Imperial College London

ProfessorCostanzaEmanueli

Faculty of MedicineNational Heart & Lung Institute

Chair in Cardiovascular Science
 
 
 
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Contact

 

c.emanueli Website

 
 
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Location

 

434ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

202 results found

Emanueli C, Badimon L, Martelli F, Potočnjak I, Carpusca I, Robinson EL, Devaux Yet al., 2020, Call to action for the cardiovascular side of COVID-19., Eur Heart J, Vol: 41, Pages: 1796-1797

Journal article

Tan SJO, Floriano JF, Nicastro L, Emanueli C, Catapano Fet al., 2020, Novel Applications of Mesenchymal Stem Cell-derived Exosomes for Myocardial Infarction Therapeutics., Biomolecules, Vol: 10

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts.

Journal article

Stoica SC, Dorobantu DM, Vardeu A, Biglino G, Ford KL, Bruno D, Zakkar M, Mumford A, Angelini GD, Caputo M, Emanueli Cet al., 2020, MicroRNAs as potential biomarkers in congenital heart surgery, JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY, Vol: 159, Pages: 1532-+, ISSN: 0022-5223

Journal article

Tikhomirov R, Donnell BR-O, Catapano F, Faggian G, Gorelik J, Martelli F, Emanueli Cet al., 2020, Exosomes: From potential culprits to new therapeutic promise in the setting of cardiac fibrosis, Cells, Vol: 9, ISSN: 2073-4409

Fibrosis is a significant global health problem associated with many inflammatory and degenerative diseases affecting multiple organs, individually or simultaneously. Fibrosis develops when extracellular matrix (ECM) remodeling becomes excessive or uncontrolled and is associated with nearly all forms of heart disease. Cardiac fibroblasts and myofibroblasts are the main effectors of ECM deposition and scar formation. The heart is a complex multicellular organ, where the various resident cell types communicate between themselves and with cells of the blood and immune systems. Exosomes, which are small extracellular vesicles, (EVs), contribute to cell-to-cell communication and their pathophysiological relevance and therapeutic potential is emerging. Here, we will critically review the role of endogenous exosomes as possible fibrosis mediators and discuss the possibility of using stem cell-derived and/or engineered exosomes as anti-fibrotic agents.

Journal article

Marchetti M, Meloni M, Anwar M, Al-Haj-Zen A, Sala-Newby G, Slater S, Ford K, Caporali A, Emanueli Cet al., 2020, MicroRNA-24-3p Targets Notch and Other Vascular Morphogens to Regulate Post-ischemic Microvascular Responses in Limb Muscles, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 21

Journal article

Gomes CPDC, Schroen B, Kuster GM, Robinson EL, Ford K, Squire IB, Heymans S, Martelli F, Emanueli C, Devaux Yet al., 2020, Regulatory RNAs in Heart Failure, CIRCULATION, Vol: 141, Pages: 313-328, ISSN: 0009-7322

Journal article

Spencer HL, Sanders R, Boulberdaa M, Meloni M, Cochrane A, Spiroski A-M, Mountford J, Emanueli C, Caporali A, Brittan M, Rodor J, Baker AHet al., 2020, The LINC00961 transcript and its encoded micropeptide SPAAR regulate endothelial cell function., Cardiovasc Res

