Proteomics of Serum Extracellular Vesicles Identifies a Novel COPD Biomarker, Fibulin-3 from Elastic Fibres

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Proteomics of Serum Extracellular Vesicles Identifies a Novel COPD Biomarker, Fibulin-3 from Elastic Fibres Title: Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres Authors: Taro Koba, Yoshito Takeda*, Ryohei Narumi, Takashi Shiromizu, Yosui Nojima, Mari Ito, Muneyoshi Kuroyama, Yu Futami, Takayuki Takimoto, Takanori Matsuki, Ryuya Edahiro, Satoshi Nojima, Yoshitomo Hayama, Kiyoharu Fukushima, Haruhiko Hirata, Shohei Koyama, Kota Iwahori, Izumi Nagatomo, Mayumi Suzuki, Yuya Shirai, Teruaki Murakami, Kaori Nakanishi, Takeshi Nakatani, Yasuhiko Suga, Kotaro Miyake, Takayuki Shiroyama, Shohei Koyama, Hiroshi Kida, Takako Sasaki, Koji Ueda, Kenji Mizuguchi, Jun Adachi, Takeshi Tomonaga, Atsushi Kumanogoh Data Supplement Sample collection and approval All serum samples were collected in Osaka University Hospital and stored at -80ºC until analysis. Approval was obtained from the Osaka University Graduate School of Medicine Institutional Review Board; all patients gave written informed consent to participate in the study, and they were arrowed to fast on free will. All methods were performed in accordance with relevant guidelines and regulations. Mouse experiments were approved by the Osaka University’s Animal Care and Use Committee, and all of the animal procedures were performed following the Osaka University guidelines on animal care. Statistical analyses Statistical analyses were conducted using JMP Pro v. 14.3.0 (SAS Institute, Cary, NC, USA). Pearson’s chi-square test or Welch’s t-test was used to compare healthy controls with COPD patients. Correlations between two parameters were calculated using Spearman’s rank correlation coefficients. Differences were considered statistically significant at p < 0.05. Ward’s hierarchical cluster analysis was used to divide COPD patients into two groups by up- and down-regulated proteins. Receiver operating characteristic curves were constructed using the SRM (selected reaction monitoring) results. Areas under the curves were calculated to evaluate the diagnostic value of each marker. Multiple logistic regression analysis was applied to calculate the predictive probability of a multimarker for the diagnosis of COPD. Analysis of covariance was applied to confirm significant difference in fibulin-3 regardless of age. Isolation of extracellular vesicles from human and mouse sera Extracellular vesicles (EVs) were isolated from less than 20 μL of mouse or human serum by differential ultracentrifugation, as previously described [1] and in accordance with the most recent guidelines (MISEV 2018) [2]. Briefly, serum samples were centrifuged at 2000 × g for 30 min to remove debris. Supernatants were then passed through a 0.22-μm spin filter (Agilent Technologies, Santa Clara, CA, USA) and centrifuged on a cushion made of sucrose/D2O for non-targeted proteomics or without sucrose for targeted proteomics at 100,000 × g for 90 min. In the sucrose cushion method, filtered supernatants were overlaid onto 0.5 mL of 30% sucrose/D2O cushion (1.21 g/mL) and spun at 100,000 × g in a swing rotor (P56ST, Hitachi Koki, Tokyo, Japan) for 1 h. The pellet and sucrose fraction were resuspended in phosphate-buffered saline (PBS) and subsequently ultra-centrifuged twice at 100,000 × g for 70 min. The resulting EV pellets were lysed with 100 µL of lysis buffer (50 mM Tris-HCl, pH 9.0, containing 6 M urea and 5% sodium deoxycholate for mouse samples; 50 mM NH4HCO3 containing 12 mM sodium deoxycholate and 12 mM sodium N-lauroyl sarcosinate for human samples), and incubated at 95 °C for 5 min. The EV lysates were stored at -80 °C until the processing of the EV proteins. Nanoparticle tracking analysis (NTA) Analysis of the size distribution and the number of EVs was carried out by using the NanoSight LM10HS with a blue laser system (NanoSight, Amesbury, UK) as previously described [3]. Briefly, nanoparticle tracking analysis (NTA) was performed on isolated EVs, previously diluted 20-fold with PBS. All the events were recorded in a 60-s video for further analysis using the NTA software. The Brownian motion of each particle was tracked between frames to calculate its size using the Stokes-Einstein equation. Tunable Resistive Pulse Sensing EVs isolated by ultracentrifugation were resuspended in a solution containing 100 mM KCl and 40 mM HEPES. The sizes and numbers of EVs were measured on an Izon qNano system with tunable resistive pulse sensor technology (Izon Science, Christchurch, New Zealand), as previously reported [4]. The instrument was equipped with an NP200A membrane (Izon Science), which contained a tunable nanopore optimized for the detection of particles in the 100-400 nm size range. Processing of EV proteins for proteomics Trypsin digestion of EV proteins was performed by phase transfer surfactant protocol [5]. Briefly, the EV lysates were reduced with dithiothreitol and alkylated with iodoacetamide as previously reported [6]. Mouse samples were diluted 10-fold with 50 mM