Biodonostia Health Research Institute

Donostia / San Sebastián, Spain

Biodonostia Health Research Institute

Donostia / San Sebastián, Spain
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Saenz-Cuesta M.,Biodonostia Health Research Institute | Osorio-Querejeta I.,Biodonostia Health Research Institute | Otaegui D.,Biodonostia Health Research Institute
Frontiers in Cellular Neuroscience | Year: 2014

Extracellular vesicles (EVs) are membrane-bound particles secreted by almost all cell types. They are classified depending on their biogenesis and size into exosomes and microvesicles or according to their cell origin. EVs play a role in cell-to-cell communication, including contact-free cell synapsis, carrying active membrane proteins, lipids, and genetic material both inside the particle and on their surface. They have been related to several physiological and pathological conditions. In particular, increasing concentrations of EVs have been found in many autoimmune diseases including multiple sclerosis (MS). MS is a central nervous system (CNS) demyelinating disease characterized by relapsing of symptoms followed by periods of remission. Close interaction between endothelial cells, leukocytes, monocytes, and cells from CNS is crucial for the development of MS. This review summarizes the pathological role of EVs in MS and the relationship of EVs with clinical characteristics, therapy, and biomarkers of the disease. © 2014 Sáenz-Cuesta, Osorio-Querejeta and Otaegui.

Zufiria M.,Biodonostia Health Research Institute | Zufiria M.,CIBER ISCIII | Gil-Bea F.J.,Biodonostia Health Research Institute | Gil-Bea F.J.,CIBER ISCIII | And 16 more authors.
Progress in Neurobiology | Year: 2016

The scientific scenario of amyotrophic lateral sclerosis (ALS) has dramatically changed since TDP-43 aggregates were discovered in 2006 as the main component of the neuronal inclusions seen in the disease, and more recently, when the implication of C9ORF72 expansion in familial and sporadic cases of ALS and frontotemporal dementia was confirmed. These discoveries have enlarged an extense list of genes implicated in different cellular processes such as RNA processing or autophagia among others and have broaden the putative molecular targets of the disease. Some of ALS-related genes such as TARDBP or SOD1 among others have important roles in the regulation of glucose and fatty acids metabolism, so that an impairment of fatty acids (FA) consumption and ketogenic deficits during exercise in ALS patients would connect the physiopathology with some of the more intriguing epidemiological traits of the disease. The current understanding of ALS as part of a continuum with other neurodegenerative diseases and a crossroads between genetic, neurometabolic and environmental factors represent a fascinating model of interaction that could be translated to other neurodegenerative diseases. In this review we summarize the most relevant data obtained in the ten last years and the key lines for future research in ALS. © 2016 Elsevier Ltd.

Ibero-Baraibar I.,University of Navarra | Navas-Carretero S.,University of Navarra | Navas-Carretero S.,CIBER ISCIII | Abete I.,Biodonostia Health Research Institute | And 4 more authors.
Clinical Nutrition | Year: 2015

The aim of this study is to further clarify the role of plasma 25(OH)D concentration after a weight-lowering nutritional intervention on body composition, blood pressure and inflammatory biomarkers in overweight/obese middle-aged subjects. Methods: This longitudinal research encompassed a total of 50 subjects [57.26 (5.24) year], who were under a 15% energy restricted diet for 4 weeks. Anthropometric and body composition variables, blood routine, inflammatory markers as well as 25(OH)D were analysed. Results: Circulating 25(OH)D levels [12.13(±17.61%)] increased while anthropometric, body composition, routine blood markers as well as the concentration of TNF-α, C-reactive protein and Lp-PLA2 were significantly reduced after the intervention. Multiple linear regression analyses evidenced that δ25(OH)D increase was linked to the decrease in weight, adiposity, SBP and IL-6 levels. Moreover, a relationship was found between δ25(OH)D, δfat mass (. r = -0.405; p = 0.007), δSBP (r = -0.355; p = 0.021) and δIL-6 (r = -0.386; p = 0.014). On the other hand, a higher increase in 25(OH)D was accompanied by reductions in weight, BMI, SBP, IL-6 and an increase in bone mineral concentration (p < 0.05). Interestingly, higher levels of 25(OH)D at the endpoint, showed a significantly higher decrease in weight, BMI and total fat mass. Conclusions: The increase in plasma 25(OH)D level is linked with the decrease in SBP and adiposity in middle-aged subjects after a weight-loss intervention. Therefore, 25(OH)D assessment is a potential marker to be accounted in metabolic measures related to blood pressure, adiposity and inflammation in obesity management. Trial registration: (NCT01596309). © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

