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Concentrations of circulating EVs in patients with SM correlate with parameters of disease severity. (A) Quantitative analysis of EV particles in serum from the indicated subject populations. EVs were isolated with ExoQuick solution from the sera of HVs and patients with SM and counted using a NanoSight NS300 system. The SM population was divided into two groups with tryptase values lower or higher than the median (110 ng/mL). Data represent mean ± SEM. (B-E) Pearson's correlation between the concentration of EVs in serum and the concentrations of (B) tryptase, (C) IL-6, (D) the activity of AP, and (E) sedimentation rate in serum. (F) EV concentrations in patients with SM with or without organomegaly. Patients within tryptase >110 ng/mL that met the criteria for SSM (53) are noted as empty red circles.
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Significance
Pathological findings in systemic mastocytosis (SM) are generally attributed to an increase in the mast cell burden and associated production of mast cell mediators. We now describe that serum from patients with SM contains extracellular vesicles (EVs) with a mast cell signature and that their concentrations correlate with surrogate ma...
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... first isolated and compared EVs using two different tech- niques as described in Materials and Methods and shown in the SI Appendix, Fig. S1 A-C, where EVs isolated by either method appeared similar and with sizes consistent with exosomes or small EVs. We then determined the number of serum EVs in patients with mastocytosis compared with those in healthy volunteers (HVs) employing nanoparticle tracking analysis (NTA) (SI Appendix, Fig. S1 D and E). As might be expected, the ...
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... EVs. We then determined the number of serum EVs in patients with mastocytosis compared with those in healthy volunteers (HVs) employing nanoparticle tracking analysis (NTA) (SI Appendix, Fig. S1 D and E). As might be expected, the EV concentration in pa- tients with mastocytosis was significantly greater than in control subjects (P < 0.0001) (Fig. 1A and SI Appendix, Fig. S2 A, Left). Similar results were obtained when the precipitation method for EV isolation was combined with purification columns to eliminate potentially contaminating serum proteins and lipoproteins as described in Materials and Methods (ExoQuick-ULTRA and ExoQuick-LP) (SI Appendix, Fig. S2B). We also found that ...
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... ExoQuick-LP) (SI Appendix, Fig. S2B). We also found that serum from patients with tryptase >110 ng/mL had significantly higher median EV concentrations than those with tryptase <110 ng/mL (Fig. 1A and SI Appendix, Fig. S2 A and B), and actually, the EV concentration in patients with mastocytosis strongly correlated with serum tryptase levels ( Fig. 1B and SI Appendix, Fig. S2 A, Right) (P < 0.0029 and P < 0.0014, respectively, for EVs isolated by precipitation and ...
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... next examined the relationships between EV concentration and additional surrogate markers of mastocytosis and aspects of disease pathology. Similar to serum tryptase (Fig. 1B), EV con- centration positively correlated to IL-6 levels ( Fig. 1C; r = 0.6112, P = 0.0042), known to increase with disease severity (6, 7). The concentration of SM-derived EVs also highly correlated with se- rum levels of AP ( Fig. 1D; r = 0.8414, P < 0.0001) and sedi- mentation rate ( Fig. 1E; r = 0.4866, P = 0.0296). Since increased ...
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... next examined the relationships between EV concentration and additional surrogate markers of mastocytosis and aspects of disease pathology. Similar to serum tryptase (Fig. 1B), EV con- centration positively correlated to IL-6 levels ( Fig. 1C; r = 0.6112, P = 0.0042), known to increase with disease severity (6, 7). The concentration of SM-derived EVs also highly correlated with se- rum levels of AP ( Fig. 1D; r = 0.8414, P < 0.0001) and sedi- mentation rate ( Fig. 1E; r = 0.4866, P = 0.0296). Since increased AP in patients with mastocytosis may associate with liver pathol- ...
