Publications
464 results found
Perbellini F, Bardi I, Watson S, et al., 2017, Cell therapy of the heart studied using adult myocardial slices in vitro, Annual Conference of the British-Society-for-Gene-and-Cell-Therapy / Joint UK-Regenerative-Medicine-Platform Meeting, Publisher: MARY ANN LIEBERT, INC, Pages: A19-A20, ISSN: 1043-0342
Guex AG, Spicer CD, Armgarth A, et al., 2017, Electrospun aniline-tetramer-co-polycaprolactone fibres for conductive, biodegradable scaffolds, MRS Communications, Vol: 7, Pages: 375-382, ISSN: 2159-6867
Conjugated polymers have been proposed as promising materials for scaffolds in tissue engineering applications. However, the restricted processability and biodegradability of conjugated polymers limit their use for biomedical applications. Here we synthesized a block-co-polymer of aniline tetramer and PCL (AT–PCL), and processed it into fibrous non-woven scaffolds by electrospinning. We showed that fibronectin (Fn) adhesion was dependent on the AT–PCL oxidative state, with a reduced Fn unfolding length on doped membranes. Furthermore, we demonstrated the cytocompatibility and potential of these membranes to support the growth and osteogenic differentiation of MC3T3-E1 cells over 21 days.
Sattler S, Fairchild P, Watt F, et al., 2017, The adaptive immune response to cardiac injury-the true roadblock to effective regenerative therapies?, npj Regenerative Medicine, Vol: 2, ISSN: 2057-3995
The regenerative capacity of adult human tissues and organs is limited, but recent developments have seen the advent of promising new technologies for regenerative therapy. The human heart is of particular interest for regenerative medicine, as cardiac tissue damage is repaired by the formation of rigid scar tissue, which causes inevitable structural changes and progressive functional decline leading to heart failure. Cardiac regenerative medicine aims to prevent scar formation or replace existing scars to halt or reverse adverse remodeling and therapeutic approaches include the use of biomaterials, gene therapies, delivery of growth factors and (stem) cell therapies. Regenerative therapies, however, face significant obstacles in a hostile microenvironment. While the early immune response to a myocardial infarct is essential to ensure tissue integrity and to avoid fatal cardiac rupture, excessive activation of endogenous repair mechanisms may lead to ongoing inflammation, fibrosis and sustained autoimmune-mediated tissue damage. Anti-cardiac auto-reactivity of the adaptive immune system has been suggested to be involved in structural remodeling, functional decline and the development of heart failure. It is, therefore, crucial to first understand the endogenous response to cardiac tissue damage and how to restore immune tolerance to cardiac tissue, before additional regenerative therapies can achieve their full potential.
Couch L, Derda AA, Thum T, et al., 2017, TAKOTSUBO SYNDROME ASSOCIATED MIR-16 AND MIR-26A REDUCE CONTRACTILITY OF CARDIOMYOCYTES IN VITRO BY AN INHIBITORY G-PROTEIN DEPENDENT MECHANISM, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A135-A135, ISSN: 1355-6037
Foldes G, Gara E, Husveth-Toth M, et al., 2017, 3D culture conditioning modulates arterial specification of human pluripotent stem cells-derived endothelial cells, 2nd Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: Karger Publishers, Pages: 12-13, ISSN: 1018-1172
Yang C, Xu Y, Yu M, et al., 2017, Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis., Human Molecular Genetics, Vol: 26, Pages: 3031-3045, ISSN: 0964-6906
Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.
