1,721,018 research outputs found
Local administration of porcine immunomodulatory, chemotactic and angiogenic extracellular vesicles using engineered cardiac scaffolds for myocardial infarction
Full text linkAltres ajuts: This work was supported in part by grants from Fundació la Marató de TV3 (201516-10, 201502-30).Altres ajuts: PERIS/SLT002-16-00234Altres ajuts: PERIS/SLT002-16-00209The administration of extracellular vesicles (EV) from mesenchymal stromal cells (MSC) is a promising cell-free nanotherapy for tissue repair after myocardial infarction (MI). However, the optimal EV delivery strategy remains undetermined. Here, we designed a novel MSC-EV delivery, using 3D scaffolds engineered from decellularised cardiac tissue as a cell-free product for cardiac repair. EV from porcine cardiac adipose tissue-derived MSC (cATMSC) were purified by size exclusion chromatography (SEC), functionally analysed and loaded to scaffolds. cATMSC-EV markedly reduced polyclonal proliferation and pro-inflammatory cytokines production (IFNγ, TNFα, IL12p40) of allogeneic PBMC. Moreover, cATMSC-EV recruited outgrowth endothelial cells (OEC) and allogeneic MSC, and promoted angiogenesis. Fluorescently labelled cATMSC-EV were mixed with peptide hydrogel, and were successfully retained in decellularised scaffolds. Then, cATMSC-EV-embedded pericardial scaffolds were administered in vivo over the ischemic myocardium in a pig model of MI. Six days from implantation, the engineered scaffold efficiently integrated into the post-infarcted myocardium. cATMSC-EV were detected within the construct and MI core, and promoted an increase in vascular density and reduction in macrophage and T cell infiltration within the damaged myocardium. The confined administration of multifunctional MSC-EV within an engineered pericardial scaffold ensures local EV dosage and release, and generates a vascularised bioactive niche for cell recruitment, engraftment and modulation of short-term post-ischemic inflammation
Immunomodulation by mesenchymal stem cells for myocardial regeneration: cellular mechanisms and extracellular vesicles
Full text linkLes respostes immunològiques descontrolades obstaculitzen la regeneració de teixits danyats i el transplantament d’òrgans, i provoquen al·lèrgies i trastorns autoimmunitaris, causant morbiditat i mortalitat. Un d’aquests casos és el dany causat per la isquèmia-reperfusió (IRI) que ocorre en un infart de miocardi (MI). El IRI provoca una intensa inflamació, que, tot i ser necessària per iniciar la neteja de les cèl·lules mortes i activar els mecanismes de reparació cardíaca, cal aturar a temps per minimitzar el dany tissular post-MI i el remodelat miocardíac, que pot esdevenir en insuficiència cardíaca. En aquest context, les cèl·lules mare mesenquimals (MSCs) es postulen com una estratègia terapèutica prometedora per contrarestar aquestes respostes immunitàries no desitjades. Tot i tenir una curta vida després de la seva administració in vivo, les MSCs han demostrat ser beneficioses tant per al tractament de patologies d’arrel immunitària com per la promoció de la regeneració cardíaca en models preclínics de MI. L’objectiu d’aquesta tesi és doncs desxifrar quins són els mecanismes cel·lulars i paracrins que capaciten les MSCs per tenir un efecte immunosupressor i regenerador a llarg termini. La hipòtesi de treball és que les MSCs aconsegueixen la generació d’ambients reguladors amb un efecte durador mitjançant la modulació de les cèl·lules immunes de l’hoste, mentre que la secreció de factors paracrins els permet tenir una acció deslocalitzada i promoure alhora la regeneració endògena. Amb aquesta idea, en primer lloc hem estudiat la influència de les MSCs en la biologia dels monòcits, com a part de la immunitat innata. Hem confirmat el paper de les MSCs en la modulació dels monòcits vers una polarització reparadora M2, descrivint la activitat enzimàtica adenosinèrgica extracel·lular com una funcionalitat afegida. Els monòcits condicionats amb MSCs mantenen l’expressió de CD39, mentre que s’indueix la de CD73, responsable de la hidròlisi seqüencial de ATP/ADP a AMP i adenosina, respectivament, per passar de l’ambient pro-inflamatori promogut per ATP extracel·lular a la regulació anti-inflamatòria de l’adenosina. Per altra banda, les MSCs també modulen la resposta immune adaptativa, ja que hem observat la supressió de la proliferació policlonal i resposta inflamatòria de limfòcits al·logènics. Pel que fa a la activitat paracrina de les MSCs, hem identificat les vesícules extracel·lulars (EVs) com un des components immunosupressors secretats per les MSCs. Concretament, hem demostrat la importància d’un