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... and additional surrogate markers of mastocytosis and aspects of disease pathology. Similar to serum tryptase (Fig. 1B), EV con- centration positively correlated to IL-6 levels ( Fig. 1C; r = 0.6112, P = 0.0042), known to increase with disease severity (6, 7). The concentration of SM-derived EVs also highly correlated with se- rum levels of AP ( Fig. 1D; r = 0.8414, P < 0.0001) and sedi- mentation rate ( Fig. 1E; r = 0.4866, P = 0.0296). Since increased AP in patients with mastocytosis may associate with liver pathol- ogy (8) and the presence of hepatomegaly with elevated risk of death (8,33,34), we also examined the correlation of EVs in serum with organomegaly. Patients with ...
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... of disease pathology. Similar to serum tryptase (Fig. 1B), EV con- centration positively correlated to IL-6 levels ( Fig. 1C; r = 0.6112, P = 0.0042), known to increase with disease severity (6, 7). The concentration of SM-derived EVs also highly correlated with se- rum levels of AP ( Fig. 1D; r = 0.8414, P < 0.0001) and sedi- mentation rate ( Fig. 1E; r = 0.4866, P = 0.0296). Since increased AP in patients with mastocytosis may associate with liver pathol- ogy (8) and the presence of hepatomegaly with elevated risk of death (8,33,34), we also examined the correlation of EVs in serum with organomegaly. Patients with organomegaly had a sig- nificantly higher serum EV concentration ...
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... Since increased AP in patients with mastocytosis may associate with liver pathol- ogy (8) and the presence of hepatomegaly with elevated risk of death (8,33,34), we also examined the correlation of EVs in serum with organomegaly. Patients with organomegaly had a sig- nificantly higher serum EV concentration than patients without organomegaly ( Fig. 1F; P = 0.0386). As expected, serum tryptase levels also generally correlated with the levels of IL-6 and AP and sedimentation rate as well as organomegaly (SI Appendix, Fig. S3 A-D). Overall, the EV concentration in mastocytosis correlated with adverse prognostic parameters, as did tryptase (compare Fig. 1 with SI Appendix, Fig. S3). ...
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... than patients without organomegaly ( Fig. 1F; P = 0.0386). As expected, serum tryptase levels also generally correlated with the levels of IL-6 and AP and sedimentation rate as well as organomegaly (SI Appendix, Fig. S3 A-D). Overall, the EV concentration in mastocytosis correlated with adverse prognostic parameters, as did tryptase (compare Fig. 1 with SI Appendix, Fig. S3). These findings are in agreement with reports that more aggressive forms of clonal diseases generate greater amounts of EVs (25) and thus may offer an additional means to assess disease in patients with ...
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... with SM over time develop hepatomegaly and elevations in AP. We have reported that liver biopsies performed on patients with SM re- veal mast cell infiltration, portal inflammation, portal fibrosis, and venopathy (9). Given the correlations between EV concentration in mastocytosis and AP activity, and sedimentation rate and orga- nomegaly ( Fig. 1), we investigated the possibility that SM-EVs could alter the function of HSCs that are involved in hepatic injury and inflammation. HSC activity and numbers are also considered useful in predicting liver fibrosis, and immortalized HSC lines such as LX-2 cells have been developed for studying liver disease in vitro ...
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... serum proteins (ULTRA) or lipoproteins (LP), were used as directed by the manufacturer to obtain further enriched preparations of EVs. These methods were also used to confirm most of the results using ExoQuick-prepared EVs. Alternatively, EVs were isolated by ultracentrifugation as described (56) and detailed in SI Appendix (also see SI Appendix, Fig. S1A). Briefly, serum samples were clarified by centrifugation at 13,000 × g for 40 min at 4 °C and subjected to ultracentrifugation at 120,000 × g for 80 min at 4 °C. Pellets were washed, recentrifuged and resuspended in 100 μL ...
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... microscopy of EVs prepared using ExoQuick revealed character- istic EV structures no different from those observed by ultracentrifugation, with cores that appeared denser in SM-derived EVs (SI Appendix, Fig. ...
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... of EV markers (57) by Western blots (as explained in the SI Appendix) of the EV preparations obtained by either precipitation or ultracentrifugation showed similar levels of CD9 and CD63 regardless of the isolation technique, and their expression was uniform between HV-and SM- derived EVs (SI Appendix, Fig. S1C). In addition, the average EV size and size distribution, as determined by NTA using a NanoSight NS300 system (58) (NanoSight), were similar and consistent with the size of exosomes (50- 150 nm) independently of the isolation technique and the origin of the sample (SI Appendix, Fig. S1 D and E). Of note, ∼91% of particles were be- ...
