vesicles (50-100 nm in diameter) of endosomal origin secreted by a variety of cells, including tumor cells. 7 Exosomes have recently gained much interest in oncology, particularly due to three properties: (i) exosomes secreted from tumor cells can suppress the immune response toward the tumor, 8,9 (ii) tumor cell-derived exosomes can accelerate tumor growth and invasiveness by horizon...
“…This exchange of signals entails either cell-to-cell contacts (juxtacrine) or gradients formed by soluble factors (paracrine) (Friedl et al, 2005) which also circulate in blood and body fluids and act in a regional or systemic manner (endocrine). Stem cell signaling may also involve the newly recognized release of extracellular membrane vesicles (EVs) (Kalra et al, 2012;Mathivanan et al, 2010;Thery et al, 2002). A schematic representation of the alternative cell signaling pathways regulating the interactions between the stem cell graft and the host immune system in inflammatory brain diseases is shown in Figure 3.…”
Section: Stem Cell Signaling and Regulation Of The Host Immune Responsesmentioning
Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.
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