AIMS: Long non-coding RNAs (lncRNAs) play functional roles in physiology and disease, yet understanding of their contribution to endothelial cell (EC) function is incomplete. We identified lncRNAs regulated during EC differentiation and investigated the role of LINC00961 and its encoded micropeptide SPAAR in EC function. METHODS AND RESULTS: Deep sequencing of human embryonic stem cell differentiation to ECs was combined with ENCODE RNA-seq data from vascular cells, identifying 278 endothelial enriched genes, including 6 lncRNAs. Expression of LINC00961, first annotated as a lncRNA but reassigned as a protein coding gene for the SPAAR micropeptide, was increased during the differentiation and was EC-enriched. LINC00961 transcript depletion significantly reduced EC adhesion, tube formation, migration, proliferation, and barrier integrity in primary ECs. Overexpression of the SPAAR open reading frame increased tubule formation, however overexpression of the full length transcript did not, despite production of SPAAR. Further, overexpression of an ATG mutant of the full length transcript reduced network formation, suggesting a bona fide non-coding RNA function of the transcript with opposing effects to SPAAR. As the LINC00961 locus is conserved in mouse, we generated a LINC00961 locus knockout (KO) mouse that underwent hind limb ischaemia to investigate the angiogenic role of this locus in vivo. In agreement with in vitro data, KO animals had a reduced capillary density in the ischaemic adductor muscle after 7 days. Finally, to characterise LINC00961 and SPAAR independent functions in ECs, we performed pull-downs of both molecules and identified protein binding partners. LINC00961 RNA binds the G-actin sequestering protein thymosin beta-4x (Tβ4) and Tβ4 depletion phenocopied the overexpression of the ATG mutant. SPAAR binding partners included the actin binding protein, SYNE1. CONCLUSION: The LINC00961 locus regulates EC function in vitro and in vivo. The gen

Journal article

Vesentini G, Barbosa AMP, Damasceno DC, Marini G, Piculo F, Matheus SMM, Hallur RLS, Nunes SK, Catinelli BB, Magalhães CG, Costa R, Abbade JF, Corrente JE, Calderon IMP, Rudge MVC, DIAMATER Study Groupet al., 2020, Alterations in the structural characteristics of rectus abdominis muscles caused by diabetes and pregnancy: A comparative study of the rat model and women., PLoS One, Vol: 15

BACKGROUND AND OBJECTIVE: In the present study, we compared the effect of diabetic pregnancy on the rectus abdominis muscle (RAM) in humans and rats. We hypothesized that our animal model could provide valuable information about alterations in the RAM of women with Gestational Diabetes (GDM). METHOD: Newborns female rats (n = 10/group) were administered streptozotocin (100 mg/kg body weight) subcutaneously and were mated on reaching adulthood, to develop the mild hyperglycemic pregnant (MHP) rat model. At the end of pregnancy, the mothers were sacrificed, and the RAM tissue was collected. Pregnant women without GDM (non-GDM group; n = 10) and those diagnosed with GDM (GDM group; n = 8) and undergoing treatment were recruited, and RAM samples were obtained at C-section. The RAM architecture and the distribution of the fast and slow fibers and collagen were studied by immunohistochemistry. RESULTS: No statistically significant differences in the maternal and fetal characters were observed between the groups in both rats and women. However, significant changes in RAM architecture were observed. Diabetes in pregnancy increased the abundance of slow fibers and decreased fast fiber number and area in both rats and women. A decrease in collagen distribution was observed in GDM women; however, a similar change was not observed in the MHP rats. CONCLUSION: Our results indicated that pregnancy- associated diabetes- induced similar structural adaptations in the RAM of women and rats with slight alterations in fiber type number and area. These findings suggest that the MHP rat model can be used for studying the effects of pregnancy-associated diabetes on the fiber structure of RAM.

Journal article

Chamorro-Jorganes A, Anwar M, Emanueli C, 2019, Changes in HDL-microRNA might create a lasting memory of high-fat diet, Cardiovascular Research, ISSN: 0008-6363

Journal article

Chen H, Moreno-Moral A, Pesce F, Devapragash N, Mancini M, Heng EL, Rotival M, Srivastava PK, Harmston N, Shkura K, Rackham OJL, Yu W-P, Sun X-M, Tee NGZ, Tan ELS, Barton PJR, Felkin LE, Lara-Pezzi E, Angelini G, Beltrami C, Pravenec M, Schafer S, Bottolo L, Hubner N, Emanueli C, Cook SA, Petretto Eet al., 2019, WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling (vol 10, 3616, 2019), NATURE COMMUNICATIONS, Vol: 10, ISSN: 2041-1723