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Purpose of Review
Patients with systemic mastocytosis, a dangerous and rare myeloid neoplasm, have long had few therapies available to them and, historically, rarely achieved from significant disease control. However, research and translational developments over the last decade have led to promising new options for disease management. In this revie...
In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown.
Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the Eu...
Background:
Patients with mastocytosis often suffer from a variety of symptoms caused by mast cell mediators where treatments remain difficult, showing various success rates. Omalizumab, a monoclonal anti-IgE antibody, has been postulated to have a positive impact on mastocytosis-associated symptoms such as flush, vertigo, gastrointestinal problem...
Systemic mastocytosis is a neoplastic proliferation of mast cells that most frequently involves cutaneous sites. Mastocytosis involves various extracutaneous sites, but the lymph node is rare. We present an interesting image of systemic mastocytosis in the lymph node with marked eosinophilia. It is a rare subtype of systemic mastocytosis requiring...
The authors present a rare case of a patient with telangiectasia macular eruptiva perstans, with confirmed D816V mutation which later progressed to systemic mastocytosis confirmed by trepanobiopsy. First-line treatment-phototherapy-had to be stopped, and systemic treatment with interferon alpha-2a was initiated. The treatment was successful with re...
Citations
... Hepatic stellate cells (HSCs) located in the space of Disse play pivotal roles in the occurrence and progression of liver fibrosis [8,9]. Under normal conditions, HSCs typically remain in a quiescent state [10]. ...
... HSC activation has been characterized as a vital factor for promoting liver fibrosis. Activated HSCs exhibit typical properties, including proliferation, migration, and enhanced ECM deposition, and are accompanied by changes in gene expression [8][9][10]. In our study, we found that the knockdown of LRRC1 inhibited the proliferation, migration, and expression of fibrogenic genes, such as α-SMA, Col-I, and Col-III, in LX-2 cells, indicating that LRRC1 has a regulatory function in the activation of HSCs. ...
Liver fibrosis poses a significant global health risk due to its association with hepatocellular carcinoma (HCC) and the lack of effective treatments. Thus, the need to discover additional novel therapeutic targets to attenuate liver diseases is urgent. Leucine-rich repeat containing 1 (LRRC1) reportedly promotes HCC development. Previously, we found that LRRC1 was significantly upregulated in rat fibrotic liver according to the transcriptome sequencing data. Herein, in the current work, we aimed to explore the role of LRRC1 in liver fibrosis and the underlying mechanisms involved. LRRC1 expression was positively correlated with liver fibrosis severity and significantly elevated in both human and murine fibrotic liver tissues. LRRC1 knockdown or overexpression inhibited or enhanced the proliferation, migration, and expression of fibrogenic genes in the human hepatic stellate cell line LX-2. More importantly, LRRC1 inhibition in vivo significantly alleviated CCl4-induced liver fibrosis by reducing collagen accumulation and hepatic stellate cells’ (HSCs) activation in mice. Mechanistically, LRRC1 promoted HSC activation and liver fibrogenesis by preventing the ubiquitin-mediated degradation of phosphorylated mothers against decapentaplegic homolog (Smad) 2/3 (p-Smad2/3), thereby activating the TGF-β1/Smad pathway. Collectively, these results clarify a novel role for LRRC1 as a regulator of liver fibrosis and indicate that LRRC1 is a promising target for antifibrotic therapies.
... KIT variants harbouring mutations that keep the receptor constitutively active have been associated with neoplastic MCs and MC disorders such as mastocytosis. Gastrointestinal stromal tumour (GIST) cells and neoplastic MCs expressing constitutively active KIT variants release abundant populations of EVs and disseminate KIT in both microvesicle-and exosome-like EVs of distinct composition (Atay et al., 2018;Kim et al., 2018;Pfeiffer et al., 2022;Xiao et al., 2014), suggesting a potential role for active KIT in the regulation of EV secretion. ...
