Publications by authors named "Costanza Emanueli"

149 Publications

To serve and protect: a new heart patrolling and recycling role for macrophages.

Cardiovasc Res 2021 Jan;117(2):e17-e20

National Heart and Lung Institute, Imperial College London, London, UK.

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http://dx.doi.org/10.1093/cvr/cvaa356DOI Listing
January 2021

Remote ischemic preconditioning in isolated valve intervention. A pooled meta-analysis.

Int J Cardiol 2021 Feb 15;324:146-151. Epub 2020 Oct 15.

Imperial College London, National Heart Lung Institute, UK.

Objective: Recent studies have shown no benefits from remote ischemic preconditioning (RIPC) in patients undergoing coronary artery bypass surgery. One possible explanation is that given previous exposure to angina and ischemia/reperfusion injury these patients, may be already 'naturally preconditioned'. The role of RIPC in a context of isolated valve intervention, both surgical and particularly transcatheter is less clear and remains under investigated, with few high-quality studies.

Methods: A systematic literature review identified 8 candidate studies that met the meta-analysis criteria. We analyzed outcomes of 610 subjects (312 RIPC and 298 SHAM) with random effects modeling. Each study was assessed for heterogeneity. The primary outcome was the extent of periprocedural myocardial injury, as reflected by the area under the curve for serum troponin concentration. Secondary endpoints included relevant intra- and post-operative outcomes; sensitivity and high-quality subgroup analysis was also carried out.

Results: Six and two studies reported the effect of RIPC in surgical and transcatheter valve intervention. There was a significant difference between-group in terms of periprocedural Troponin release (standardized mean difference (SMD: 0.74 [95% CI: 0.52; 0.95], p = 0.02) with no heterogeneity (χ 2.40, I 0%, p = 0.88). RIPC was not associated with any improvement in post-operative outcomes. No serious adverse RIPC related events were reported.

Conclusions: RIPC seems to elicit overall periprocedural cardioprotection in patients undergoing valvular intervention, yet with no benefit on early clinical outcomes.
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http://dx.doi.org/10.1016/j.ijcard.2020.10.020DOI Listing
February 2021

Analysis of Neat Biofluids Obtained During Cardiac Surgery Using Nanoparticle Tracking Analysis: Methodological Considerations.

Front Cell Dev Biol 2020 25;8:367. Epub 2020 May 25.

Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol, United Kingdom.

Small extracellular vesicles (sEVs) are those nanovesicles 30-150 nm in size with a role in cell signalling and potential as biomarkers of disease. Nanoparticle tracking analysis (NTA) techniques are commonly used to measure sEV concentration in biofluids. However, this quantification technique can be susceptible to sample handing and machine settings. Moreover, some classes of lipoproteins are of similar sizes and could therefore confound sEV quantification, particularly in blood-derived preparations, such serum and plasma. Here we have provided methodological information on NTA measurements and systematically investigated potential factors that could interfere with the reliability and repeatability of results obtained when looking at neat biofluids (i.e., human serum and pericardial fluid) obtained from patients undergoing cardiac surgery and from healthy controls. Data suggest that variables that can affect vesicle quantification include the level of contamination from lipoproteins, number of sample freeze/thaw cycles, sample filtration, using saline-based diluents, video length and keeping the number of particles per frame within defined limits. Those parameters that are of less concern include focus, the "Maximum Jump" setting and the number of videos recorded. However, if these settings are clearly inappropriate the results obtained will be spurious. Similarly, good experimental practice suggests that multiple videos should be recorded. In conclusion, NTA is a perfectible, but still commonly used system for sEVs analyses. Provided users handle their samples with a highly robust and consistent protocol, and accurately report these aspects, they can obtain data that could potentially translate into new clinical biomarkers for diagnosis and monitoring of cardiovascular disease.
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http://dx.doi.org/10.3389/fcell.2020.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262431PMC
May 2020

Native and bioengineered extracellular vesicles for cardiovascular therapeutics.

Nat Rev Cardiol 2020 11 1;17(11):685-697. Epub 2020 Jun 1.