Journal article

Chen H, Moreno-Moral A, Pesce F, Devapragash N, Mancini M, Heng E, Rotival M, Srivastava P, Harmston N, Shkura K, Rackham O, Yu W-P, Sun X-M, Gui Zhen Tee N, Tan E, Barton P, Felkin L, Lara-Pezzi E, Angelini G, Beltrami C, Pravenec M, Schafer S, Bottolo L, Hubner N, Emanueli C, Cook S, Petretto Eet al., 2019, WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling, Nature Communications, Vol: 10, ISSN: 2041-1723

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

Journal article

Machado MJC, Boardman R, Riu F, Emanueli C, Benest A, Bates DOet al., 2019, Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia, MICROCIRCULATION, Vol: 26, ISSN: 1073-9688

Journal article

Dang Z, Avolio E, Albertario A, Sala-Newby GB, Thomas AC, Wang N, Emanueli C, Madeddu Pet al., 2019, Nerve growth factor gene therapy improves bone marrow sensory innervation and nociceptor-mediated stem cell release in a mouse model of type 1 diabetes with limb ischaemia, DIABETOLOGIA, Vol: 62, Pages: 1297-1311, ISSN: 0012-186X

Journal article

Gomes CPDC, Agg B, Andova A, Arslan S, Baker A, Bartekova M, Beis D, Betsou F, Wettinger SB, Bugarski B, Condorelli G, da Silva GJJ, Danilin S, de Gonzalo-Calvo D, Buil A, Carmo-Fonseca M, Enguita FJ, Felekkis K, Ferdinandy P, Gyoengyoesi M, Hackl M, Karaduzovic-Hadziabdic K, Hellemans J, Heymans S, Hlavackova M, Hoydal MA, Jankovic A, Jusic A, Kardassis D, Kerkela R, Kuster GM, Lakkisto P, Leszek P, Lustrek M, Maegdefessel L, Martelli F, Novella S, O'Brien T, Papaneophytou C, Pedrazzini T, Pinet F, Popescu O, Potocnjak I, Robinson E, Sasson S, Scholz M, Simionescu M, Stoll M, Varga ZV, Vinciguerra M, Xuereb A, Yilmaz MB, Emanueli C, Devaux Yet al., 2019, Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129, NON-CODING RNA, Vol: 5

Journal article

Besnier M, Shantikumar S, Anwar M, Dixit P, Chamorro-Jorganes A, Sweaad W, Sala-Newby G, Madeddu P, Thomas AC, Howard L, Mushtaq S, Petretto E, Caporali A, Emanueli Cet al., 2019, miR-15a/-16 inhibit angiogenesis by targeting the Tie2 coding sequence: Therapeutic potential of a miR-15a/16 decoy system in limb ischemia., Molecular Therapy : Nucleic Acids, Vol: 17, Pages: 49-62, ISSN: 2162-2531

MicroRNA-15a (miR-15a) and miR-16, which are transcribed from the miR-15a/miR-16-1 cluster, inhibit post-ischemic angiogenesis. MicroRNA (miRNA) binding to mRNA coding sequences (CDSs) is a newly emerging mechanism of gene expression regulation. We aimed to (1) identify new mediators of the anti-angiogenic action of miR-15a and -16, (2) develop an adenovirus (Ad)-based miR-15a/16 decoy system carrying a luciferase reporter (Luc) to both sense and inhibit miR-15a/16 activity, and (3) investigate Ad.Luc-Decoy-15a/16 therapeutic potential in a mouse limb ischemia (LI) model. LI increased miR-15a and -16 expression in mouse muscular endothelial cells (ECs). The miRNAs also increased in cultured human umbilical vein ECs (HUVECs) exposed to serum starvation, but not hypoxia. Using bioinformatic tools and luciferase activity assays, we characterized miR-15a and -16 binding to Tie2 CDS. In HUVECs, miR-15a or -16 overexpression reduced Tie2 at the protein, but not the mRNA, level. Conversely, miR-15a or -16 inhibition improved angiogenesis in a Tie2-dependent manner. Local Ad.Luc-Decoy-15a/16 delivery increased Tie2 levels in ischemic skeletal muscle and improved post-LI angiogenesis and perfusion recovery, with reduced toe necrosis. Bioluminescent imaging (in vivo imaging system [IVIS]) provided evidence that the Ad.Luc-Decoy-15a/16 system responds to miR-15a/16 increases. In conclusion, we have provided novel mechanistic evidence of the therapeutic potential of local miR-15a/16 inhibition in LI.