... Neoplastic MCs expressing constitutively active KIT have been recognised to secrete substantial quantities of EVs. In addition, patients with oncogenic KIT-driven diseases have higher concentrations of circulating EVs than healthy controls (Atay et al., 2018;Kim et al., 2021Kim et al., , 2018. Here, seeking an explanation for these observations, we investigated a potential role for KIT receptor activation in regulating EV secretion. ...
... The differences in EV markers in the context of KIT activation raise the possibility of other accompanying changes in the molecular composition of sEVs, potentially with functional consequences in the in vivo environment in KIT-related diseases. This is supported by the proposed role of circulating EVs in the pathogenesis of oncogenic KIT-driven diseases where EVs may alter the phenotypes of distal bone (Kim et al., 2021), and liver cells (Kim et al., 2018); and by the effects EVs released from oncogenic KIT-expressing cells have on numerous cell types (Al-Nedawi et al., 2005;Atay et al., 2014;Elsemüller et al., 2019;Shelke et al., 2019;Xiao et al., 2014;Yin et al., 2020). EV-mediated transfer of KIT protein and subsequent activation of signalling pathways in recipient cells have been reported to contribute to these effects (Atay et al., 2014;Kim et al., 2018;Xiao et al., 2014). ...
The receptor tyrosine kinase (RTK) KIT and its ligand stem cell factor (SCF) are essential for human mast cell (huMC) survival and proliferation. HuMCs expressing oncogenic KIT variants secrete large numbers of extracellular vesicles (EVs). The role KIT plays in regulating EV secretion has not been examined. Here, we investigated the effects of stimulation or inhibition of KIT activity on the secretion of small EVs (sEVs). In huMCs expressing constitutively active KIT, the quantity and quality of secreted sEVs positively correlated with the activity status of KIT. SCF‐mediated stimulation of KIT in huMCs or murine MCs, or of transiently expressed KIT in HeLa cells, enhanced the release of sEVs expressing exosome markers. In contrast, ligand‐mediated stimulation of the RTK EGFR in HeLa cells did not affect sEV secretion. The release of sEVs induced by either constitutively active or ligand‐activated KIT was remarkably decreased when cells were treated with KIT inhibitors, concomitant with reduced exosome markers in sEVs. Similarly, inhibition of oncogenic KIT signalling kinases like PI3K, and MAPK significantly reduced the secretion of sEVs. Thus, activation of KIT and its early signalling cascades stimulate the secretion of exosome‐like sEVs in a regulated fashion, which may have implications for KIT‐driven functions.
... These tables can be consulted by attending physicians, too, when trying to gain clarity about MC mediators which may be involved in patients with MC disease symptoms which are often resistant to therapy, such as hyper-/hypotension, transient tachyarrhthmias, or migrating pain. Such a procedure might be extraordinarily effective if, based on the available tables and with the help of special computer programs to be developed, all the information (Theoharides et al. 1982) Untargeted by differential release (Theoharides and Douglas 1978;Theoharides et al. 1982;Moon et al. 2014) Targeted by synaptic contact with with the target cell (Carroll-Portillo et al. 2012) Targeted by mast cell extracellular traps of DNA (Möllerherm et al. 2016;Garcia-Rodriguez et al. 2020) • Release of exosomes containing mRNA, microRNA,and proteins (D'Incà and Pucillo 2015;Liang et al. 2018;Kim et al. 2018;Klein and Sagi-Eisenberg 2019;Shefler et al. 2021) • Diffusion of mediators into the extracellular space (Kritikou et al. 2016;Chen and Popel 2007) • Formation of nanotubules with exchange of intracellular material (Elishmereni et al. 2011;Ahani et al. 2022) contained in relevant databases such as GeneCards ® , Pub-Med, EMBL's European Bioinformatics Institute, Embase, Cochrane Library, and others could help link the symptoms in a patient to given mediator expression profiles, thereby hopefully providing personalized therapeutic insights. This might enable the selection of treatments ) more likely to help patients exhibiting specific MC-mediator-induced symptoms. ...
