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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 34231

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Prof. Dr. Angela Chambery

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Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania “Luigi Vanvitelli”, Via Vivaldi 43, I-81100 Caserta, Italy
Interests: protein biochemistry; proteomics; mass spectrometry; secretomics

Special Issue Information

Dear Colleagues,

Over the last few decades, the investigation of extracellular molecules has been gaining attention to unravel mechanisms at the basis of cellular communication. The elucidation of cellular secretomes, i.e., the subpopulations of proteins secreted by cells, tissues or organisms, is eliciting a growing interest, mainly related to potential implications in biomarker discovery of diagnostic and prognostic significance. Secreted proteins (e.g., growth factors, cytokines, chemokines, and proteases) are actively involved in the regulation and modulation of intracellular signaling pathways. Furthermore, extracellular signaling molecules also affect tissue niches and surrounding microenvironment, thereby influencing cellular cross-talk and coordinating most cell functions through paracrine or autocrine mechanisms.

The understanding of this molecular language may provide an integrated and broader view of cellular regulatory networks under physiological and pathological conditions, especially in the area of cancer biology.

Given the increasing interest regarding the roles of extracellular molecules in cellular signaling, this Special Issue aims to establish a comprehensive collection of broad knowledge regarding cellular secretome characterization of model systems including cells, stem cells, tumor cells, and biological fluids. Articles addressing potential strategies to profile secreted proteins by proteomics and mass spectrometry-based strategies are all welcome.

Prof. Angela Chambery
Guest Editor

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Keywords

secretome
proteomics
mass spectrometry
biomarkers
exosomes
microvescicles

Published Papers (9 papers)

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10 pages, 2146 KiB

Open AccessArticle

Secreted Ligands of the NK Cell Receptor NKp30: B7-H6 Is in Contrast to BAG6 Only Marginally Released via Extracellular Vesicles

by Viviane Ponath, Nathalie Hoffmann, Leonie Bergmann, Christina Mäder, Bilal Alashkar Alhamwe, Christian Preußer and Elke Pogge von Strandmann

Int. J. Mol. Sci. 2021, 22(4), 2189; https://doi.org/10.3390/ijms22042189 - 22 Feb 2021

Cited by 11 | Viewed by 3658

Abstract

NKp30 (Natural Cytotoxicity Receptor 1, NCR1) is a powerful cytotoxicity receptor expressed on natural killer (NK) cells which is involved in tumor cell killing and the regulation of antitumor immune responses. Ligands for NKp30, including BAG6 and B7-H6, are upregulated in virus-infected and tumor cells but rarely detectable on healthy cells. These ligands are released by tumor cells as part of the cellular secretome and interfere with NK cell activity. BAG6 is secreted via the exosomal pathway, and BAG6-positive extracellular vesicles (EV-BAG6) trigger NK cell cytotoxicity and cytokine release, whereas the soluble protein diminishes NK cell activity. However, the extracellular format and activity of B7-H6 remain elusive. Here, we used HEK293 as a model cell line to produce recombinant ligands and to study their impact on NK cell activity. Using this system, we demonstrate that soluble B7-H6 (sB7-H6), like soluble BAG6 (sBAG6), inhibits NK cell-mediated target cell killing. This was associated with a diminished cell surface expression of NKG2D and NCRs (NKp30, NKp40, and NKp46). Strikingly, a reduced NKp30 mRNA expression was observed exclusively in response to sBAG6. Of note, B7-H6 was marginally released in association with EVs, and EVs collected from B7-H6 expressing cells did not stimulate NK cell-mediated killing. The molecular analysis of EVs on a single EV level using nano flow cytometry (NanoFCM) revealed a similar distribution of vesicle-associated tetraspanins within EVs purified from wildtype, BAG6, or B7-H6 overexpressing cells. NKp30 is a promising therapeutic target to overcome NK cell immune evasion in cancer patients, and it is important to unravel how extracellular NKp30 ligands inhibit NK cell functions. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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21 pages, 4245 KiB