CNC-Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have certain properties that allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be bioengineered to increase their stability, bioactivity, presentation to acceptor cells and capacity for on-target binding at both cell-type-specific and tissue-specific levels. Bioengineering of EVs involves the modification of the donor cell before EV isolation or direct modification of the EV properties after isolation. The therapeutic potential of native EVs and bioengineered EVs has been only minimally explored in the context of cardiovascular diseases. Efforts to harness the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of research into molecular-compound delivery. In this Review, we outline the endogenous properties of EVs that make them natural delivery agents as well as the features that can be improved by bioengineering. We also discuss the therapeutic applications of native and bioengineered EVs to cardiovascular diseases and examine the opportunities and challenges that need to be addressed to advance this research area, with an emphasis on clinical translation.
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http://dx.doi.org/10.1038/s41569-020-0389-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874903PMC
November 2020

A Year in the Life of the EU-CardioRNA COST Action: CA17129 Catalysing Transcriptomics Research in Cardiovascular Disease.

Noncoding RNA 2020 05 18;6(2). Epub 2020 May 18.

Cardiovascular Research Unit, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg.

The EU-CardioRNA Cooperation in Science and Technology (COST) Action is a European-wide consortium established in 2018 with 31 European country members and four associate member countries to build bridges between translational researchers from academia and industry who conduct research on non-coding RNAs, cardiovascular diseases and similar research areas. EU-CardioRNA comprises four core working groups (WG1-4). In the first year since its launch, EU-CardioRNA met biannually to exchange and discuss recent findings in related fields of scientific research, with scientific sessions broadly divided up according to WG. These meetings are also an opportunity to establish interdisciplinary discussion groups, brainstorm ideas and make plans to apply for joint research grants and conduct other scientific activities, including knowledge transfer. Following its launch in Brussels in 2018, three WG meetings have taken place. The first of these in Lisbon, Portugal, the second in Istanbul, Turkey, and the most recent in Maastricht, The Netherlands. Each meeting includes a scientific session from each WG. This meeting report briefly describes the highlights and key take-home messages from each WG session in this first successful year of the EU-CardioRNA COST Action.
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http://dx.doi.org/10.3390/ncrna6020017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345156PMC
May 2020

Novel Applications of Mesenchymal Stem Cell-derived Exosomes for Myocardial Infarction Therapeutics.

Biomolecules 2020 05 2;10(5). Epub 2020 May 2.

National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.

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.
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http://dx.doi.org/10.3390/biom10050707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277090PMC
May 2020

Call to action for the cardiovascular side of COVID-19.

Eur Heart J 2020 05;41(19):1796-1797

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg.

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http://dx.doi.org/10.1093/eurheartj/ehaa301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529147PMC
May 2020

Exosomes Could Offer New Options to Combat the Long-Term Complications Inflicted by Gestational Diabetes Mellitus.

Cells 2020 03 10;9(3). Epub 2020 Mar 10.

National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.

Gestational diabetes Mellitus (GDM) is a complex clinical condition that promotes pelvic floor myopathy, thus predisposing sufferers to urinary incontinence (UI). GDM usually regresses after birth. Nonetheless, a GDM history is associated with higher risk of subsequently developing type 2 diabetes, cardiovascular diseases (CVD) and UI. Some aspects of the pathophysiology of GDM remain unclear and the associated pathologies (outcomes) are poorly addressed, simultaneously raising public health costs and diminishing women's quality of life. Exosomes are small extracellular vesicles produced and actively secreted by cells as part of their intercellular communication system. Exosomes are heterogenous in their cargo and depending on the cell sources and environment, they can mediate both pathogenetic and therapeutic functions. With the advancement in knowledge of exosomes, new perspectives have emerged to support the mechanistic understanding, prediction/diagnosis and ultimately, treatment of the post-GMD outcomes. Here, we will review recent advances in knowledge of the role of exosomes in GDM and related areas and discuss the possibilities for translating exosomes as therapeutic agents in the GDM clinical setting.
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http://dx.doi.org/10.3390/cells9030675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140615PMC
March 2020

MicroRNA-24-3p Targets Notch and Other Vascular Morphogens to Regulate Post-ischemic Microvascular Responses in Limb Muscles.

Int J Mol Sci 2020 Mar 3;21(5). Epub 2020 Mar 3.

Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol BS2 8HW, UK.