Journal article

Moscarelli M, Fiorentino F, Suleiman M-S, Emanueli C, Reeves BC, Punjabi PP, Angelini GDet al., 2019, Remote ischaemic preconditioning in isolated aortic valve and coronary artery bypass surgery: a randomized trial, EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY, Vol: 55, Pages: 905-912, ISSN: 1010-7940

Journal article

Sophocleous F, Biffi B, Milano EG, Bruse J, Caputo M, Rajakaruna C, Schievano S, Emanueli C, Bucciarelli-Ducci C, Biglino Get al., 2019, Aortic morphological variability in patients with bicuspid aortic valve and aortic coarctation, European Journal of Cardio-Thoracic Surgery, Vol: 55, Pages: 704-713, ISSN: 1010-7940

OBJECTIVES: This study aimed to explore aortic morphology and the associations between morphological features and cardiovascular function in a population of patients with bicuspid aortic valve, while further assessing differences between patients with repaired coarctation, patients with unrepaired coarctation and patients without coarctation. METHODS: This is a single-centre retrospective study that included patients with available cardiovascular magnetic resonance imaging data and native bicuspid aortic valve diagnosis (n = 525). A statistical shape analysis was performed on patients with a 3-dimensional magnetic imaging resonance (MRI) dataset (n = 108), deriving 3-dimensional aortic reconstructions and computing a mean aortic shape (template) for the whole population as well as for the 3 subgroups of interest (no coarctation, repaired coarctation and unrepaired coarctation). Shape deformations (modes) were computed and correlated with demographic variables, 2-dimensional MRI measurements and volumetric and functional data. RESULTS: Overall, the results showed that patients with coarctation tended towards a more Gothic arch architecture, with decreased ascending and increased descending aorta diameters, with the unrepaired-aortic coarctation subgroup exhibiting more ascending aorta dilation. Careful assessment of patients with repaired coarctation only revealed that a more Gothic arch, increased descending aorta dimensions and ascending aorta dilation were associated with reduced ejection fraction (P ≤ 0.04), increased end-diastolic volume (P ≤ 0.04) and increased ventricular mass (P ≤ 0.02), with arch morphology distinguishing patients with and without recoarctation (P = 0.05). CONCLUSIONS: A statistical shape modelling framework was applied to a bicuspid aortic valve population revealing nuanced differences in arch morphology and demonstrating that morphological features

Journal article

Ford KL, Anwar M, Heys R, Ahmed EM, Caputo M, Game L, Reeves BC, Punjabi PP, Angelini GD, Petretto E, Emanueli Cet al., 2019, Optimisation of laboratory methods for whole transcriptomic RNA analyses in human left ventricular biopsies and blood samples of clinical relevance, PLoS ONE, Vol: 14, ISSN: 1932-6203

This study aimed to optimise techniques for whole transcriptome and small RNA analyses on clinical tissue samples from patients with cardiovascular disease. Clinical samples often represent a particular challenge to extracting RNA of sufficient quality for robust RNA sequencing analysis, and due to availability, it is rarely possible to optimise techniques on the samples themselves. Therefore, we have used equivalent samples from pigs undergoing cardiopulmonary bypass surgery to test different protocols for optimal RNA extraction, and then validated the protocols in human samples. Here we present an assessment of the quality and quantity of RNA obtained using a variety of commercially-available RNA extraction kits on both left ventricular biopsies and blood plasma. RNA extraction from these samples presents different difficulties; left ventricular biopsies are small and fibrous, while blood plasma has a low RNA content. We have validated our optimised extraction techniques on human clinical samples collected as part of the ARCADIA (Association of non-coding RNAs with Coronary Artery Disease and type 2 Diabetes) cohort study, resulting in successful whole transcriptome and small RNA sequencing of human left ventricular tissue.