Schobesberger S, Wright P, Tokar S, et al., 2017, T-tubule remodelling disturbs localised β2-adrenergic signalling in rat ventricular myocyte during the progression of heart failure, Cardiovascular Research, Vol: 113, Pages: 770-782, ISSN: 0008-6363
AimsCardiomyocyte β2-adrenergic receptor (β2AR) cyclic adenosine monophosphate (cAMP) signalling is regulated by the receptors’ subcellular location within transverse tubules (T-tubules), via interaction with structural and regulatory proteins, which form a signalosome. In chronic heart failure (HF), β2ARs redistribute from T-tubules to the cell surface, which disrupts functional signalosomes and leads to diffuse cAMP signalling. However, the functional consequences of structural changes upon β2AR-cAMP signalling during progression from hypertrophy to advanced HF are unknown.Methods and resultsRat left ventricular myocytes were isolated at 4-, 8-, and 16-week post-myocardial infarction (MI), β2ARs were stimulated either via whole-cell perfusion or locally through the nanopipette of the scanning ion conductance microscope. cAMP release was measured via a Förster Resonance Energy Transfer-based sensor Epac2-camps. Confocal imaging of di-8-ANNEPS-stained cells and immunoblotting were used to determine structural alterations. At 4-week post-MI, T-tubule regularity, density and junctophilin-2 (JPH2) expression were significantly decreased. The amplitude of local β2AR-mediated cAMP in T-tubules was reduced and cAMP diffused throughout the cytosol instead of being locally confined. This was accompanied by partial caveolin-3 (Cav-3) dissociation from the membrane. At 8-week post-MI, the β2AR-mediated cAMP response was observed at the T-tubules and the sarcolemma (crest). Finally, at 16-week post-MI, the whole cell β2AR-mediated cAMP signal was depressed due to adenylate cyclase dysfunction, while overall Cav-3 levels were significantly increased and a substantial portion of Cav-3 dissociated into the cytosol. Overexpression of JPH2 in failing cells in vitro or AAV9.SERCA2a gene therapy in vivo did not improve β2AR-mediated signal compartmentation or reduce cAMP diffusion.ConclusionAlthough changes in T-tubule structure
Sikkel MB, Kumar S, Maioli V, et al., 2017, Erratum: High speed sCMOS-based oblique plane microscopy applied to the study of calcium dynamics in cardiac myocytes: [J. Biophotonics 9, No. 3, 311-323 (2016)]., J Biophotonics, Vol: 10, Pages: 744-745
In the article by M.B. Sikkel et al. (doi: 10.1002/jbio.201500193), published in J. Biophotonics 9, 311-323 (2016), an error occurred in the computer code that was used to generate Figure 3. This erratum is published to correct Figure 3, the calculated value of tgeom and the experimentally determined value of toptics in the text of the article.
Marjot J, Kaier TE, Martin ED, et al., 2017, Quantifying the Release of Biomarkers of Myocardial Necrosis from Cardiac Myocytes and Intact Myocardium, CLINICAL CHEMISTRY, Vol: 63, Pages: 990-996, ISSN: 0009-9147
Watson S, Perbellini F, Harding SE, et al., 2017, Structural and functional plasticity of myocardial slices in response to prolonged mechanical loading and unloading in vitro, European Society of Cardiology Congress 2017
Hasham MG, Baxan N, Stuckey D, et al., 2017, Systemic autoimmunity induced by Toll-like receptor 7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy: a new model of autoimmune heart disease, Disease Models & Mechanisms, Vol: 10, Pages: 259-270, ISSN: 1754-8411
Systemic autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) show significant heart involvement and cardiovascular morbidity, which can be due to systemically increased levels of inflammation or direct autoreactivity targeting cardiac tissue. Despite high clinical relevance, cardiac damage secondary to systemic autoimmunity lacks inducible rodent models. Here we characterize immune-mediated cardiac tissue damage in a new model of SLE induced by topical application of the TLR-7/8 agonist Resiquimod. We observe a cardiac phenotype reminiscent of autoimmune-mediated dilated cardiomyopathy, and identify auto-antibodies as major contributors to cardiac tissue damage. Resiquimod-induced heart disease is a highly relevant mouse model for mechanistic and therapeutic studies aiming to protect the heart during autoimmunity.