MicroRNAs (miRs) regulate complex processes, including angiogenesis, by targeting multiple mRNAs. miR-24-3p-3p directly represses eNOS, GATA2, and PAK4 in endothelial cells (ECs), thus inhibiting angiogenesis during development and in the infarcted heart. miR-24-3p is widely expressed in cardiovascular cells, suggesting that it could additionally regulate angiogenesis by acting on vascular mural cells. Here, we have investigated: 1) new miR-24-3p targets; 2) the expression and the function of miR-24-3p in human vascular ECs; 3) the impact of miR-24-3p inhibition in the angiogenesis reparative response to limb ischemia in mice. Using bioinformatics target prediction platforms and 3'-UTR luciferase assays, we newly identified Notch1 and its Delta-like ligand 1 (Dll1) to be directly targeted by miR-24-3p. miR-24-3p was expressed in human ECs and pericytes cultured under normal conditions. Exposure to hypoxia increased miR-24-3p in ECs but not in pericytes. Transfection with a miR-24-3p precursor (pre-miR-24-3p) increased miR-24-3p expression in ECs, reducing the cell survival, proliferation, and angiogenic capacity. Opposite effects were caused by miR-24-3p inhibition. The anti-angiogenic action of miR-24-3p overexpression could be prevented by simultaneous adenovirus (Ad)-mediated delivery of constitutively active Notch intracellular domain (NICD) into cultured ECs. We next demonstrated that reduced Notch signalling contributes to the anti-angiogenic effect of miR-24-3p in vitro. In a mouse unilateral limb ischemia model, local miR-24-3p inhibition (by adenovirus-mediated miR-24-3p decoy delivery) restored endothelial Notch signalling and increased capillary density. However, the new vessels appeared disorganised and twisted, worsening post-ischemic blood perfusion recovery. To better understand the underpinning mechanisms, we widened the search for miR-24-3p target genes, identifying several contributors to vascular morphogenesis, such as several members of the Wingless (Wnt) signalling pathway, β-catenin signalling components, and VE-cadherin, which synergise to regulate angiogenesis, pericytes recruitment to neoformed capillaries, maturation, and stabilization of newly formed vessels. Among those, we next focussed on β-catenin to demonstrate that miR-24-3p inhibition reduces β-catenin expression in hypoxic ECs, which is accompanied by reduced adhesion of pericytes to ECs. In summary, miR-24-3p differentially targets several angiogenesis modulators and contributes to autonomous and non-autonomous EC crosstalk. In ischemic limbs, miR-24-3p inhibition increases the production of dysfunctional microvessels, impairing perfusion. Caution should be observed in therapeutic targeting of miR-24-3p.
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http://dx.doi.org/10.3390/ijms21051733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084374PMC
March 2020

Exosomes: From Potential Culprits to New Therapeutic Promise in the Setting of Cardiac Fibrosis.

Cells 2020 03 2;9(3). Epub 2020 Mar 2.

National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.

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.
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http://dx.doi.org/10.3390/cells9030592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140485PMC
March 2020

The LINC00961 transcript and its encoded micropeptide, small regulatory polypeptide of amino acid response, regulate endothelial cell function.

Cardiovasc Res 2020 Oct;116(12):1981-1994

University/BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.

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, small regulatory polypeptide of amino acid response (SPAAR), in EC function.

Methods And Results: Deep sequencing of human embryonic stem cell differentiation to ECs was combined with Encyclopedia of DNA Elements (ENCODE) RNA-seq data from vascular cells, identifying 278 endothelial enriched genes, including 6 lncRNAs. Expression of LINC00961, first annotated as an 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. Furthermore, 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 an LINC00961 locus knockout (KO) mouse that underwent hind limb ischaemia (HLI) 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 characterize 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 gene produces two molecules with opposing effects on angiogenesis: SPAAR and LINC00961.
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http://dx.doi.org/10.1093/cvr/cvaa008DOI Listing
October 2020

Regulatory RNAs in Heart Failure.

Circulation 2020 01 27;141(4):313-328. Epub 2020 Jan 27.

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg (C.P.d.C.G., Y.D.).

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012349PMC
January 2020

Changes in high-density lipoprotein microRNA might create a lasting memory of high-fat diet.

Cardiovasc Res 2020 06;116(7):1237-1239

National Heart and Lung Institute, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.

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http://dx.doi.org/10.1093/cvr/cvz334DOI Listing
June 2020

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

Nat Commun 2019 08 9;10(1):3616. Epub 2019 Aug 9.

Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore.

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.
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http://dx.doi.org/10.1038/s41467-019-11551-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689010PMC
August 2019

miR-15a/-16 Inhibit Angiogenesis by Targeting the Tie2 Coding Sequence: Therapeutic Potential of a miR-15a/16 Decoy System in Limb Ischemia.

Mol Ther Nucleic Acids 2019 Sep 17;17:49-62. Epub 2019 May 17.