De La Iglesia R.,University of Navarra | Lopez-Legarrea P.,University of Navarra | Abete I.,BioDonostia Health Research Institute | Bondia-Pons I.,University of Navarra | And 7 more authors.
British Journal of Nutrition | Year: 2014

The long-term effects of dietary strategies designed to combat the metabolic syndrome (MetS) remain unknown. The present study evaluated the effectiveness of a new dietary strategy based on macronutrient distribution, antioxidant capacity and meal frequency (MEtabolic Syndrome REduction in NAvarra (RESMENA) diet) for the treatment of the MetS when compared with the American Heart Association guidelines, used as Control. Subjects with the MetS (fifty-two men and forty-one women, age 49 (se 1) years, BMI 36·11 (se 0·5)A kg/m2) were randomly assigned to one of two dietary groups. After a 2-month nutritional-learning intervention period, during which a nutritional assessment was made for the participants every 15A d, a 4-month self-control period began. No significant differences were found between the groups concerning anthropometry, but only the RESMENA group exhibited a significant decrease in body weight (A-A 1·7A %; P=A 0·018), BMI (A-A 1·7A %; P=A 0·019), waist circumference (A-A 1·8A %; P=A 0·021), waist:hip ratio (A-A 1·4A %; P=A 0·035) and android fat mass (A-A 6·9A %; P=A 0·008). The RESMENA group exhibited a significant decrease in alanine aminotransferase and aspartate aminotransferase (AST) concentrations (A-A 26·8A %; P=A 0·008 and-A 14·0A %; P=A 0·018, respectively), while the Control group exhibited a significant increase in glucose (7·9A %; P=A 0·011), AST (11·3A %; P=A 0·045) and uric acid (9·0A %; P