Tris-HCl (pH 9.0), while human samples were diluted 5-fold with 50 mM NH4HCO3. The diluted samples were digested at 37°C overnight with 1 µg trypsin for human samples or a trypsin-to-protein ratio of 1:20 (w/w) for mouse samples (proteomics grade; Roche, Mannheim, Germany). After digestion, the sample was mixed with an equal volume of ethyl acetate, acidified with 0.5% trifluoroacetic acid, and then vortexed. After centrifugation, the upper organic phase was discarded. The resulting tryptic peptides for non-targeted proteomics were desalted with a pipette-tip column of C18 resin as previously reported [7], while the ones for targeted proteomics were cleaned up with pipette-tip columns of C18 and strong cation exchange resins as previously reported [8]. Isobaric chemical labeling and prefractionation of EV peptides. The desalted peptides for non-targeted EV proteomics were labeled with the reagents for isobaric-peptides-labeling [iTRAQ and tandem mass tag (TMT) reagents]. The iTRAQ 4plex (AB Sciex, Warrington, UK) or the TMT10plex (Thermo Fisher Scientific, Bremen, Germany) reagents were used for the mouse or human samples, respectively, according to each manufacturer’s protocol. In iTRAQ labeling of peptides, each of the dried samples was dissolved in 30 μL of 1.0 M trimethylamine bicarbonate buffer (Sigma-Aldrich, St. Louis, MO, USA) and then incubated with the iTRAQ reagents for 1 hour at room temperature. The samples were combined after termination of the reaction with 100 μL of water. The iTRAQ-labeled sample mixture was separated into 22 fractions using a high-performance liquid chromatography system (Prominence UFLC; Shimadzu Corporation, Kyoto, Japan) with a ZORBAX 300 Extend-C18 column (Agilent Technologies), and then the fractions were stored at -80°C until liquid chromatography-mass spectrometry (LC-MS) was performed. In TMT labeling of peptides, each of the dried samples was dissolved in 10 μL of 0.1 M trimethylamine bicarbonate buffer and then incubated with 4 μL TMT reagents for 1 hour at room temperature. The samples were combined after termination of the reaction with 0.8 μL of 5% hydroxylamine (Wako Pure Chemical, Osaka, Japan). The TMT-labeled sample mixtures were separated into seven fractions by pipette-tip columns of C18 and strong cation exchange resins as previously reported [8], and then the fractions were stored at -80°C until LC-MS was performed. Synthetic peptides Stable synthetic isotope-labeled peptides with C-terminal 15N- and 13C-labeled arginine or lysine residue (isotopic purity > 99%) were purchased from JPT Peptide Technologies Gmbh (Berlin, Germany) (crude purity). Liquid chromatography-mass spectrometry in EV proteomics The samples for non-targeted proteomics were analyzed by hybrid quadrupole-Orbitrap mass spectrometers (Q-Exactive and Q-Exactive Plus, Thermo Fisher Scientific); the Q-Exactive and Q-Exactive Plus were used for mouse and human samples, respectively. Meanwhile, the samples for targeted proteomics were analyzed by a triple quadrupole mass spectrometer (TSQ-Vantage, Thermo Fisher Scientific). The Q-Exactive and Q-Exactive Plus were coupled with UltiMate™ 3000 RSLCnano ultra-high-performance liquid chromatography (UHPLC) System (Thermo Scientific) while the TSQ-Vantage was coupled with a Paradigm MS2 Nano-LC system (Michrom Bioresources, Auburn, CA, USA). Each of the nano-LC-MS systems was equipped with an HTC-PAL autosampler (CTC Analytics, Zwingen, Switzerland) with a trap column (0.075 × 20 mm, Acclaim PepMap RSLC Nano-Trap Column; Thermo Fisher Scientific) for sample injection and a nano-LC-MS interface (AMR, Tokyo, Japan) that ionized peptides using nano-electrospray ionization (ESI) in positive ion mode. Analytical columns, which were in-house columns with a spray needle, were packed with reverse-phase material ReproSil-Pur C18-AQ, 1.9-μm resin (Dr. Maisch, Ammerbuch-Entringen, Germany) into a self-pulled needle (column lengths were 150 mm, 300 mm, and 100 mm for Q-Exactive, Q-Exactive Plus, and TSQ-Vantage, respectively, while every inner diameter was 75 μm). The mobile phases consisted of buffers A (0.1% formic acid and 2% acetonitrile) and B (0.1% formic acid and 90% acetonitrile). The nano-LC gradient was ramped up from 5–35% buffer B for 95 min for Q-Exactive, 145 min for Q-Exactive Plus, and 75 min for TSQ-Vantage. The flow rates were set at 280 nL/min for Q-Exactive and Q-Exactive Plus and at 200 nL/min for TSQ-Vantage. The MS parameters of Q-Exactive and Q-Exactive Plus were the following: full MS scans were performed using an Orbitrap mass analyzer (scan range, 350–1800 m/z, with a resolution of 70,000 after accumulation of ions to a 3 × 106 target value). The 12 most intense precursor ions were selected and fragmented in the collision cell by higher-energy collisional dissociation with a maximum injection time of 120 ms, normalized collision energy of 30%, and a resolution of 35,000. The MS/MS ion-selection threshold was set to 5 × 104 counts. The isolation widths were 3.0 Da for Q-Exactive and 1.0 Da for Q-Exactive Plus, respectively.
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