Bristol Heart Institute, University of Bristol, Bristol, UK; National Heart and Lung Institute, Imperial College London, London, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.omtn.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586592PMC
September 2019

MicroRNAs as potential biomarkers in congenital heart surgery.

J Thorac Cardiovasc Surg 2020 04 4;159(4):1532-1540.e7. Epub 2019 Apr 4.

Bristol Heart Institute, University of Bristol, Bristol, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom. Electronic address:

Objective: Pediatric congenital heart surgery (CHS) involves intracardiac, valvular, and vascular repairs. Accurate tools to aid short-term outcome prediction in pediatric CHS are lacking. Clinical scores, such as the vasoactive-inotrope score and ventilation index, are used to define outcome in clinical studies. MicroRNA-1-3p (miR-1) is expressed by both cardiomyocytes and vascular cells and is regulated by hypoxia. In adult patients, miR-1 increases in the circulation after open-heart cardiac surgery, suggesting its potential as a clinical biomarker. Thus, we investigated whether perioperative circulating miR-1 measurements can help predict post-CHS short-term outcomes in pediatric patients.

Methods: Plasma miR-1 was retrospectively measured in a cohort of 199 consecutive pediatric CHS patients (median age 1.2 years). Samples were taken before surgery and at the end of the operation. Plasma miR-1 concentration was measured by reverse transcription-quantitative polymerase chain reaction and expressed as miR-1 copies/μL and as relative expression to spiked-in exogenous cel-miR-39.

Results: Baseline plasma miR-1 did not vary across different diagnoses, increased during surgery (204-fold median relative increase, P < .001), and was associated with aortic crossclamp duration postoperatively (P < .001). Importantly, miR-1 levels at the end of the operation positively correlated with intensive care stay (P < .001), early severe cardiovascular events (P = .01), and with high vasoactive-inotrope score (P = .001) and ventilation index (P < .001), suggesting that miR-1 could accelerate the identification of patients with cardiopulmonary bypass-related ischemic complications, requiring more intensive support.

Conclusions: Our study suggests miR-1 as a novel potential circulating biomarker to predict early postoperative outcome and inform clinical management in pediatric heart surgery.
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http://dx.doi.org/10.1016/j.jtcvs.2019.03.062DOI Listing
April 2020

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 2019 07 24;62(7):1297-1311. Epub 2019 Apr 24.

Experimental Cardiovascular Medicine, Faculty of Translational Health Sciences, Bristol Medical School, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.

Aims/hypothesis: Sensory neuropathy is common in people with diabetes; neuropathy can also affect the bone marrow of individuals with type 2 diabetes. However, no information exists on the state of bone marrow sensory innervation in type 1 diabetes. Sensory neurons are trophically dependent on nerve growth factor (NGF) for their survival. The aim of this investigation was twofold: (1) to determine if sensory neuropathy affects the bone marrow in a mouse model of type 1 diabetes, with consequences for stem cell liberation after tissue injury; and (2) to verify if a single systemic injection of the NGF gene exerts long-term beneficial effects on these phenomena.

Methods: A mouse model of type 1 diabetes was generated in CD1 mice by administration of streptozotocin; vehicle was administered to non-diabetic control animals. Diabetic animals were randomised to receive systemic gene therapy with either human NGF or β-galactosidase. After 13 weeks, limb ischaemia was induced in both groups to study the recovery post injury. When the animals were killed, samples of tissue and peripheral blood were taken to assess stem cell mobilisation and homing, levels of substance P and muscle vascularisation. An in vitro cellular model was adopted to verify signalling downstream to human NGF and related neurotrophic or pro-apoptotic effects. Normally distributed variables were compared between groups using the unpaired Student's t test and non-normally distributed variables were assessed by the Wilcoxon-Mann-Whitney test. The Fisher's exact test was employed for categorical variables.

Results: Immunohistochemistry indicated a 3.3-fold reduction in the number of substance P-positive nociceptive fibres in the bone marrow of type 1 diabetic mice (p < 0.001 vs non-diabetic). Moreover, diabetes abrogated the creation of a neurokinin gradient which, in non-diabetic mice, favoured the mobilisation and homing of bone-marrow-derived stem cells expressing the substance P receptor neurokinin 1 receptor (NK1R). Pre-emptive gene therapy with NGF prevented bone marrow denervation, contrasting with the inhibitory effect of diabetes on the mobilisation of NK1R-expressing stem cells, and restored blood flow recovery from limb ischaemia. In vitro hNGF induced neurite outgrowth and exerted anti-apoptotic actions on rat PC12 cells exposed to high glucose via activation of the canonical neurotrophic tyrosine kinase receptor type 1 (TrkA) signalling pathway.