Open AccessArticle

Atherosclerotic Pre-Conditioning Affects the Paracrine Role of Circulating Angiogenic Cells Ex-Vivo

by Sara Eslava-Alcon, Mª Jesús Extremera-García, Ismael Sanchez-Gomar, Lucía Beltrán-Camacho, Antonio Rosal-Vela, Javier Muñoz, Nuria Ibarz, Jose Angel Alonso-Piñero, Marta Rojas-Torres, Margarita Jiménez-Palomares, Almudena González-Rovira, Rosario Conejero, Esther Doiz, Manuel Rodriguez-Piñero, Rafael Moreno-Luna and Mª Carmen Durán-Ruiz

Int. J. Mol. Sci. 2020, 21(15), 5256; https://doi.org/10.3390/ijms21155256 - 24 Jul 2020

Cited by 11 | Viewed by 3197

Abstract

In atherosclerosis, circulating angiogenic cells (CAC), also known as early endothelial progenitor cells (eEPC), are thought to participate mainly in a paracrine fashion by promoting the recruitment of other cell populations such as late EPC, or endothelial colony-forming cells (ECFC), to the injured areas. There, ECFC replace the damaged endothelium, promoting neovascularization. However, despite their regenerative role, the number and function of EPC are severely affected under pathological conditions, being essential to further understand how these cells react to such environments in order to implement their use in regenerative cell therapies. Herein, we evaluated the effect of direct incubation ex vivo of healthy CAC with the secretome of atherosclerotic arteries. By using a quantitative proteomics approach, 194 altered proteins were identified in the secretome of pre-conditioned CAC, many of them related to inhibition of angiogenesis (e.g., endostatin, thrombospondin-1, fibulins) and cell migration. Functional assays corroborated that healthy CAC released factors enhanced ECFC angiogenesis, but, after atherosclerotic pre-conditioning, the secretome of pre-stimulated CAC negatively affected ECFC migration, as well as their ability to form tubules on a basement membrane matrix assay. Overall, we have shown here, for the first time, the effect of atherosclerotic factors over the paracrine role of CAC ex vivo. The increased release of angiogenic inhibitors by CAC in response to atherosclerotic factors induced an angiogenic switch, by blocking ECFC ability to form tubules in response to pre-conditioned CAC. Thus, we confirmed here that the angiogenic role of CAC is highly affected by the atherosclerotic environment. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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12 pages, 1474 KiB

Open AccessArticle

Microenvironment Molecular Profile Combining Glycation Adducts and Cytokines Patterns on Secretome of Short-term Blood-derived Cultures during Tumour Progression

by Maria Laura Coluccio, Ivan Presta, Marta Greco, Rita Gervasi, Domenico La Torre, Maria Renne, Carlo Pietro Voci, Lorenzo Lunelli, Giuseppe Donato and Natalia Malara

Int. J. Mol. Sci. 2020, 21(13), 4711; https://doi.org/10.3390/ijms21134711 - 1 Jul 2020

Cited by 10 | Viewed by 2107

Abstract

Cancer cells are known to secrete many bioactive factors acting both with paracrine and autocrine mechanisms by which they condition the surrounding microenvironment. At the same time, the intracytoplasmic metabolic activities microenvironment influences the profile of this secretion. It is well known that cancer cells exhibit prevalent glycolytic metabolism and a more oxidative atmosphere compared to their healthy counterparts; this metabolic phenotype promotes glycate adducts formation and secretion. Considering the exacerbation of metabolic changes during the cancer progression, it is suggestive to explore the potential correlation between the increasing rate of glycan adducts and the specific pattern of secreted cytokines in different phases of cancer disease. We analyzed the secretomes of blood-derived cancer cell cultures from cancer patients and healthy subjects. The relative glycate adducts content in cancer secretomes was higher in comparison to that of healthy samples. Moreover, the stratification based on different phases of cancer disease correlated with a specific cytokines panel. The results obtained open a new perspective of observation of the intricate relationship between metabolome and inflammation in cancer. By using the analysis of secretome combined with a standardized protocol of liquid biopsy, it would be possible to identify specific profiles of molecular markers useful to arrange alternative and personalized medicine strategies. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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20 pages, 9792 KiB

Open AccessArticle

Prediction of the Secretome and the Surfaceome: A Strategy to Decipher the Crosstalk between Adipose Tissue and Muscle during Fetal Growth

by Muriel Bonnet, Nicolas Kaspric, Kimberly Vonnahme, Didier Viala, Christophe Chambon and Brigitte Picard

Int. J. Mol. Sci. 2020, 21(12), 4375; https://doi.org/10.3390/ijms21124375 - 19 Jun 2020