News Article | February 15, 2017

RICHLAND, Wash. - Patients with inflammatory bowel disease are more likely to see dramatic shifts in the make-up of the community of microbes in their gut than healthy people, according to the results of a study published online Feb. 13 in Nature Microbiology. While scientists have known that there are differences in the bacteria and other microbes that make up the gut microbiome in IBD patients, this is one of the largest studies to watch the microbiome over a period of time. The findings indicate that the biggest difference in the microbiome of patients is the way it fluctuates - what the researchers call "volatile dysbiosis." The results help physicians and scientists understand the disease more fully and potentially offer new ways to track the disease and monitor patients. The findings come from a team of scientists from Sweden, Spain, Germany and the United States. Janet Jansson of the Department of Energy's Pacific Northwest National Laboratory is the corresponding author of the paper. "We know that there are some key beneficial microbes that are lower in number in people with inflammatory bowel disease. Sometimes the differences are quite substantial," said Jansson. "Our latest results show that patients affected by this condition also have a much less stable gut microbiome than healthy people." IBD encompasses a group of diseases where the body's immune system attacks microbes in the gut, causing chronic inflammation in the digestive tract and giving rise to symptoms such as diarrhea, abdominal pain, and other unpleasant and sometimes life-threatening symptoms. Many patients have periods when the condition causes minor problems, then flares up and becomes more serious. Medications such as powerful anti-inflammatory drugs and steroids are common treatments, and surgery is an option in severe cases. Scientists know that there are some differences in the microbiomes of patients with IBD patients compared to healthy people - for instance, patients generally have fewer beneficial microbes and they are more likely to carry bacteria such as Enterobacteriaceae and E. coli. But questions remain. "It's important to know not just what microbes are present, but also to understand how the microbial community changes as patients' symptoms improve or worsen over time," said author Colin Brislawn, a PNNL scientist who contributed to the statistical analysis. "We explored the dynamic nature of the disease as it relates to the dynamic nature of the human gut microbiome." To do the study, gastroenterologist Jonas Halfvarson of Örebro University in Sweden and colleagues studied 137 people for two years. Participants included patients with ulcerative colitis, colonic Crohn's disease, ileal Crohn's disease, and healthy controls. Physicians collected fecal samples from patients every three months for up to two years and monitored patients' symptoms. Overall 683 fecal samples were collected. Scientists then used genetic sequencing technology to identify the microbes in the samples. The team found that in healthy people, the gut microbial community is much more consistent over time than in patients with IBD. Patients with IBD have dramatic shifts in their microbiomes, with some bacteria disappearing almost completely at times - something that rarely happened in the healthy people studied. In some IBD patients, more than half their microbiome was displaced by other microbes in just a few months. The biggest swings were seen in patients with ileal Crohn's disease who had had part of their intestine removed to alleviate their symptoms. The scientists also noted that changes in medication to treat the disease affected the microbiome; for example, patients who had taken steroids as part of treatment had more fluctuations in their microbiome than patients who had not. And patients who were experiencing a flare-up in their symptoms were more likely to have dramatic fluctuations in their microbiome. The scientists say the findings might one day contribute to the diagnosis of patients or allow physicians to follow the course of the disease and track the effectiveness of medication in patients more closely. "The results are an important step in our aim to understand how the microbiome relates to the dynamics of inflammatory bowel disease," said Halfvarson. "Ultimately, manipulation of the microbiome, aiming to mimic the situation and the trajectories of healthy individuals, might become an attractive treatment strategy to maintain IBD patients in remission, especially if immunosuppressants such as corticosteroids can be avoided." The study includes authors from PNNL, Örebro University in Sweden, the University of California at San Diego, the Max Planck Institute in Germany, the Karolinska Institute in Sweden, the Biodonostia Health Research Institute in Spain, and Juniata College in Pennsylvania. The study was funded primarily by the National Institutes of Health. Additional support came from the Crohn's and Colitis Foundation of America, the Örebro University Hospital Research Foundation, the Swedish Research Council, and other organizations. Jonas Halfvarson, Colin J. Brislawn, Regina Lamendella, Yoshiki Vázquez-Baeza, William A. Walters, Lisa M. Bramer, Mauro D'Amato, Ferdinando Bonfiglio, Daniel McDonald, Antonio Gonzalez, Erin E. McClure, Mitchell F. Dunklebarger, Rob Knight and Janet K. Jansson, Dynamics of the human gut microbiome in inflammatory bowel disease, Nature Microbiology, Feb. 13, 2017, http://dx. .

Moore D.L.,University of Zürich | Pilz G.A.,University of Zürich | Arauzo-Bravo M.J.,Biodonostia Health Research Institute | Arauzo-Bravo M.J.,Ikerbasque | And 2 more authors.
Science | Year: 2015

Throughout life, neural stem cells (NSCs) generate neurons in the mammalian brain. Using photobleaching experiments, we found that during cell division in vitro and within the developing mouse forebrain, NSCs generate a lateral diffusion barrier in the membrane of the endoplasmic reticulum, thereby promoting asymmetric segregation of cellular components. The diffusion barrier weakens with age and in response to impairment of lamin-associated nuclear envelope constituents.Weakening of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Damaged proteins are asymmetrically inherited by the nonstem daughter cell in embryonic and young adult NSC divisions, whereas in the older adult brain, damaged proteins are more symmetrically distributed between progeny. Thus, these data identify a mechanism of how damage that accumulates with age is asymmetrically distributed during somatic stem cell division.

Kim J.S.,Konkuk University | Choi H.W.,Konkuk University | Arauzo-Bravo M.J.,Biodonostia Health Research Institute | Arauzo-Bravo M.J.,Ikerbasque | And 2 more authors.
Journal of Cell Science | Year: 2015

Direct reprogramming of somatic cells to pluripotent stem cells entails the obliteration of somatic cell memory and the reestablishment of epigenetic events. Induced pluripotent stem cells (iPSCs) have been created by reprogramming somatic cells through the transduction of reprogramming factors. During cell reprogramming, female somatic cells must overcome at least one more barrier than male somatic cells in order to enter a pluripotent state, as they must reactivate an inactive X chromosome (Xi). In this study, we investigated whether the sex of somatic cells affects reprogramming efficiency, differentiation potential and the posttranscriptional processing of Xist RNA after reprogramming. There were no differences between male and female iPSCs with respect to reprogramming efficiency or their differentiation potential in vivo. However, reactivating Xi took longer than reactivating pluripotencyrelated genes. We also found that direct reprogramming leads to gender-appropriate post-transcriptional reprogramming - like male embryonic stem cells (ESCs), male iPSCs expressed only the long Xist isoform, whereas female iPSCs, like female ESCs, expressed both the long and short isoforms. © 2015. Published by The Company of Biologists Ltd.