Mast cells (MCs) occupy a central role in immunological as well as non-immunological processes as reflected in the variety of the mediators by which MCs influence other cells. Published lists of MC mediators have all shown only subsets—usually quite small—of the full repertoire. The full repertoire of MC mediators released by exocytosis is comprehensively compiled here for the first time. The compilation of the data is essentially based on the largely cytokine-focused database COPE®, supplemented with data on the expression of substances in human MCs published in several articles, plus extensive research in the PubMed database. Three hundred and ninety substances could be identified as mediators of human MCs which can be secreted into the extracellular space by activation of the MC. This number might still be an underestimate of the actual number of MC mediators since, in principle, all substances produced by MCs can become mediators because of the possibility of their release by diffusion into the extracellular space, mast cell extracellular traps, and intercellular exchange via nanotubules. When human MCs release mediators in inappropriate manners, this may lead to symptoms in any or all organs/tissues. Thus, such MC activation disorders may clinically present with a myriad of potential combinations of symptoms ranging from trivial to disabling or even life-threatening. The present compilation can be consulted by physicians when trying to gain clarity about MC mediators which may be involved in patients with MC disease symptoms refractory to most therapies.
... Once significant difference was recognized, Tukey's HSD test as a post hoc analysis was conducted to compare the differences between the different groups. Other methods not described in this study were the same as those recently reported [29][30][31][36][37][38][39][40][41][42][43]. ...
Plants-releasing exosome-like nanovesicles (PENs) contain miRNA, bioactive lipids, mRNAs, and proteins to exert antioxidant, anti-inflammatory, and regenerative activity. Substances extracted from yams have been reported to promote osteoblast growth in bone regeneration, which prevent weak and brittle bones in osteoporosis. Herein, we describe the beneficial effects of yam-derived exosome-like nanovesicles (YNVs) on promoting differentiation and mineralization of osteoblasts for bone regeneration in ovariectomized (OVX)-induced osteoporotic mice. YNVs were successfully isolated and characterized. YNVs stimulate the proliferation, differentiation, and mineralization of osteoblasts with increased bone differentiation markers (OPN, ALP, and COLI). Interestingly, YNVs do not contain saponins including diosgenin and dioscin known to mainly exert osteogenic activity of yams. Instead, the osteogenic activity of YNVs was revealed to be resulted from activation of the BMP-2/p-p38-dependent Runx2 pathway. As a result, YNVs promote longitudinal bone growth and mineral density of the tibia in the OVX-induced osteoporotic mice in vivo, and these results positively correlate the significant increases in osteoblast-related parameters. In addition, the orally administered YNVs were transported through the GI tract and absorbed through the small intestine. These results showed an excellent systemic biosafety determined by histological analysis and liver/kidney toxicity tests. Taken together, YNVs can serve as a safe and orally effective agent in the treatment of osteoporosis.
... EVs released by activated mast cells have been proposed to contribute to allergic reactions (Carroll-Portillo et al., 2012;Molfetta et al., 2020) and contain the receptor KIT (Groot Kormelink et al., 2016;Liang et al., 2020). Moreover, EVs containing KIT are increased in the serum of patients with systemic mastocytosis (Kim et al., 2018), a clonal disease of the huMC compartment associated with KIT variants, and in the plasma of patients with CD34 + acute myeloid leukaemia (Boyiadzis & Whiteside, 2017;Hong et al., 2014;Szczepanski et al., 2011). We and others have also reported that KIT is shuttled from neoplastic huMC EVs into recipient cells in vitro and in vivo, affecting cell phenotypes and functions (Kim et al., 2018;Kim et al., 2021;Xiao et al., 2014). ...
... Moreover, EVs containing KIT are increased in the serum of patients with systemic mastocytosis (Kim et al., 2018), a clonal disease of the huMC compartment associated with KIT variants, and in the plasma of patients with CD34 + acute myeloid leukaemia (Boyiadzis & Whiteside, 2017;Hong et al., 2014;Szczepanski et al., 2011). We and others have also reported that KIT is shuttled from neoplastic huMC EVs into recipient cells in vitro and in vivo, affecting cell phenotypes and functions (Kim et al., 2018;Kim et al., 2021;Xiao et al., 2014). In this way, huMC-derived KIT-EVs may contribute to the pleiotropic clinical manifestations of mastocytosis, opening possibilities for investigating disease biomarkers (Falduto et al., 2020). ...