Cited by 2 | Viewed by 2578

Abstract

Crosstalk between adipose and muscular tissues is hypothesized to regulate the number of muscular and adipose cells during fetal growth, with post-natal consequences on lean and fat masses. Such crosstalk largely remains, however, to be described. We hypothesized that a characterization of the proteomes of adipose and muscular tissues from bovine fetuses may enhance the understanding of the crosstalk between these tissues through the prediction of their secretomes and surfaceomes. Proteomic experiments have identified 751 and 514 proteins in fetal adipose tissue and muscle. These are mainly involved in the regulation of cell proliferation or differentiation, but also in pathways such as apoptosis, Wnt signalling, or cytokine-mediated signalling. Of the identified proteins, 51 adipokines, 11 myokines, and 37 adipomyokines were predicted, together with 26 adipose and 13 muscular cell surface proteins. Analysis of protein–protein interactions suggested 13 links between secreted and cell surface proteins that may contribute to the adipose–muscular crosstalk. Of these, an interaction between the adipokine plasminogen and the muscular cell surface alpha-enolase may regulate the fetal myogenesis. The in silico secretome and surfaceome analyzed herein exemplify a powerful strategy to enhance the elucidation of the crosstalk between cell types or tissues. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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25 pages, 11118 KiB

Open AccessArticle

Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo

by Iria Samper Agrelo, Jessica Schira-Heinen, Felix Beyer, Janos Groh, Christine Bütermann, Veronica Estrada, Gereon Poschmann, Ana Bribian, Janusz J. Jadasz, Laura Lopez-Mascaraque, David Kremer, Rudolf Martini, Hans Werner Müller, Hans Peter Hartung, James Adjaye, Kai Stühler and Patrick Küry

Int. J. Mol. Sci. 2020, 21(12), 4350; https://doi.org/10.3390/ijms21124350 - 18 Jun 2020

Cited by 16 | Viewed by 5038

Abstract

Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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19 pages, 4910 KiB

Open AccessArticle

Low Doses of Arsenic in a Mouse Model of Human Exposure and in Neuronal Culture Lead to S-Nitrosylation of Synaptic Proteins and Apoptosis via Nitric Oxide

by Haitham Amal, Guanyu Gong, Hongmei Yang, Brian A. Joughin, Xin Wang, Charles G. Knutson, Maryam Kartawy, Igor Khaliulin, John S. Wishnok and Steven R. Tannenbaum

Int. J. Mol. Sci. 2020, 21(11), 3948; https://doi.org/10.3390/ijms21113948 - 31 May 2020

Cited by 18 | Viewed by 3371

Abstract

Background: Accumulating public health and epidemiological literature support the hypothesis that arsenic in drinking water or food affects the brain adversely. Methods: Experiments on the consequences of nitric oxide (NO) formation in neuronal cell culture and mouse brain were conducted to probe the mechanistic pathways of nitrosative damage following arsenic exposure. Results: After exposure of mouse embryonic neuronal cells to low doses of sodium arsenite (SA), we found that Ca²⁺ was released leading to the formation of large amounts of NO and apoptosis. Inhibition of NO synthase prevented neuronal apoptosis. Further, SA led to concerted S-nitrosylation of proteins significantly associated with synaptic vesicle recycling and acetyl-CoA homeostasis. Our findings show that low-dose chronic exposure (0.1–1 ppm) to SA in the drinking water of mice led to S-nitrosylation of proteomic cysteines. Subsequent removal of arsenic from the drinking water reversed the biochemical alterations. Conclusions: This work develops a mechanistic understanding of the role of NO in arsenic-mediated toxicity in the brain, incorporating Ca²⁺ release and S-nitrosylation as important modifiers of neuronal protein function. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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22 pages, 3190 KiB

Open AccessArticle

Differential Secretome Profiling of Human Osteoarthritic Synoviocytes Treated with Biotechnological Unsulfated and Marine Sulfated Chondroitins

by Rosita Russo, Valentina Vassallo, Antonietta Stellavato, Mariangela Valletta, Donatella Cimini, Paolo Vincenzo Pedone, Chiara Schiraldi and Angela Chambery

Int. J. Mol. Sci. 2020, 21(11), 3746; https://doi.org/10.3390/ijms21113746 - 26 May 2020