aïllament acurat de les MSC-EVs per evidenciar el seu potencial immunosupressor, que es pot aconseguir eficientment mitjançant la cromatografia d’exclusió per mida (SEC). Finalment, aquest coneixement ens ha permès dissenyar un nou constructe format per una matriu biocompatible 3D de bioenginyeria cardíaca integrada amb MSC-EVs per al tractament local del MI i promoure regeneració cardíaca. La validació in vitro d’aquest constructe va reforçar la importància de la secreció de EVs com un mecanisme de les MSCs per modular el sistema immunitari i fomentar els processos de reparació endògena, donat que les MSC-EVs poden reclutar activament cèl·lules pro-regeneradores. Els nostres resultats aporten nous mecanismes a aprofitar per generar nous productes terapèutics dirigits, innovadors i fàcilment translacionals.Exacerbated immune responses hamper regeneration of injured tissues and organ transplantation, and lead to allergies and autoimmune disorders causing morbidity and mortality. One of these scenarios is the ischaemia-reperfusion injury (IRI) occurring upon myocardial infarction (MI). IRI triggers an intense inflammatory response that is initially necessary for dead cell clearance and the induction of cardiac repair, but its timely suppression is critical to minimize post-MI tissue damage, cardiac remodelling and ultimately, heart failure. In this context, mesenchymal stem cells (MSCs) are promising as a therapeutic strategy to counteract such unwanted immune responses, as MSC administration has a beneficial effect for the treatment of immune-related disorders and promote cardiac repair in preclinical models of MI, albeit their short lifespan after in vivo infusion. The aim of this thesis is to decipher the cellular and paracrine mechanisms that would help explain MSCs’ long-lasting immunosuppressive and regenerative effects. The working hypothesis is that these could be mediated by the modulation of the host’s immune cells for the generation of regulatory environments and enduring effect, in addition to the secretion of paracrine factors for a delocalized action that would also foster endogenous repair. With this in mind, we first studied MSC’s influence on monocytes as part of the innate immune response. We confirmed MSCs’ modulation of monocytes towards a wound-healing M2-like polarization, but with the added functionality of an active extracellular adenosinergic enzymatic activity. MSC-conditioned monocytes maintained CD39 and induced CD73 expression, which are responsible of the sequential hydrolysis of ATP/ADP to AMP and to Adenosine, respectively, to shift the pro-inflammatory milieu induced by extracellular ATP to the anti-inflammatory regulation by Adenosine. On the other side, MSCs also modulate the adaptive immune response, as we observed the immunosuppression of allogeneic lymphocyte polyclonal proliferation and inflammatory cytokine release. Regarding the paracrine activity of MSCs, we could identify extracellular vesicles (EVs) as one of the active components of MSC’s immunosuppressive secreted factors. Specifically, we demonstrated the importance of accurate isolation of MSC-EVs to unravel their immunosuppressive functionality, which can be efficiently performed by size-exclusion chromatography (SEC). Finally, this knowledge made us design a novel construct composed of MSC-EVs embedded in a biocompatible three-dimensional engineered cardiac scaffold, envisioned for the local treatment of MI to foster cardiac repair. Its in vitro validation reinforced EV secretion as an important mechanism of MSCs to both modulate the immune system and foster endogenous repair, as they could actively recruit pro-regenerative cells. Our findings unravel new mechanisms for the engineering of innovative, targeted and off-the-shelf therapeutic products
Immunomodulatory effect of MSC on B cells is independent of secreted extracellular vesicles
Full text linkAltres ajuts: this work was supported in part by Fundació La Marató de TV3 (201516-10, 201502-30). MM-T is sponsored by the PERIS (SLT002/16/00234) from the Generalitat de Catalunya; FB is a researcher from Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol, supported by the Health Department of the Catalan Government (Direcció General de Recerca i Innovació, Department Salut, Generalitat de Catalunya) and MF is funded by the Catalan Health Department (Generalitat de Catalunya) contract PERIS (SLT002/16/00069).Mesenchymal stem or stromal cells (MSC) have proven immunomodulatory properties toward B cell activation and induce regulatory B cells (Breg), through a dual mechanism of action that relies both on cell contact and secreted factors. One