Paracrine Anti-inflammatory Effects of Adipose Tissue-Derived Mesenchymal Stem Cells in Human Monocytes

[EN] The inflammatory process is an essential phenomenon in the induction of immune responses. Monocytes are key effector cells during the inflammatory process. A wide range of evidence indicates that mesenchymal stem cells from adipose tissue (ASC) are endowed with immunomodulatory capacity. However, the interaction between ASC and monocytes in the innate immune response is not well understood. The aim of this work was to investigate the possible paracrine anti-inflammatory effects of ASC in human monocytes. Monocytes were isolated from buffy coats and ASC from fat of non-obese patients. Conditioned medium (CM) from ASC in primary culture was used. We have assessed the effects of CM on the production of inflammatory mediators, degranulation, migration, phagocytic activity, senescence, oxidative stress, mitochondrial membrane potential and macrophage polarization. We have shown that ASC exert paracrine anti-inflammatory actions on human monocytes. CM significantly reduced the production of TNF alpha, NO and PGE2 and the activation of NF-kappa B. In addition, we observed a significant reduction of degranulation, phagocytic activity and their migratory ability in the presence of the chemokine CCL2. The senescence process and the production of oxidative stress and mitochondrial dysfunction were inhibited by CM which also reduced the production of TNF alpha by M1 macrophages while enhanced TGF beta 1 and IL-10 release by M2 macrophages. This study have demonstrated relevant interactions of ASC with human monocytes and macrophages which are key players of the innate immune response. Our results indicate that ASC secretome mediates the anti-inflammatory actions of these cells. This paracrine mechanism would limit the duration and amplitude of the inflammatory response.This work has been funded by grants SAF2017-85806-R (MINECO and FEDER), PROMETEOII/2014/071 (Generalitat Valenciana) and PRCEU-UCH20/11.Guillen Salazar, MI.; Platas, J.; Perez Del Caz, M.; Mirabet, V.; Alcaraz Tormo, MJ. (2018). Paracrine Anti-inflammatory Effects of Adipose Tissue-Derived Mesenchymal Stem Cells in Human Monocytes. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.00661S9Akahoshi, T., Wada, C., Endo, H., Hirota, K., Hosaka, S., Takagishi, K., … Matsushima, K. (1993). Expression of monocyte chemotactic and activating factor in rheumatoid arthritis. regulation of its production in synovial cells by interleukin-1 and tumor necrosis factor. Arthritis & Rheumatism, 36(6), 762-771. doi:10.1002/art.1780360605Akira, S., & Takeda, K. (2004). Toll-like receptor signalling. 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Diagnóstico no invasivo de la enfermedad vascular del injerto en receptores de un trasplante cardiaco