Gerovska D.,Biodonostia Health Research Institute | Arauzo-Bravo M.J.,Biodonostia Health Research Institute | Arauzo-Bravo M.J.,Ikerbasque
Molecular Human Reproduction | Year: 2015

Study hypothesis: Does primordial germ cell (PGC) activation start before mouse embryo implantation, and does the possible regulation of the DNA (cytosine-5-)-methyltransferase 3-like (Dnmt3l) by transcription factor AP-2, gamma (TCFAP2C) have a role in this activation and in the primitive endoderm (PE)-epiblast (EPI) lineage specification? Study finding: A burst of expression of PGC markers, such as Dppa3/Stella, Ifitm2/Fragilis, Fkbp6 and Prdm4, is observed from embryonic day (E) 3.25, and some of them, together with the late germ cell markers Zp3, Mcf2 and Morc1,become restricted to the EPI subpopulation at E4.5, while the dynamics analysis of the PE-EPI transitions in the single-cell data suggests that TCFAP2C transitorily represses Dnmt3l in EPI cells at E3.5 and such repression is withdrawn with reactivation of Dnmt3l expression in PE and EPI cells at E4.5. What is known already: In the mouse preimplantation embryo, cells with the same phenotype take different fates based on the orchestration between topological clues (cell polarity, positional history and division orientation) and gene regulatory rules (at transcriptomics and epigenomics level), prompting the proposal of positional, stochastic and combined models explaining the specification mechanism. PGC specification starts at E6.0-6.5 post-implantation. In view of the important role of DNA methylation in developmental events, the cross-talk between some transcription factors and DNA methyltransferases is of particular relevance. TCFAP2C has a CpG DNA methylation motif that is not methylated in pluripotent cells and that could potentially bind on DNMT3L, the stimulatory DNA methyltransferase co-factor that assists in the process of de novo DNA methylation. Chromatin-immunoprecipitation analysis has demonstrated that Dnmt3l is indeed a target of TCFAP2C. Study design, samples/materials, methods: We aimed to assess the timing of early preimplantation events and to understand better the segregation of the inner cell mass (ICM) into PE and EPI. We designed a single-cell transcriptomics dynamics computational study to identify markers of the PE-EPI bifurcation in ICM cells through searching for statistically significant (using the Student's t-test method) differently expressed genes (DEGs) between PE and EPI cells from E3.5 to E4.5. The DEGs common for E3.5 and E4.5 were used as the markers defining the steady states. We collected microarray and next-generation sequencing transcriptomics data from public databases from bulk populations and single cells from mice at E3.25, E3.5 and E4.5. The results are based on three independent single-cell transcriptomics data sets, with a fold change of 3 and P-value <0.01 for the DEG selection. Main results and the role of chance: The dynamics analysis revealed new transitory E3.5 and steady PE and EPI markers. Among the transitory E3.5 PE markers (Dnmt3l, Dusp4, Cpne8, Akap13, Dcaf12l1, Aaed1, B4galt6, BC100530, Rnpc3, Tfpi, Lgalsl, Ckap4 and Fbxl20), several (Dusp4, Akap13, Cpn8, Dcaf12l1 and Tfpi) are related to the extracellular regulated kinase pathway. We also identified new transitory E3.5 EPI markers (Sgk1, Mal, Ubxn2a, Atg16l2, Gm13102, Tcfap2c, Hexb, Slc1a1, Svip, Liph and Mier3), six new stable PE markers (Sdc4, Cpn1, Dkk1, Havcr1, F2r/Par1 and Slc7a6os) as well as three new stable EPI markers (Zp3, Mcf2 and Hexb), which are known to be late stage germ cell markers. We found that mouse PGC marker activation starts at least at E3.25 preimplantation. The transcriptomics dynamics analyses support the regulation of Dnmt3l expression by TCFAP2C. Limitations, reasons for caution: Since the regulation of Dnmt3l by TCFAP2C is based on computational prediction of DNA methylation motifs, Chip-Seq and transcriptomics data, functional studies are required to validate this result. Wider implications of thefindings: We identified a collection of previously undescribed E3.5-specific PE and EPI markers, and new steady PE and EPI markers. Identification of these genes, many of which encode cell membrane proteins, will facilitate the isolation and characterization of early PE and EPI populations. Since it is so well established in the literature that mouse PGC specification is a post-implantation event, it was surprising for us to see activation of PGC markers as early as E3.25 preimplantation, and identify the newly found steady EPI markers as late germ cell markers. The discovery of such early activation of PGC markers has important implications in the derivation of germ cells from pluripotent cells (embryonic stem cells or induced pluripotent stem cells), since the initial stages of such derivation resemble early development. The early activation of PGC markers points out the difficulty of separating PGC cells from pluripotent populations. Collectively, our results suggest that the combining of the precision of single-cell omics data with dynamic analysis of time-series data can establish the timing of some developmental stages as earlier than previously thought. Large-scale data: Not applicable. Study funding and competing interest(s): This work was supported by grants DFG15/14 and DFG15/020 from Diputación Foral de Gipuzkoa (Spain), and grant II14/00016 from I + D + I National Plan 2013-2016 (Spain) and FEDER funds. The authors declare no conflict of interest. © The Author 2015.