Cited by 17 | Viewed by 3086

Abstract

Symptomatic slow-acting drugs (SYSADOA) are increasingly used as effective therapies for osteoarthritis, representing an attractive alternative to analgesics or non-steroidal anti-inflammatory drugs to relieve disease symptoms. Pharmaceutical preparations of chondroitin sulfate, derived from animal sources, alone or in combination with glucosamine sulfate, are widely recognized for their beneficial effect on osteoarthritis treatment. A growing interest has also been devoted to understanding the molecular mechanisms modulated by SYSADOA using -omic strategies, most of which rely on chondrocytes as a model system. In this work, by using an integrated strategy based on unbiased proteomics and targeted cytokine profiling by a multiplexed protein array, we identified differences in the secretomes of human osteoarthritic synoviocytes in response to biotechnological unsulfated, and marine sulfated chondroitins treatments. The combined strategy allowed the identification of candidate proteins showing both common and distinct regulation responses to the two treatments of chondroitins. These molecules, mainly belonging to ECM proteins, enzymes, enzymatic inhibitors and cytokines, are potentially correlated to treatment outcomes. Overall, the present results provide an integrated overview of protein changes in human osteoarthritic synoviocytes secretome associated to different chondroitin treatments, thus improving current knowledge of the biochemical effects driven by these drugs potentially involved in pathways associated to osteoarthritis pathogenesis. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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33 pages, 2184 KiB

Open AccessArticle

Aggregation of Omic Data and Secretome Prediction Enable the Discovery of Candidate Plasma Biomarkers for Beef Tenderness

by Sabrina Boudon, Joelle Henry-Berger and Isabelle Cassar-Malek

Int. J. Mol. Sci. 2020, 21(2), 664; https://doi.org/10.3390/ijms21020664 - 19 Jan 2020

Cited by 11 | Viewed by 3781

Abstract

Beef quality is a complex phenotype that can be evaluated only after animal slaughtering. Previous research has investigated the potential of genetic markers or muscle-derived proteins to assess beef tenderness. Thus, the use of low-invasive biomarkers in living animals is an issue for the beef sector. We hypothesized that publicly available data may help us discovering candidate plasma biomarkers. Thanks to a review of the literature, we built a corpus of articles on beef tenderness. Following data collection, aggregation, and computational reconstruction of the muscle secretome, the putative plasma proteins were searched by comparison with a bovine plasma proteome atlas and submitted to mining of biological information. Of the 44 publications included in the study, 469 unique gene names were extracted for aggregation. Seventy-one proteins putatively released in the plasma were revealed. Among them 13 proteins were predicted to be secreted in plasma, 44 proteins as hypothetically secreted in plasma, and 14 additional candidate proteins were detected thanks to network analysis. Among these 71 proteins, 24 were included in tenderness quantitative trait loci. The in-silico workflow enabled the discovery of candidate plasma biomarkers for beef tenderness from reconstruction of the secretome, to be examined in the cattle plasma proteome. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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Review

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16 pages, 950 KiB

Open AccessReview

Oxidative Phosphorylation Dysfunction Modifies the Cell Secretome

by Nuria Garrido-Pérez, Ana Vela-Sebastián, Ester López-Gallardo, Sonia Emperador, Eldris Iglesias, Patricia Meade, Cecilia Jiménez-Mallebrera, Julio Montoya, M. Pilar Bayona-Bafaluy and Eduardo Ruiz-Pesini

Int. J. Mol. Sci. 2020, 21(9), 3374; https://doi.org/10.3390/ijms21093374 - 10 May 2020

Cited by 8 | Viewed by 6570

Abstract

Mitochondrial oxidative phosphorylation disorders are extremely heterogeneous conditions. Their clinical and genetic variability makes the identification of reliable and specific biomarkers very challenging. Until now, only a few studies have focused on the effect of a defective oxidative phosphorylation functioning on the cell’s secretome, although it could be a promising approach for the identification and pre-selection of potential circulating biomarkers for mitochondrial diseases. Here, we review the insights obtained from secretome studies with regard to oxidative phosphorylation dysfunction, and the biomarkers that appear, so far, to be promising to identify mitochondrial diseases. We propose two new biomarkers to be taken into account in future diagnostic trials. Full article

(This article belongs to the Special Issue Cellular Secretomes)

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