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018La enfermedad vascular del injerto (EVI) es junto con las neoplasias uno de los principales factores limitantes de supervivencia a partir del primer año del trasplante cardíaco. Consiste en la afectación de los vasos de los corazones implantados, incluyendo arterias, venas y microcirculación. Se caracteriza desde el punto de vista histológico por una hiperplasia de la íntima con proliferación de células musculares lisas, depósito de proteoglicanos, matriz extracelular y fibrosis, que lleva a la obliteración progresiva de la luz vascular. Aunque la etiologia de la EVI no es del todo bien conocida, se cree que la base de la enfermedad está en la disfunción endotelial causada por diferentes mecanismos inmunológicos y no inmunológicos. La denervación de los corazones implantados condiciona que la EVI sea un fenómeno habitualmente silente y que las manifestacions clínicas aparezcan en estadios avanzados de la enfermedad. El diagnóstico se realiza habitualmente con coronariografia y últimamente disponemos del TAC de arterias coronarias. Ambos procedimientos no pueden realizarse de forma repetitiva debido a la morbilidad asociada. Las opciones de tratamiento son limitadas. Si bien algunos inmunosupresores han demostrado ser eficaces en retrasar la aparición de EVI si se administran en los primeros meses tras el trasplante, el tratamiento farmacológico no ha mostrado ser útil en evitar la progresión de la EVI establecida; la revascularización quirúrgica a menudo no es técnicamente factible y los procedimientos de revascularización percutáneos no han demostrado hasta la actualidad impacto sobre la supervivencia. La única opción terapéutica definitiva es el retrasplante, cuya indicación se lleva a cabo de manera excepcional y en casos muy seleccionados. Teniendo en cuenta las limitaciones terapéuticas cuando la enfermedad está evolucionada sería fundamental prevenir su aparición y realizar un diagnóstico precoz. El objetivo de este estudio fue evaluar la utilidad de los biomarcadores sAXl, GAS6, Lp-PLA2, GDF-15, c-TnT-hs y del cociente Th1/Treg en el diagnóstico de la EVI y en la predicción de eventos clínicos en un grupo de 96 pacientes trasplantados de corazón. La determinación de los biomarcadores se realizó en un margen de 6 meses respecto la coronariografía o TAC de coronarias programado de acuerdo con el protocolo asistencial de nuestro centro. Los resultados muestran que la determinación de cTnT-hs y sAXL es útil en la detección de vasculopatía del injerto, siendo cTnT-hs el biomarcador con mayor poder predictivo independiente. El cociente Th1/Treg es el marcador que presenta mayor sensibilidad en el diagnóstico de EVI. Los niveles de cTnT-hs y sAXL se han asociado de manera independiente a mayor riesgo de eventos clínicos en pacientes receptores de trasplante cardiaco y las concentraciones de cTnT-hs son además predictoras de eventos clínicos en pacientes con EVI moderada-severa. Los biomarcadores GAS6, Lp-PLA2 y GDF-15 no han mostrado ser de utilidad en la detección de la EVI. En consecuencia la determinación de las concentraciones de cTnT-hs y del cociente de poblaciones linfocitarias Th1/Treg en el seguimiento de los receptores de trasplante cardíaco podría plantearse como alternativa no invasiva en el diagnóstico de la vasculopatía del injertoCardiac allograft vasculopathy (CAV) and neoplasms are the main limiting factors for long term survival after heart transplantation. CAV is characterized by intimal hyperplasia with proliferation of smooth muscle cells, deposition of proteoglycans, extracellular matrix and fibrosis which leads to progressive obliteration of the lumen. It involves all the vessels of the implanted hearts, including arteries, veins and microcirculation. It has been proposed that endothelial damage is a primary precipitating event in the pathogenesis of CAV. Different immunological and non-immunological mechanisms are responsable of the endothelial dysfunction. CAV is usually a silent phenomenon due to the denervation of the implanted heart. Clinical symptoms appear in advanced stages of the disease. The diagnosis is usually made with coronary angiography. In the last years coronary CT scan has also been used for the diagnosis. Both procedures can not be performed repeatedly because of the morbidity. Treatment options are limited. Although some immunosuppressive drugs have proven effective in delaying the onset of CAV given in the first months after transplantation, drug therapy has not shown to be useful in preventing the progression of established CAV. Surgical revascularization is often not technically feasible and percutaneous revascularization procedures have not demonstrated impact on survival. The definitive treatment is re-transplantation. However this option is available only for selected cases. Given the relatively poor prognosis of CAV, prevention and early diagnosis remain an important strategy. The aim of this study was to evaluate the usefulness of sAXL, GAS6, Lp-PLA2, GDF-15, c-TnT-hs biomarkers and Th1 / Treg lymphocyte populations ratio in the diagnosis of CAV and in predicting clinical events in a group of 96 heart transplanted patients. The results show that the determination of hs-cTnT and sAXL is useful in detecting cardíac allograft vasculopathy. The biomarker hs-cTnT has the more independent predictive power. The Th1 / Treg ratio is the marker that has higher sensitivity in the diagnosis of CAV. Levels of hs-cTnT and sAXL were independently associated with increased risk of clinical events in patients receiving heart transplants. hs-cTnT concentrations are also predictors of clinical events in patients with moderate to severe CAV. The GAS6, Lp-PLA2 and GDF-15 biomarkers have not been useful in the detection of CAV. The evaluation of hs-cTnT concentrations and the Th1 / Treg ratio could be a non-invasive method to identify heart transplant patients at high risk of develop cardiac allograft vasculopathy

Lasting effects of butyrate and low FM/FO diets on growth performance, blood haematology/biochemistry and molecular growth-related markers in gilthead sea bream (Sparus aurata)