Kim S.M.,Konkuk University | Flasskamp H.,Max Planck Institute for Molecular Biomedicine | Hermann A.,TU Dresden | Arauzo-Bravo M.J.,Max Planck Institute for Molecular Biomedicine | And 11 more authors.
Nature Protocols | Year: 2014

Terminally differentiated cells can be directly converted into different types of somatic cells by using defined factors, thus circumventing the pluripotent state. However, low reprogramming efficiency, along with the absence of proliferation of some somatic cell types, makes it difficult to generate large numbers of cells with this method. Here we describe a protocol to directly convert mouse fibroblasts into self-renewing induced neural stem cells (iNSCs) that can be expanded in vitro, thereby overcoming the limitations associated with low reprogramming efficiency. The four transcription factors required for direct conversion into iNSCs (Sox2, Klf4, Myc (also known as c-Myc) and Pou3f4 (also known as Brn4)) do not generate a pluripotent cell state, and thus the risk for tumor formation after transplantation is reduced. By following the current protocol, iNSCs are observed 4-5 weeks after transduction. Two additional months are required to establish clonal iNSC cell lines that exhibit retroviral transgene silencing and that differentiate into neurons, astrocytes and oligodendrocytes. © 2014 Nature America, Inc. All rights reserved.

Sugawa F.,Max Planck Institute for Molecular Biomedicine | Arauzo-Bravo M.J.,Max Planck Institute for Molecular Biomedicine | Arauzo-Bravo M.J.,Biodonostia Health Research Institute | Arauzo-Bravo M.J.,Ikerbasque | And 9 more authors.
EMBO Journal | Year: 2015

Primordial germ cells (PGCs) develop only into sperm and oocytes in vivo. The molecular mechanisms underlying human PGC specification are poorly understood due to inaccessibility of cell materials and lack of in vitro models for tracking the earliest stages of germ cell development. Here, we describe a defined and stepwise differentiation system for inducing pre-migratory PGC-like cells (PGCLCs) from human pluripotent stem cells (PSCs). In response to cytokines, PSCs differentiate first into a heterogeneous mesoderm-like cell population and then into PGCLCs, which exhibit minimal PRDM14 expression. PGC specification in humans is similar to the murine process, with the sequential activation of mesodermal and PGC genes, and the suppression of neural induction and of de novo DNA methylation, suggesting that human PGC formation is induced via epigenesis, the process of germ cell specification via inductive signals from surrounding somatic cells. This study demonstrates that PGC commitment in humans shares key features with that of the mouse, but also highlights key differences, including transcriptional regulation during the early stage of human PGC development (3-6 weeks). A more comprehensive understanding of human germ cell development may lead to methodology for successfully generating PSC-derived gametes for reproductive medicine. © 2015 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

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