... HuMC-derived EVs can transfer KIT to other cell types altering the recipient cell phenotypes and potentially contributing to the pathogenesis of mastocytosis (Kim et al., 2018;Kim et al., 2021;Xiao et al., 2014). Enrichment of KIT-containing exosomes from GIST cell lines and patient plasma has also been reported (Atay et al., 2018). ...
Activating mutations in the receptor KIT promote the dysregulated proliferation of human mast cells (huMCs). The resulting neoplastic huMCs secrete extracellular vesicles (EVs) that can transfer oncogenic KIT among other cargo into recipient cells. Despite potential contributions to diseases, KIT-containing EVs have not been thoroughly investigated. Here, we isolated and characterized KIT-EV subpopulations released by neoplastic huMCs using an immunocapture approach that selectively isolates EVs containing KIT in its proper topology. Immunocapture of EVs on KIT antibody-coated electron microscopy (EM) affinity grids allowed to assess the morphology and size of KIT-EVs. Immunoblot analysis demonstrated KIT-EVs have a distinct protein profile from KIT-depleted EVs, contain exosome and microvesicle markers, and are separated into these subtypes by ultracentrifugation. Cell treatment with sphingomyelinase inhibitors shifted the protein content among KIT-EV subtypes, suggesting different biogenesis routes. Proteomic analysis revealed huMC KIT-EVs are enriched in proteins involved in signalling, immune responses, and cell migration, suggesting diverse biological functions, and indicated neoplastic huMCs disseminate KIT via shuttling in heterogeneous microvesicle- and exosome-like EVs. Further, selective KIT-immunocapture will enable the enrichment of specific huMC-derived EVs from complex human biosamples and facilitate an understanding of their in vivo functions and potential to serve as biomarkers of specific biological pathologies.
... 55 MRGPRX2 may be released by exocytosis and can be detected in serum on extracellular vesicles. 58 Levels of circulating MRGPRX2 may reflect the activation and degranulation of MCs in the skin and other organs. For example, in patients with systemic mastocytosis, the concentration of MRGPRX2-bearing extracellular vesicles correlated with serum tryptase, IL-6, alkaline phosphatase, and organomegaly. ...
... For example, in patients with systemic mastocytosis, the concentration of MRGPRX2-bearing extracellular vesicles correlated with serum tryptase, IL-6, alkaline phosphatase, and organomegaly. 58 Our results link increased CST-positive cell (or MC) numbers in the lesional skin of patients with severe disease, high itch intensity, and severe quality-of-life impairment (Fig E3). Together with our MRGPRX2 findings, this suggests that CST is a major pathogenic driver of CPG and that MRGPRX2 is the main CST receptor involved. ...
Background
Chronic prurigo (CPG) is characterized by intensive itch and nerve-neuropeptide-mast cell interactions. The role of some neuropeptides such as cortistatin and its receptor MRGPRX2 in CPG is poorly investigated.
Objectives
We evaluated (i) whether cortistatin activates human skin mast cells (hsMCs), and (ii) whether cortistatin and MRGPRX2 are expressed in the skin of CPG patients and by which cells.
Methods
Skin prick tests and microdialysis with cortistatin were performed in six and one healthy volunteers, respectively. Degranulation of hsMCs was assessed using β-hexosaminidase and histamine release assays. Skin samples from 10 patients with CPG and 10 control subjects were stained for cortistatin, mast cells and MRGPRX2 (protein and mRNA) using immunohistochemistry, immunofluorescence and/or in situ hybridization. Flow cytometry was used to assess cortistatin in hsMCs. MRGPRX2 levels were measured in serum by ELISA.
Results
Cortistatin induced concentration-dependent degranulation of hsMCs in vivo and ex vivo. Skin lesions of CPG patients exhibited markedly higher numbers of cortistatin-expressing cells, cortistatin-expressing mast cells, MRGPRX2-expressing cells and MRGPRX2 mRNA-expressing cells than nonlesional skin. Mast cells were the main MRGPRX2 mRNA-expressing cells in the lesions of most CPG patients (70%). Stimulation of hsMCs with anti-IgE led to a release of cortistatin. The number of MRGPRX2-expressing cells correlated with disease severity (r=0.649, p=0.04). MRGPRX2 serum levels in CPG patients correlated with disease severity (r=0.704, p=0.023) and QoL impairment (r=0.687, p=0.028).