Four isoproteic/isolipidic plant protein-based diets were formulated to assess the lasting effects of feed additives and low fish meal (FM) and fish oil (FO) diet formulations on gilthead sea bream growth performance. FM was included at 23% in the control diet (D1) and at 3% in the other three diets (D2, D3, D4). Added oil was either FO (D1) or a blend of vegetable oils replacing 58% (D2) and 84% (D3, D4 diets) of FO. A commercial sodium butyrate preparation (NOREL, 70-BP) was added to the D4 diet at 0.4%. Each diet was allocated to triplicate groups of juvenile fish fed to satiety over an 8-month feeding trial (May-December). All fish grew efficiently from 15. g of initial body weight to 296-320. g with an overall feed efficiency (FE) of 0.95-1.01, although fish fed D3 and D4 diets showed transient growth impairments over the course of the first four weeks of the trial. Data on biometric indexes, whole body composition, haematology and blood biochemistry revealed a strong effect of sampling time in fish sampled at mid-summer (August) and late autumn (December). In contrast, the diet effect was mostly reduced to a few blood parameters. Low inclusion levels of FM reduced plasma haemoglobin levels (D2, D3), but these effects were reversed by butyrate supplementation (D4). The same phenomena occurred for total cholesterol with the highest circulating concentration of choline and IGF-I in fish fed the D4 diet during their summer growth spurt. At the transcriptional level, gene expression profiling of liver and skeletal muscle with a PCR-array of 87 growth markers provided additional evidence for an overall well-growth condition in all of the experimental groups. Up to 73 genes were found at detectable levels in the liver tissue, but only 13 were differentially expressed. Likewise, 84 genes were actively transcribed in the skeletal muscle, but only nine were differentially expressed in at least one experimental group. Butyrate supplementation reversed the up-regulated expression of inflammatory cytokines (TNFα) and muscle markers of cellular morphogenesis and protein breakdown (CDH15, CAPN3, PSMA5, PSMB1, UBE2N) in the muscle of fish fed the extreme D3 diet. These results support the use of low FM/FO diets alone or supplemented with feed additives, which have the potential to improve or reverse metabolic steady-states. Statement of relevance: Butyrate effect on low fish meal/fish oil diets.This study was funded by the European Union (ARRAINA, FP7-KBBE-2011-5-288925, Advanced research initiatives for nutrition and aquaculture) projects. Additional funding was obtained from the Spanish MINECO (MI2-Fish, AGL2013-48560) and from Generalitat Valenciana (PROMETEO FASE II-2014/085).Peer Reviewe

Conditioned Media from Adipose-Tissue-Derived Mesenchymal Stem Cells Downregulate Degradative Mediators Induced by Interleukin-1β in Osteoarthritic Chondrocytes

Osteoarthritis (OA) is the most frequent joint disorder and an important cause of disability. Recent studies have shown the potential of adipose-tissue-derived mesenchymal stem cells (AD-MSC) for cartilage repair. We have investigated whether conditioned medium from AD-MSC (CM) may regulate in OA chondrocytes a number of key mediators involved in cartilage degeneration. CM enhanced type II collagen expression in OA chondrocytes while decreasing matrix metalloproteinase (MMP) activity in cell supernatants as well as the levels of MMP-3 and MMP-13 proteins and mRNA in OA chondrocytes stimulated with interleukin- (IL-) 1β. In addition, CM increased IL-10 levels and counteracted the stimulating effects of IL-1β on the production of tumor necrosis factor-α, IL-6, prostaglandin E2, and NO measured as nitrite and the mRNA expression of these cytokines, CCL-2, CCL-3, CCL-4, CCL-5, CCL-8, CCL-19, CCL-20, CXCL-1, CXCL-2, CXCL-3, CXCL-5, CXCL-8, cyclooxygenase-2, microsomal prostaglandin E synthase-1, and inducible NO synthase. These effects may be dependent on the inhibition of nuclear factor-κB activation by CM. Our data demonstrate the chondroprotective actions of CM and provide support for further studies of this approach in joint disease

Tissue-Specific Orchestration of Gilthead Sea Bream Resilience to Hypoxia and High Stocking Density