Kriston-Vizi J, Harding SE, Foldes G, 2017, Structural Toxicity: Hypertrophy Models of Human Pluripotent Stem Cell-Derived Cardiomyocytes, STEM CELL-DERIVED MODELS IN TOXICOLOGY, Editors: Clements, Roquemore, Publisher: HUMANA PRESS INC, Pages: 271-291, ISBN: 978-1-4939-6659-2
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Mawad D, Mansfield C, Lauto A, et al., 2016, A conducting polymer with enhanced electronic stability applied in cardiac models, Science Advances, Vol: 2, ISSN: 2375-2548
Electrically active constructs can have a beneficial effect on electroresponsive tissues, such as the brain, heart, and nervous system. Conducting polymers (CPs) are being considered as components of these constructs because of their intrinsic electroactive and flexible nature. However, their clinical application has been largely hampered by their short operational time due to a decrease in their electronic properties. We show that, by immobilizing the dopant in the conductive scaffold, we can prevent its electric deterioration. We grew polyaniline (PANI) doped with phytic acid on the surface of a chitosan film. The strong chelation between phytic acid and chitosan led to a conductive patch with retained electroactivity, low surface resistivity (35.85 ± 9.40 kilohms per square), and oxidized form after 2 weeks of incubation in physiological medium. Ex vivo experiments revealed that the conductive nature of the patch has an immediate effect on the electrophysiology of the heart. Preliminary in vivo experiments showed that the conductive patch does not induce proarrhythmogenic activities in the heart. Our findings set the foundation for the design of electronically stable CP-based scaffolds. This provides a robust conductive system that could be used at the interface with electroresponsive tissue to better understand the interaction and effect of these materials on the electrophysiology of these tissues.
Sarvananthan S, Lewis FC, Gritti G, et al., 2016, The Distribution and Characteristics of Endogenous Cardiac Stem Cells in All Four Chambers of the Adult Human Heart, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Bagdadi AV, Safari M, Dubey P, et al., 2016, Poly(3-hydroxyoctanoate), a promising new material for cardiac tissue engineering., Journal of Tissue Engineering and Regenerative Medicine, Vol: 12, Pages: e495-e512, ISSN: 1932-6254
Cardiac tissue engineering (CTE) is currently a prime focus of research due to an enormous clinical need. In this work, a novel functional material, Poly(3-hydroxyoctanoate), P(3HO), a medium chain length polyhydroxyalkanoate (PHA), produced using bacterial fermentation, was studied as a new potential material for CTE. Engineered constructs with improved mechanical properties, crucial for supporting the organ during new tissue regeneration, and enhanced surface topography, to allow efficient cell adhesion and proliferation, were fabricated. Our results showed that the mechanical properties of the final patches were close to that of cardiac muscle. Biocompatibility of the P(3HO) neat patches, assessed using Neonatal ventricular rat myocytes (NVRM), showed that the polymer was as good as collagen in terms of cell viability, proliferation and adhesion. Enhanced cell adhesion and proliferation properties were observed when porous and fibrous structures were incorporated to the patches. Also, no deleterious effect was observed on the adults cardiomyocytes' contraction when cardiomyocytes were seeded on the P(3HO) patches. Hence, P(3HO) based multifunctional cardiac patches are promising constructs for efficient CTE. This work will provide a positive impact on the development of P(3HO) and other PHAs as a novel new family of biodegradable functional materials with huge potential in a range of different biomedical applications, particularly CTE, leading to further interest and exploitation of these materials.