Conclusions
Cortistatin and MRGPRX2 may contribute to the pathogenesis of CPG and should be evaluated in further studies as potential biomarkers and novel therapeutic targets.
... The authors also demonstrated that injection of SM-EVs, but not EVs from healthy control subjects, into recipient mice resulted in increased α-SMA expression, a marker of HSC activation, around portal areas. These findings suggest a role for KIT within SM-EVs in the activation of HSC in vivo [55]. ...
Mast cells are major effector cells in eliciting allergic responses. They also play a significant role in establishing innate and adaptive immune responses, as well as in modulating tumor growth. Mast cells can be activated upon engagement of the high-affinity receptor FcεRI with specific IgE to multivalent antigens or in response to several FcεRI-independent mechanisms. Upon stimulation, mast cells secrete various preformed and newly synthesized mediators. Emerging evidence indicates their ability to be a rich source of secreted extracellular vesicles (EVs), including exosomes and microvesicles, which convey biological functions. Mast cell-derived EVs can interact with and affect other cells located nearby or at distant sites and modulate inflammation, allergic response, and tumor progression. Mast cells are also affected by EVs derived from other cells in the immune system or in the tumor microenvironment, which may activate mast cells to release different mediators. In this review, we summarize the latest data regarding the ability of mast cells to release or respond to EVs and their role in allergic responses, inflammation, and tumor progression. Understanding the release, composition, and uptake of EVs by cells located near to or at sites distant from mast cells in a variety of clinical conditions, such as allergic inflammation, mastocytosis, and lung cancer will contribute to developing novel therapeutic approaches.
... Differential cytokine and miR expression was reported in plasma EVs from patients with alpha-1 antitrypsin deficiency (in whom hepatic inflammation and fibrosis occur due to accumulated misfolded ZAAT protein in hepatocytes) and these EVs activated JAK/STAT, NF-κB, and CXCR3/CXCL10 in human HSC in vitro [271]. In systemic mastocytosis (SM), a condition in which mast cells accumulate in excessive numbers in multiple organs and can result in hepatic fibrosis, serum EVs were enhanced and correlated with disease progression, contained common mast cell proteins and stimulated proliferation, fibrogenesis and activation in human LX2 HSC in vitro [272]. This interaction involved the delivery of phospho-KIT from EVs to HSC and its neutralization using blocking KIT antibody negated EV-mediated HSC proliferation and activation. ...
... Action of EVs from the Circulation Differential cytokine and miR expression was reported in plasma EVs from patients with alpha-1 antitrypsin deficiency (in whom hepatic inflammation and fibrosis occur due to accumulated misfolded ZAAT protein in hepatocytes) and these EVs activated JAK/STAT, NF-κB, and CXCR3/CXCL10 in human HSC in vitro [271]. In systemic mastocytosis (SM), a condition in which mast cells accumulate in excessive numbers in multiple organs and can result in hepatic fibrosis, serum EVs were enhanced and correlated with disease progression, contained common mast cell proteins and stimulated proliferation, fibrogenesis and activation in human LX2 HSC in vitro [272]. This interaction involved the delivery of phospho-KIT from EVs to HSC and its neutralization using blocking KIT antibody negated EV-mediated HSC proliferation and activation. ...
... This interaction involved the delivery of phospho-KIT from EVs to HSC and its neutralization using blocking KIT antibody negated EV-mediated HSC proliferation and activation. Moreover, administration of SM-EVs in mice resulted in HSC activation and the delivery of EV-derived KIT into the HSC population [272]. ...