Two different O-2 levels (normoxia: 75-85% O-2 saturation; moderate hypoxia: 42-43% O-2 saturation) and stocking densities (LD: 9.5, and HD: 19 kg/m(3)) were assessed on gilthead sea bream (Sparus aurata) in a 3-week feeding trial. Reduced O-2 availability had a negative impact on feed intake and growth rates, which was exacerbated by HD despite of the improvement in feed efficiency. Blood physiological hallmarks disclosed the enhancement in O-2-carrying capacity in fish maintained under moderate hypoxia. This feature was related to a hypo-metabolic state to cope with a chronic and widespread environmental O-2 reduction, which was accompanied by a differential regulation of circulating cortisol and growth hormone levels. Customized PCR-arrays were used for the simultaneous gene expression profiling of 34-44 selected stress and metabolic markers in liver, white skeletal muscle, heart, and blood cells. The number of differentially expressed genes ranged between 22 and 19 in liver, heart, and white skeletal muscle to 5 in total blood cells. Partial Least-Squares Discriminant Analysis (PLS-DA) explained [R2Y(cum)] and predicted [Q2Y(cum)] up to 95 and 65% of total variance, respectively. The first component (R2Y = 0.2889) gathered fish on the basis of O-2 availability, and liver and cardiac genes on the category of energy sensing and oxidative metabolism (cs, hif-1 alpha, pgc1 alpha, pgc1 beta, sirts 1-2-4-5-6-7), antioxidant defense and tissue repair (prdx5, sod2, mortalin, gpx4, gr, grp-170, and prdx3) and oxidative phosphorylation (nd2, nd5, and coxi) highly contributed to this separation. The second component (R2Y = 0.2927) differentiated normoxic fish at different stocking densities, and the white muscle clearly promoted this separation by a high over-representation of genes related to GH/IGF system (ghr-i, igfbp6b, igfbp5b, insr, igfbp3, and igf-i). The third component (R2Y = 0.2542) discriminated the effect of stocking density in fish exposed to moderate hypoxia by means of hepatic fatty acid desaturases (fads2, scd1a, and scd1b) and muscle markers of fatty acid oxidation (cpt1a). All these findings disclose the different contribution of analyzed tissues (liver >= heart > muscle > blood) and specific genes to the hypoxic- and crowding stress-mediated responses. This study will contribute to better explain and understand the different stress resilience of farmed fish across individuals and species

Targeting the Mild-Hypoxia Driving Force for Metabolic and Muscle Transcriptional Reprogramming of Gilthead Sea Bream (Sparus aurata) Juveniles

Reduced oxygen availability generates a number of adaptive features across all the animal kingdom, and the goal of this study was targeting the mild-hypoxia driving force for metabolic and muscle transcriptional reprogramming of gilthead sea bream juveniles. Attention was focused on blood metabolic and muscle transcriptomic landmarks before and after exhaustive exercise. Our results after mild-hypoxia conditioning highlighted an increased contribution of lipid metabolism to whole energy supply to preserve the aerobic energy production, a better swimming performance regardless of changes in feed intake, as well as reduced protein turnover and improved anaerobic fitness with the restoration of normoxia. On-growing juveniles of gilthead sea bream were acclimated for 45 days to mild-hypoxia (M-HYP, 40-60% O-2 saturation), whereas normoxic fish (85-90% O-2 saturation) constituted two different groups, depending on if they were fed to visual satiety (control fish) or pair-fed to M-HYP fish. Following the hypoxia conditioning period, all fish were maintained in normoxia and continued to be fed until visual satiation for 3 weeks. The time course of hypoxia-induced changes was assessed by changes in blood metabolic landmarks and muscle transcriptomics before and after exhaustive exercise in a swim tunnel respirometer. In M-HYP fish, our results highlighted a higher contribution of aerobic metabolism to whole energy supply, shifting towards a higher anaerobic fitness following normoxia restoration. Despite these changes in substrate preference, M-HYP fish shared a persistent improvement in swimming performance with a higher critical speed at exercise exhaustion. The machinery of muscle contraction and protein synthesis and breakdown was also largely altered by mild-hypoxia conditioning, contributing this metabolic re-adjustment to the positive regulation of locomotion and to the catch-up growth response during the normoxia recovery period. Altogether, these results reinforce the presence of large phenotypic plasticity in gilthead sea bream, and highlights mild-hypoxia as a promising prophylactic measure to prepare these fish for predictable stressful events.This work was financially supported by a grant from the European Commission of the European Union under the Horizon 2020 research infrastructure project AQUAEXCEL2020 (652831) to J.P-S. Additional funding was obtained by a Spanish MICINN project (Bream-AquaINTECH, RTI2018-094128-B-I00). J.A.M.-S. received a Postdoctoral Research Fellowship (Juan de la Cierva-Formacion, Reference FJCI-2014-20,161)

Skin mucus of gilthead sea bream (sparus aurata l.). protein mapping and regulation in chronically stressed fish

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Growth differentiation factor 15 as mortality predictor in heart failure patients with non-reduced ejection fraction