of them are MSC-derived extracellular vesicles (EVs), membrane nanovesicles that mediate cell communication and typically reflect the phenotype of the cell of origin. MSC-EVs could resemble MSC functions, and are being contemplated as an improved alternative to the MSC-based immunomodulatory therapy. In the present work, we focused on the factors secreted by MSC and aimed to elucidate the putative role of MSC-EVs in the immunomodulation of B cells. EVs and soluble protein-enriched fractions (PF) were isolated from MSC-conditioned medium (CM) using size-exclusion chromatography (SEC) and their capacity to modulate B cell activation, induction of Breg and B cell proliferation was compared to that of the whole MSCs. Co-culture with MSC or unfractionated CM induced naïve and CD24hiCD38hi, IL-10 producing (Breg) phenotypes on B cells while not affecting proliferation. MSC-PF had a comparable effect to MSCs, inducing a naïve phenotype, and even though they did not induce the shift toward a CD24hiCD38hi population, MSC-PF fostered IL-10 production by B cells. Conversely, MSC-EVs failed to promote naïve B cells and to reduce memory B cells. MSC-EVs induced CD24hiCD38hi B cells to a similar extent of that of MSC, but not bona fide Bregs since they did not produce IL-10. Our results show that B cell modulation by MSC is partially mediated by soluble factors other than EVs
High-resolution H α imaging of the northern Galactic plane and the IGAPS image database
No full textGreimel, R., et al.The INT Galactic Plane Survey (IGAPS) is the merger of the optical photometric surveys IPHAS and UVEX based on data from the Isaac Newton Telescope (INT) obtained between 2003 and 2018. It captures the entire northern Galactic plane within the Galactic coordinate range |b|< 5° and 30° < ℓ < 215°. From the beginning, the incorporation of narrow-band Hα imaging has been a unique and distinctive feature of this effort. Alongside a focused discussion of the nature and application of the Hα data, we present the IGAPS world-accessible database of images for all five survey filters, i, r, g, URGO, and narrow-band Hα, observed on a pixel scale of 0.33 arcsec and at an effective (median) angular resolution of 1.1-1.3 arcsec. The background, noise, and sensitivity characteristics of the narrow-band Hα filter images are outlined. Typical noise levels in this band correspond to a surface brightness at full ∼1 arcsec resolution of around 2 × 10-16 erg cm-2 s-1 arcsec-2. Illustrative applications of the Hα data to planetary nebulae and Herbig-Haro objects are outlined and, as part of a discussion of the mosaicking technique, we present a very large background-subtracted narrow-band mosaic of the supernova remnant Simeis 147. Finally, we lay out a method that exploits the database via an automated selection of bright ionised diffuse interstellar emission targets for the coming generation of wide-field massive-multiplex spectrographs. Two examples of the diffuse Hα map output from this selection process are presented and compared with previously published data.RG benefitted from support via STFC grant ST/M001334/1 as a visitor to UCL. JED and MM acknowledge the support of research grants funded by the Science, Technology and Facilities Council of the UK (STFC, grants ST/M001008/1 and ST/J001333/1). MM was partially supported by the MINECO (Spanish Ministry of Economy) through grant ESP2016-80079-C2-1-R and RTI2018-095076-B-C21 (MINECO/FEDER, UE), and MDM-2014-0369 of ICCUB (Unidad de Excelencia ‘María de Maeztu’). AM acknowledges support from the State Research Agency (AEI) of the Spanish Ministry of Science, Innovation and Universities (MCIU) and the European Regional Development Fund (FEDER) under grant AYA2017-83383-P. PJG is partially supported by NRF-SARChI grant 111692 and acknowledges support from the Netherlands Organisation for Scientific Research (NWO), in contributing to the Isaac Newton Group of Telescopes and through grant 614.000.601. Aspects of the analysis presented have been carried out via TOPCAT and STILTS (Taylor 2006). This research has made use of both the SIMBAD database and the “Aladin sky atlas”, respectively operated and developed at CDS, Strasbourg, France. This research has also made use of the image manipulation software, MONTAGE. It is funded by the National Science Foundation under Grant Number ACI-1440620, and was previously funded by the National Aeronautics and Space Administration’s Earth Science Technology Office, Computation Technologies Project, under Cooperative Agreement Number NCC5-626 between NASA and the California Institute of Technology
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