Journal article

Shanmuganathan M, Vughs J, Noseda M, Emanueli Cet al., 2018, Exosomes: Basic biology and technological advancements suggesting their potential as ischemic heart disease therapeutics, Frontiers in Physiology, Vol: 9, ISSN: 1664-042X

Exosomes are small nano-sized vesicles that deliver biologically active RNA molecules and proteins to recipient cells through binding, fusion or endocytosis. There is emerging evidence that endogenous exosomes released by cardiovascular cells and progenitor cells impact cell survival and proliferation, thus regulating angiogenesis, cardiac protection and repair. These cardioprotective and regenerative traits have the potential to translate in to novel therapeutic options for post-ischaemic cardiac regeneration, thus potentially delaying the progression to ischaemic heart failure. Cellular stressors influence exosomes' secretion and the molecular composition of the exosome cargo, thus impacting on the above processes. Evidences are emerging that loading of proteins and RNAs in the exosomes cargos can be manipulated. Similarly, manipulation of exosomes surface proteins' expression to target exosomes to specific cells and tissues is doable. In addition, nature-inspired synthetic exosomes can be assembled to deliver specific clues to the recipient cells, including proliferative and differentiation stimuli, or shed paracrine signals enabling to reconstructing the heart homeostatic micro-environment. This review will describe exosome biogenesis and emerging evidence of exosome-mediated regenerative cell-to-cell communications and will conclude discussing possibilities of using exosomes to treat ischemic heart disease.

Journal article

Descamps B, Saif J, Benest AV, Biglino G, Bates DO, Chamorro-Jorganes A, Emanueli Cet al., 2018, BDNF (brain-derived neurotrophic factor) promotes embryonic stem cells differentiation to endothelial cells via a molecular pathway, including microRNA-214, EZH2 (enhancer of zeste homolog 2), and eNOS (endothelial nitric oxide synthase), Arteriosclerosis, Thrombosis, and Vascular Biology, Vol: 38, Pages: 2117-2125, ISSN: 1079-5642

Objective—The NTs (neurotrophins), BDNF (brain-derived neurotrophic factor) and NT-3 promote vascular development and angiogenesis. This study investigated the contribution of endogenous NTs in embryonic stem cell (ESC) vascular differentiation and the potential of exogenous BDNF to improve the process of ESC differentiation to endothelial cells (ECs).Approach and Results—Mouse ESCs were differentiated into vascular cells using a 2-dimensional embryoid body (EB) model. Supplementation of either BDNF or NT-3 increased EC progenitors’ abundance at day 7 and enlarged the peripheral vascular plexus with ECs and SM22α+ (smooth muscle 22 alpha-positive) smooth muscle cells by day 13. Conversely, inhibition of either BDNF or NT-3 receptor signaling reduced ECs, without affecting smooth muscle cells spread. This suggests that during vascular development, endogenous NTs are especially relevant for endothelial differentiation. At mechanistic level, we have identified that BDNF-driven ESC-endothelial differentiation is mediated by a pathway encompassing the transcriptional repressor EZH2 (enhancer of zeste homolog 2), microRNA-214 (miR-214), and eNOS (endothelial nitric oxide synthase). It was known that eNOS, which is needed for endothelial differentiation, can be transcriptionally repressed by EZH2. In turn, miR-214 targets EZH2 for inhibition. We newly found that in ESC-ECs, BDNF increases miR-214 expression, reduces EZH2 occupancy of the eNOS promoter, and increases eNOS expression. Moreover, we found that NRP-1 (neuropilin 1), KDR (kinase insert domain receptor), and pCas130 (p130 Crk-associated substrate kinase), which reportedly induce definitive endothelial differentiation of pluripotent cells, were increased in BDNF-conditioned ESC-EC. Mechanistically, miR-214 mediated the BDNF-induced expressional changes, contributing to BDNF-driven endothelial differentiation. Finally, BDNF-conditioned ESC-ECs promoted angiogenesis in vitro and in vivo.Concl