Conclusions/interpretation: This study shows, for the first time, the occurrence of sensory neuropathy in the bone marrow of type 1 diabetic mice, which translates into an altered modulation of substance P and depressed release of substance P-responsive stem cells following ischaemia. NGF therapy improves bone marrow sensory innervation, with benefits for healing on the occurrence of peripheral ischaemia. Nociceptors may represent a new target for the treatment of ischaemic complications in diabetes.
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http://dx.doi.org/10.1007/s00125-019-4860-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560027PMC
July 2019

Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia.

Microcirculation 2019 08 19;26(6):e12549. Epub 2019 Jun 19.

Division of Cancer and Stem Cells, Tumour and Vascular Biology Laboratories, Cancer Biology, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, UK.

Introduction: Arteriolargenesis can be induced by concomitant stimulation of nitric Oxide (NO)-Angiopoietin receptor (Tie)-Vascular Endothelial Growth Factor (VEGF) signaling in the rat mesentery angiogenesis assay. We hypothesized that the same combination of exogenously added growth factors would also have a positive impact on arteriolargenesis and, consequently, the recovery of blood flow in a model of unilateral hindlimb ischemia.

Results And Methods: NO-Tie mice had faster blood flow recovery compared to control mice, as assessed by laser speckle imaging. There was no change in capillary density within the ischemic muscles, but arteriole density was higher in NO-Tie mice. Given the previously documented beneficial effect of VEGF signaling, we tested whether NO-Tie-VEGF mice would show further improvement. Surprisingly, these mice recovered no differently from control, arteriole density was similar and capillary density was lower. Dll4 is a driver of arterial specification, so we hypothesized that Notch1 expression would be involved in arteriolargenesis. There was a significant upregulation of Notch1 transcripts in NO-Tie-VEGF compared with NO-Tie mice. Using soluble Dll4 (sDll4), we stimulated Notch signaling in the ischemic muscles of mice. NO-Tie-sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery.

Conclusion: These results suggest that Dll4 activation early on in revascularization can lead to unproductive angiogenesis and arteriolargenesis, despite increased vascular densities. These results suggest spatial and temporal balance of growth factors needs to be perfected for ideal functional and anatomical revascularisation.
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http://dx.doi.org/10.1111/micc.12549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899699PMC
August 2019

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129.

Noncoding RNA 2019 03 29;5(2). Epub 2019 Mar 29.

Cardiovascular Research Unit, Luxembourg Institute of Health, L-1445 Strassen, Luxembourg.

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).
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http://dx.doi.org/10.3390/ncrna5020031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630366PMC
March 2019

Optimisation of laboratory methods for whole transcriptomic RNA analyses in human left ventricular biopsies and blood samples of clinical relevance.

PLoS One 2019 14;14(3):e0213685. Epub 2019 Mar 14.

National Heart and Lung Institute, ICTEM, The Hammersmith Hospital, Imperial College London, London, United Kingdom.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213685PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417664PMC
December 2019

Remote ischaemic preconditioning in isolated aortic valve and coronary artery bypass surgery: a randomized trial†.

Eur J Cardiothorac Surg 2019 May;55(5):905-912

Faculty of Health Sciences, Bristol Heart Institute, The Bristol Medical School, University of Bristol, Bristol, UK.

Objectives: This trial was designed and patients were recruited at a time when the benefits of remote ischaemic preconditioning during open-heart surgery were still controversial. We focused on a homogeneous patient population undergoing either isolated aortic valve replacement or coronary artery bypass grafting (CABG) surgery by investigating cardiac injury, metabolic stress and inflammatory response.

Methods: A 2-centre randomized controlled trial recruited a total of 124 patients between February 2013 and April 2015. Of them, 64 patients underwent CABG and 60 patients underwent aortic valve replacement. Patients were randomized to either sham or preconditioning. Remote ischaemic preconditioning was applied following anaesthesia and before sternotomy. Myocardial injury and inflammatory response were assessed by serially measuring cardiac troponin I, and interleukin-6, 8, 10 and the tumour necrosis factor (TNF-α). Biopsies from the left and the right ventricles were harvested after ischaemic reperfusion injury for nucleotides analysis.

Results: Application of remote ischaemic preconditioning did not alter the degree of troponin I release, levels of inflammatory markers and cardiac energetics in both the CABG and the aortic valve replacement groups.