Altres ajuts: This study was supported by Fundació d'Investigació Sant Pau (G-60136934).The prognostic value of biomarkers in patients with heart failure (HF) and mid-range (HFmrEF) or preserved ejection fraction (HFpEF) has not been widely addressed. The aim of this study was to assess whether the prognostic value of growth differentiation factor 15 (GDF-15) is superior to that of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with HFmrEF or HFpEF. Heart failure patients with either HFpEF or HFmrEF were included in the study. During their first visit to the HF unit, serum samples were obtained and stored for later assessment of GDF-15 and NT-proBNP concentrations. Patients were followed up by the HF unit. The main endpoint was all-cause mortality. A total of 311 patients, 90 (29%) HFmrEF and 221 (71%) HFpEF, were included. Mean age was 72 ± 13 years, and 136 (44%) were women. No differences were found in GDF-15 or NT-proBNP concentrations between both HF groups. During a median follow-up of 15 months (Q1-Q3: 9-30 months), 98 patients (32%) died, most (71%) of cardiovascular causes. Patients who died had higher median concentrations of GDF-15 (4085 vs. 2270 ng/L, P 65 years (P 4330 ng/L), and survival curves were evaluated using the Kaplan-Meier technique. Patients in the highest tertile had the poorest 5 year survival, at 16%, whereas the lowest tertile had the best survival, of 78% (P < 0.001). Growth differentiation factor 15 was superior to NT-proBNP for assessing prognosis in patients with HFpEF and HFmrEF. GDF-15 emerges as a strong, independent biomarker for identifying HFmrEF and HFpEF patients with worse prognosis

Mobile health to improve adherence and patient experience in heart transplantation recipients : The mheart trial

Altres ajuts: Amgen SL, General Pharmaceutical Council of Barcelona i Astellas Pharma USBackground:Non-adherence after heart transplantation (HTx) is a significant problem. The main objective of this study was to evaluate if a mHealth strategy is more effective than standard care in improving adherence and patients' experience in heart transplant recipients. Methods: This was a single-center, randomized controlled trial (RCT) in adult recipients >1.5 years post-HTx. Participants were randomized to standard care (control group) or to the mHeart Strategy (intervention group). For patients randomized to the mHeart strategy, multifaceted theory-based interventions were provided during the study period to optimize therapy management using the mHeart mobile application. Patient experience regarding their medication regimens were evaluated in a face-to-face interview. Medication adherence was assessed by performing self-reported questionnaires. A composite adherence score that included the SMAQ questionnaire, the coefficient of variation of drug levels and missing visits was also reported. Results: A total of 134 HTx recipients were randomized (intervention N = 71; control N = 63). Mean follow-up was 1.6 (SD 0.6) years. Improvement in adherence from baseline was significantly higher in the intervention group versus the control group according to the SMAQ questionnaire (85% vs. 46%, OR = 6.7 (2.9; 15.8), p-value < 0.001) and the composite score (51% vs. 23%, OR = 0.3 (0.1; 0.6), p-value = 0.001). Patients' experiences with their drug therapy including knowledge of their medication timing intakes (p-value = 0.019) and the drug indications or uses that they remembered (p-value = 0.003) significantly improved in the intervention versus the control group. Conclusions: In our study, the mHealth-based strategy significantly improved adherence and patient beliefs regarding their medication regimens among the HTx population. The mHeart mobile application was used as a feasible tool for providing long-term, tailor-made interventions to HTx recipients to improve the goals assessed

Heart transplantation using allografts from older donors: multicenter study results

33rd Annual Meeting and Scientific Session of the International Society for Heart and Lung Transplantation, April 24–27, 2013, Montreal, Canada.[Abstract] Background. The lengthy waiting time for heart transplantation is associated with high mortality. To increase the number of donors, new strategies have emerged, including the use of hearts from donors ≥50 years old. However, this practice remains controversial. The aim of this study was to evaluate outcomes of patients receiving heart transplants from older donors. Methods. We retrospectively analyzed 2,102 consecutive heart transplants in 8 Spanish hospitals from 1998 to 2010. Acute and overall mortality were compared in patients with grafts from donors ≥50 years old versus grafts from younger donors. Results. There were 1,758 (84%) transplanted grafts from donors < 50 years old (Group I) and 344 (16%) from donors ≥50 years old (Group II). Group I had more male donors than Group II (71% vs 57%, p = 0.0001). The incidence of cardiovascular risk factors was higher in older donors. There were no differences in acute mortality or acute rejection episodes between the 2 groups. Global mortality was higher in Group II (rate ratio, 1.40; 95% confidence interval, 1.18–1.67; p = 0.001) than in Group I. After adjusting for donor cause of death, donor smoking history, recipient age, induction therapy, and cyclosporine therapy, the differences lost significance. Group II had a higher incidence of coronary allograft vasculopathy at 5 years (rate ratio, 1.67; 95% confidence interval, 1.22–2.27; p = 0.001). Conclusions. There were no differences in acute and overall mortality after adjusting for confounding factors. However, there was a midterm increased risk of coronary allograft vasculopathy with the use of older donors. Careful selection of recipients and close monitoring of coronary allograft vasculopathy are warranted in these patients.Instituto de Salud Carlos III; RD12/0042/00