Journal article

MacAskill MG, Saif J, Condie A, Jansen MA, MacGillivray TJ, Tavares AAS, Fleisinger L, Spencer HL, Besnier M, Martin E, Biglino G, Newby DE, Hadoke PWF, Mountford JC, Emanueli C, Baker AHet al., 2018, Robust revascularization in models of limb ischemia using a clinically translatable human stem cell-derived endothelial cell product, Molecular Therapy, Vol: 26, Pages: 1669-1684, ISSN: 1525-0016

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy.

Journal article

Besnier M, Gasparino S, Vono R, Sangalli E, Facoetti A, Bollati V, Cantone L, Zaccagnini G, Maimone B, Fuschi P, Da Silva D, Schiavulli M, Aday S, Caputo M, Madeddu P, Emanueli C, Martelli F, Spinetti Get al., 2018, miR-210 enhances the therapeutic potential of bone-marrow-derived circulating proangiogenic cells in the setting of limb ischemia, Molecular Therapy, Vol: 26, Pages: 1694-1705, ISSN: 1525-0016

Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood. miR-210 expression was modulated with either an inhibitory complementary oligonucleotide (anti-miR-210) or a miRNA mimic (pre-miR-210). Scramble and absence of transfection served as controls. As expected, hypoxia increased miR-210 in PACs. In vivo, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. In vitro, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and enhanced by pre-miR-210. Moreover, pre-miR-210 increased PAC adhesion to ECs and supported angiogenic responses in co-cultured ECs. These responses were not associated with changes in extracellular miR-210 and were abrogated by lentivirus-mediated EFNA3 overexpression. Finally, ex-vivo pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic neovascularization and blood flow recovery in an immunodeficient mouse limb ischemia model. In conclusion, miR-210 modulates PAC functions and improves their therapeutic potential in limb ischemia.

Journal article

Sophocleous F, Milano EG, Pontecorboli G, Chivasso P, Caputo M, Rajakaruna C, Bucciarelli-Ducci C, Emanueli C, Biglino Get al., 2018, Enlightening the Association between Bicuspid Aortic Valve and Aortopathy, JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE, Vol: 5, ISSN: 2308-3425

Journal article

Alvino VV, Fernandez-Jimenez R, Rodriguez-Arabaolaza I, Slater S, Mangialardi G, Avolio E, Spencer H, Culliford L, Hassan S, Sueiro Ballesteros L, Herman A, Ayaon-Albarran A, Galan-Arriola C, Sanchez-Gonzalez J, Hennessey H, Delmege C, Ascione R, Emanueli C, Angelini GD, Ibanez B, Madeddu Pet al., 2018, Transplantation of allogeneic pericytes improves myocardial vascularization and reduces interstitial fibrosis in a swine model of reperfused acute myocardial infarction, Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease, Vol: 7, ISSN: 2047-9980

BackgroundTransplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model.Methods and ResultsWe performed a blind, randomized, placebo‐controlled APC therapy trial in a swine model of reperfused myocardial infarction. A first study used human APCs (hAPCs) from patients undergoing coronary artery bypass graft surgery. A second study used allogeneic swine APCs (sAPCs). Primary end points were (1) ejection fraction as assessed by cardiac magnetic resonance imaging and (2) myocardial vascularization and fibrosis as determined by immunohistochemistry. Transplantation of hAPCs reduced fibrosis but failed to improve the other efficacy end points. Incompatibility of the xenogeneic model was suggested by the occurrence of a cytotoxic response following in vitro challenge of hAPCs with swine spleen lymphocytes and the failure to retrieve hAPCs in transplanted hearts. We next considered sAPCs as an alternative. Flow cytometry, immunocytochemistry, and functional/cytotoxic assays indicate that sAPCs are a surrogate of hAPCs. Transplantation of allogeneic sAPCs benefited capillary density and fibrosis but did not improve cardiac magnetic resonance imaging indices of contractility. Transplanted cells were detected in the border zone.ConclusionsImmunologic barriers limit the applicability of a xenogeneic swine model to assess hAPC efficacy. On the other hand, we newly show that transplantation of allogeneic sAPCs is feasible, safe, and immunologically acceptable. The approach induces proangiogenic and antifibrotic benefits, though these effects were not enough to result in functional improvements.