Conclusions: Preconditioning did not confer any additional cardioprotection in terms of reducing the levels of troponin I and inflammatory markers and preserving left and right ventricle energy metabolites in patients undergoing isolated CABG or aortic valve surgery.

Clinical Trial Registration Number: International Standard Randomized Controlled Trial Number (ISRCTN) registry ID 33084113 (doi: 10.1186/ISRCTN33084113) and UK controlled randomized trial number (UKCRN) registry ID 13672.
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http://dx.doi.org/10.1093/ejcts/ezy404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477640PMC
May 2019

Exosomes: Basic Biology and Technological Advancements Suggesting Their Potential as Ischemic Heart Disease Therapeutics.

Front Physiol 2018 19;9:1159. Epub 2018 Nov 19.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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.
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http://dx.doi.org/10.3389/fphys.2018.01159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262308PMC
November 2018

Aortic morphological variability in patients with bicuspid aortic valve and aortic coarctation.

Eur J Cardiothorac Surg 2019 Apr;55(4):704-713

Bristol Medical School, University of Bristol, Bristol, UK.

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, not immediately described by conventional measurements, can indicate those shape phenotypes associated with compromised function and thus possibly warranting closer follow-up.
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http://dx.doi.org/10.1093/ejcts/ezy339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459283PMC
April 2019

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).

Arterioscler Thromb Vasc Biol 2018 09;38(9):2117-2125

From the Bristol Heart Institute, School of Clinical Sciences, University of Bristol, United Kingdom (B.D., J.S., G.B., C.E.).

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 pCas (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. Conclusions- BDNF promotes ESC-endothelial differentiation acting via miR-214.
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http://dx.doi.org/10.1161/ATVBAHA.118.311400DOI Listing
September 2018

miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia.

Mol Ther 2018 07 15;26(7):1694-1705. Epub 2018 Jun 15.

Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ymthe.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036333PMC
July 2018

Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product.

Mol Ther 2018 07 28;26(7):1669-1684. Epub 2018 Mar 28.

University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ymthe.2018.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035339PMC
July 2018

Enlightening the Association between Bicuspid Aortic Valve and Aortopathy.

J Cardiovasc Dev Dis 2018 Apr 19;5(2). Epub 2018 Apr 19.

Bristol Heart Institute, Bristol Medical School, University of Bristol, Bristol BS2 89HW, UK.

Bicuspid aortic valve (BAV) patients have an increased incidence of developing aortic dilation. Despite its importance, the pathogenesis of aortopathy in BAV is still largely undetermined. Nowadays, intense focus falls both on BAV morphology and progression of valvular dysfunction and on the development of aortic dilation. However, less is known about the relationship between aortic valve morphology and aortic dilation. A better understanding of the molecular pathways involved in the homeostasis of the aortic wall, including the extracellular matrix, the plasticity of the vascular smooth cells, TGFβ signaling, and epigenetic dysregulation, is key to enlighten the mechanisms underpinning BAV-aortopathy development and progression. To date, there are two main theories on this subject, i.e., the and the theory, with an ongoing debate over the pathogenesis of BAV-aortopathy. Furthermore, the lack of early detection biomarkers leads to challenges in the management of patients affected by BAV-aortopathy. Here, we critically review the current knowledge on the driving mechanisms of BAV-aortopathy together with the current clinical management and lack of available biomarkers allowing for early detection and better treatment optimization.
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http://dx.doi.org/10.3390/jcdd5020021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023468PMC
April 2018

Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction.

J Am Heart Assoc 2018 01 22;7(2). Epub 2018 Jan 22.

Bristol Heart Institute, School of Clinical Sciences, University of Bristol, United Kingdom

Background: Transplantation 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 Results: We 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.

Conclusions: Immunologic 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.
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http://dx.doi.org/10.1161/JAHA.117.006727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850145PMC
January 2018

Synthetic microparticles conjugated with VEGF improve the survival of endothelial progenitor cells via microRNA-17 inhibition.

Nat Commun 2017 09 29;8(1):747. Epub 2017 Sep 29.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal.

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)-VEGF, 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.Soluble vascular endothelial growth factor (VEGF) enhances vascular engraftment of transplanted cells but the efficacy is low. Here, the authors show that VEGF-immobilized microparticles prolong survival of endothelial progenitors in vitro and in vivo by downregulating miR17 and upregulating CDKN1A and ZNF652.
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http://dx.doi.org/10.1038/s41467-017-00746-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622042PMC
September 2017