Athanasiou T, Patel V, Garas G, et al., 2016, Mentoring perception, scientific collaboration and research performance: is there a ‘gender gap’ in academic medicine? An Academic Health Science Centre perspective, Postgraduate Medical Journal, Vol: 92, Pages: 581-256, ISSN: 1469-0756
OBJECTIVES: The 'gender gap' in academic medicine remains significant and predominantly favours males. This study investigates gender disparities in research performance in an Academic Health Science Centre, while considering factors such as mentoring and scientific collaboration. MATERIALS AND METHODS: Professorial registry-based electronic survey (n=215) using bibliometric data, a mentoring perception survey and social network analysis. Survey outcomes were aggregated with measures of research performance (publications, citations and h-index) and measures of scientific collaboration (authorship position, centrality and social capital). Univariate and multivariate regression models were constructed to evaluate inter-relationships and identify gender differences. RESULTS: One hundred and four professors responded (48% response rate). Males had a significantly higher number of previous publications than females (mean 131.07 (111.13) vs 79.60 (66.52), p=0.049). The distribution of mentoring survey scores between males and females was similar for the quality and frequency of shared core, mentor-specific and mentee-specific skills. In multivariate analysis including gender as a variable, the quality of managing the relationship, frequency of providing corrective feedback and frequency of building trust had a statistically significant positive influence on number of publications (all p<0.05). CONCLUSIONS: This is the first study in healthcare research to investigate the relationship between mentoring perception, scientific collaboration and research performance in the context of gender. It presents a series of initiatives that proved effective in marginalising the gender gap. These include the Athena Scientific Women's Academic Network charter, new recruitment and advertisement strategies, setting up a 'Research and Family Life' forum, establishing mentoring circles for women and projecting female role models.
Gara E, Kiraly SZ, Kiszler G, et al., 2016, FOXO1A modifies arterial and venous endothelial development from human pluripotent stem cells; they establish 3D vascular structures in vitro and quantifiable vascular networks in vivo, Congress of the European-Society-of-Cardiology (ESC), Publisher: Oxford University Press, Pages: 703-703, ISSN: 1522-9645
Fedorowski A, Yasa E, Ricci F, et al., 2016, Hospital admissions for syncope and orthostatic hypotension predict incident cardiovascular disease in older middle-aged patients, Congress of the European-Society-of-Cardiology (ESC), Publisher: Oxford University Press (OUP), Pages: 699-699, ISSN: 1522-9645
Owen TJ, Smith JG, Garcia D, et al., 2016, Towards an engineered heart tissue model of HCM using hiPSC expressing the ACTC E99K mutation, Frontiers in CardioVascular Biology Meeting (FCVB), Publisher: Oxford University Press, Pages: S32-S32, ISSN: 1755-3245
Foldes G, Hellen N, Vittay O, et al., 2016, Hippo signalling modulates survival of human induced pluripotent stem cell-derived cardiomyocytes, Frontiers in CardioVascular Biology Meeting (FCVB), Publisher: Oxford University Press, Pages: S92-S93, ISSN: 1755-3245
Elder JM, O'Gara P, Sanchez-Alonso JL, et al., 2016, Doxorubicin modulates the real-time oxygen consumption rate of freshly isolated adult rat and human ventricular cardiomyocytes, Frontiers in CardioVascular Biology Meeting (FCVB), Publisher: Oxford University Press, Pages: S111-S111, ISSN: 1755-3245
Perbellini F, Watson S, Scigliano M, et al., 2016, Cell therapy of the heart studied using adult myocardial slices in vitro, Cardiovascular Research, Vol: 111, Pages: S94-S94, ISSN: 1755-3245
Mansfield C, Mawad D, Perbellini F, et al., 2016, A novel conductive patch for application in cardiac tissue engineering, Cardiovascular Research, Vol: 111, Pages: S41-S41, ISSN: 1755-3245
Hellen N, Owen T, Jabbour RJ, et al., 2016, Constitutive beta-adrenoceptor-mediated cAMP production controls spontaneous automaticity of human induced pluripotent stem cell-derived cardiomyocytes, Cardiovascular Research, Vol: 111, Pages: S17-S17, ISSN: 1755-3245
Cappelletti S, Ciallella C, Aromatario M, et al., 2016, Takotsubo Cardiomyopathy and Sepsis: A Systematic Review., Angiology, ISSN: 1940-1574
Takotsubo cardiomyopathy (TTC) is characterized by a systolic dysfunction localized in the apical and medial aspect of the left ventricle. It is usually related to physical or emotional stress. Recent evidence highlighting the role of infection led us to analyze the links between TTC and sepsis. A systematic review of the literature was undertaken to assess any trends in clinical findings, diagnosis, and outcomes in such patients. We identified 23 selected papers reporting a total of 26 patients, having sepsis, in whom TTC occurred. For each case, we collected data identifying population characteristics, source of sepsis, clinical disease description, and the results of cardiovascular investigations. The majority of patients were females (n = 16), mean age was 62.8 (14.0 standard deviation) years, and clinical outcome was favorable in 92.3% of the cases once the management of sepsis was initiated. A better understanding of the mechanisms of sepsis-associated TTC may generate novel strategies to treat the complications of this cardiomyopathy and may even help predict and prevent its occurrence.