Journal article

MacAskill MG, Saif J, Condie A, Jansen MA, MacGillivray TJ, Tavares AS, Fleisinger L, Newby DE, Hadoke PW, Mountford JC, Emanueli C, Baker AHet al., 2017, GMP-Compatible hESC-EC Improve Blood Flow in Multiple Peripheral Ischemia Mouse Models, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Dorobantu DM, Stoica S, Vardeu A, Bruno D, Zakkar M, Mumford A, Angelini G, Caputo M, Emanueli Cet al., 2017, Potential of Circulating MicroRNA-1 as New Perioperative Biomarker of Short-Term Outcome After Pediatric Congenital Heart Surgery, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Aday S, Zoldan J, Besnier M, Carreto L, Saif J, Fernandes R, Santos T, Bernardino L, Langer R, Emanueli C, Ferreira Let al., 2017, Synthetic microparticles conjugated with VEGF(165) improve the survival of endothelial progenitor cells via microRNA-17 inhibition, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723

Several cell-based therapies are under pre-clinical and clinical evaluation for the treatment of ischemic diseases. Poor survival and vascular engraftment rates of transplanted cells force them to work mainly via time-limited paracrine actions. Although several approaches, including the use of soluble vascular endothelial growth factor (sVEGF)—VEGF165, have been developed in the last 10 years to enhance cell survival, they showed limited efficacy. Here, we report a pro-survival approach based on VEGF-immobilized microparticles (VEGF-MPs). VEGF-MPs prolong VEGFR-2 and Akt phosphorylation in cord blood-derived late outgrowth endothelial progenitor cells (OEPCs). In vivo, OEPC aggregates containing VEGF-MPs show higher survival than those treated with sVEGF. Additionally, VEGF-MPs decrease miR-17 expression in OEPCs, thus increasing the expression of its target genes CDKN1A and ZNF652. The therapeutic effect of OEPCs is improved in vivo by inhibiting miR-17. Overall, our data show an experimental approach to improve therapeutic efficacy of proangiogenic cells for the treatment of ischemic diseases.

Journal article

Gomes CPC, Spencer H, Ford KL, Michel LYM, Baker AH, Emanueli C, Balligand J-L, Devaux Yet al., 2017, The Function and Therapeutic Potential of Long Non-coding RNAs in Cardiovascular Development and Disease, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 8, Pages: 494-507, ISSN: 2162-2531

Journal article

Rodriguez Martinez A, Posma JM, Ayala R, Neves AL, Anwar M, Petretto E, Emanueli C, Gauguier D, Nicholson JK, Dumas Met al., 2017, MWASTools: an R/Bioconductor package for metabolome-wide association studies, Bioinformatics, Vol: 34, Pages: 890-892, ISSN: 1367-4803

Summary: MWASTools is an R package designed to provide an integrated pipeline to analyze metabonomic data in large-scale epidemiological studies. Key functionalities of our package include: quality control analysis; metabolome-wide association analysis using various models (partial correlations, generalized linear models); visualization of statistical outcomes; metabolite assignment using statistical total correlation spectroscopy (STOCSY); and biological interpretation of MWAS results.Availability: The MWASTools R package is implemented in R (version > =3.4) and is available from Bioconductor: https://bioconductor.org/packages/MWASTools/

Journal article

Dykes IM, Emanueli C, 2017, Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA, GENOMICS PROTEOMICS & BIOINFORMATICS, Vol: 15, Pages: 177-186, ISSN: 1672-0229

Journal article

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