Fibrosis is the unrelenting deposition of excessively large amounts of insoluble interstitial collagen due to profound matrigenic activities of wound-associated myofibroblasts during chronic injury in diverse tissues and organs. It is a highly debilitating pathology that affects millions of people globally and leads to decreased function of vital organs and increased risk of cancer and end-stage organ disease. Extracellular vesicles (EVs) produced within the chronic wound environment have emerged as important vehicles for conveying pro-fibrotic signals between many of the cell types involved in driving the fibrotic response. On the other hand, EVs from sources such as stem cells, uninjured parenchymal cells, and circulation have in vitro and in vivo anti-fibrotic activities that have provided novel and much-needed therapeutic options. Finally, EVs in body fluids of fibrotic individuals contain cargo components that may have utility as fibrosis biomarkers, which could circumvent current obstacles to fibrosis measurement in the clinic, allowing fibrosis stage, progression, or regression to be determined in a manner that is accurate, safe, minimally-invasive, and conducive to repetitive testing. This review highlights the rapid and recent progress in our understanding of EV-mediated fibrotic pathogenesis, anti-fibrotic therapy, and fibrosis staging in the lung, kidney, heart, liver, pancreas, and skin.
... Notably, patients with systemic mastocytosis have increased levels of exosomes with an MC signature including constitutively activated KIT, enabling transfer of mutant proteins to other cells. 30 Given the broad distribution of MCs and their multifunctional role, the variety of mediators released, the symptoms associated with MC mediators (Figure 3), they have been implicated in many diseases beyond allergy. [31][32][33] For example, recent reviews highlight the role of MCs in cardiovascular diseases, 34 cancer, 35 airway diseases, 36 as well as in viral, bacterial, and fungal infections. ...
Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non‐immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells, and epithelial cells. During recent years, clinical and experimental studies on human mast cells, as well as experiments using animal models, have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review, we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity, and reactivity. We also highlight the development in our understanding of mast cell‐driven diseases and discuss the development of novel strategies to treat such conditions.
... Delivery of these bioactive molecules may cause functional changes in recipient cells 21 . Recently, we demonstrated that patients with SM have increased concentrations of small EVs in circulation with characteristic mast cell markers that have the potential of altering the phenotype of non-hematopoietic cells 22 . Because mast cells also accumulate in the BM of patients with SM, we thus investigated the possibility that mast cell-derived EVs from these patients could alter normal bone coupling. ...
... Herein, we demonstrate that SM-derived EVs (SM-EVs) with a mast cell signature 22 and EVs derived from neoplastic mast cells contain fate-modifying miRNAs that are taken up by preosteoblastic cells and prevent their differentiation into osteoblasts in vitro and in vivo. Specifically, miRNA-30a and miRNA-23a caused repression of the master regulator of osteogenesis, runtrelated transcription factor 2 (RUNX2), and SMAD proteins, which transduce signals from bone morphogenic proteins (BMPs), also critical drivers of osteoblast differentiation. ...
... Our study brings forward the concept that increased numbers of neoplastic mast cells in patients with SM, via the production of EVs, can cause perturbations in the pool of miRNAs that regulate normal bone homeostasis. This underscores the potential of SM-EVs to contribute to various aspects of pathogenesis in SM by a broad spectrum of mechanisms including transfer of oncogenic proteins, as we previously reported in hepatic stellate cells 22 or, as shown here, causing epigenetic alterations in targets cells. To our knowledge this is the first report identifying neoplastic mast-cellderived EVs and the miRNAs they carry and deliver, in the negative regulation of osteogenesis. ...
Osteoporosis and other manifestations of bone disease are frequent in patients with systemic mastocytosis (SM) in association with the presence of mast cell infiltrates in bone marrow, although the mechanisms behind bone disease remain poorly understood. We find that extracellular vesicles (EVs) released by neoplastic mast cells and present in the serum of patients with SM (SM-EVs) block osteoblast differentiation and mineralization in culture, and when injected into mice diminish the expression of osteoblast markers, and trabecular bone volume and microarchitecture. We demonstrate that miRNA-30a and miRNA-23a, increased in SM-EVs and neoplastic mast cell-derived EVs, attenuate osteoblast maturation by suppressing expression of RUNX2 and SMAD1/5, essential drivers of osteogenesis. Thus, SM-EVs carry and deliver miRNAs that epigenetically interfere with bone formation and can contribute to bone mass reduction in SM. These findings also suggest possibilities for novel approaches to the management of bone disease in mast cell proliferative disorders.