Leong KMW, Ng FS, Yao C, et al., 2016, Contribution of Conduction and Repolarisation Abnormalities to the Type I Brugada Pattern: A Study Using Non-Invasive Electrocardiographic Imaging, Annual Conference of the British Cardiovascular Society (BCS) on Prediction and Prevention, Publisher: BMJ Publishing Group, Pages: A105-A106, ISSN: 1468-201X
Kooij V, Viswanathan MC, Lee DI, et al., 2016, Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy, Cardiovascular Research, Vol: 110, Pages: 238-248, ISSN: 1755-3245
Aims: Heart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin-cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multi-functional actin-binding protein, whose role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodeling. Methods and Results: Profilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signaling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function. Conclusion: Our results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodeling, and silencing of profilin attenuates the hypertrophic response.
Sikkel MB, Kumar S, Maioli V, et al., 2016, High speed sCMOS-based oblique plane microscopy applied to the study of calcium dynamics in cardiac myocytes, Journal of Biophotonics, Vol: 9, Pages: 311-323, ISSN: 1864-0648
blique plane microscopy (OPM) is a form of light sheet microscopy that uses a single high numerical aperture microscope objective for both fluorescence excitation and collection. In this paper, measurements of the relative collection efficiency of OPM are presented. An OPM system incorporating two sCMOS cameras is then introduced that enables single isolated cardiac myocytes to be studied continuously for 22 seconds in two dimensions at 667 frames per second with 960 × 200 pixels and for 30 seconds with 960 × 200 × 20 voxels at 25 volumes per second. In both cases OPM is able to record in two spectral channels, enabling intracellular calcium to be studied via the probe Fluo-4 AM simultaneously with the sarcolemma and transverse tubule network via the membrane dye Cellmask Orange. The OPM system was then applied to determine the spatial origin of spontaneous calcium waves for the first time and to measure the cell transverse tubule structure at their point of origin. Further results are presented to demonstrate that the OPM system can also be used to study calcium spark parameters depending on their relationship to the transverse tubule structure.
Morley-Smith AC, Hayward C, Harding SE, et al., 2016, Gene therapy for heart failure: The end of the beginning?, Dialogues in Cardiovascular Medicine, Vol: 21, Pages: 45-58, ISSN: 1272-9949
New therapies are required to improve myocardial function in patients with severe heart failure. Within the failing cardiomyocyte, a fundamental abnormality and potential therapeutic target is dysfunctional cellular calcium homeostasis and excitation-contraction coupling. Viral vector-mediated delivery and transduction of cardiomyocytes with a cardiac sarco(endo)plasmic reticulum Ca2+ ATPase type 2a (SERCA2a) transgene can recover electrophysiological properties and contractile function in animal models and in ex vivo human cardiomyocytes. However, a recent phase 2b study failed to show clinical benefit in heart failure patients. This article reflects on the experience to date and looks ahead to what is next in gene therapy for heart failure.
Merkely B, Gara E, Lendvai Z, et al., 2015, Signaling via PI3K/FOXO1A pathway modulates formation and survival of human embryonic stem cell-derived endothelial cells, Stem Cells and Development, Vol: 24, Pages: 869-878, ISSN: 1557-8534
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