Publications
302 results found
Kane C, Terracciano CM, 2015, Induced pluripotent stem cell-derived cardiac myocytes to understand and test calcium handling: Pie in the sky?, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 89, Pages: 376-378, ISSN: 0022-2828
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- Citations: 8
Kane C, Dias P, Gorelik J, et al., 2015, Human Cardiac Fibroblasts Increase SR-Dependency of Induced Pluripotent Stem Cell-Derived Cardiomyocyte Calcium Handling by Increasing SR Calcium Uptake and SERCA2a Expression via Direct Physical Contact, Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association (AHA), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Kane C, Couch L, Terracciano CMN, 2015, Excitation-contraction coupling of human induced pluripotent stem cell-derived cardiomyocytes, Frontiers in Cell and Developmental Biology, Vol: 3, Pages: 59-59, ISSN: 2296-634X
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold enormous potential in many fields of cardiovascular research. Overcoming many of the limitations of their embryonic counterparts, the application of iPSC-CMs ranges from facilitating investigation of familial cardiac disease and pharmacological toxicity screening to personalized medicine and autologous cardiac cell therapies. The main factor preventing the full realization of this potential is the limited maturity of iPSC-CMs, which display a number of substantial differences in comparison to adult cardiomyocytes. Excitation-contraction (EC) coupling, a fundamental property of cardiomyocytes, is often described in iPSC-CMs as being more analogous to neonatal than adult cardiomyocytes. With Ca(2+) handling linked, directly or indirectly, to almost all other properties of cardiomyocytes, a solid understanding of this process will be crucial to fully realizing the potential of this technology. Here, we discuss the implications of differences in EC coupling when considering the potential applications of human iPSC-CMs in a number of areas as well as detailing the current understanding of this fundamental process in these cells.
Kane C, Dias P, Gorelik J, et al., 2015, Human cardiac fibroblasts increase SR-dependency of induced pluripotent stem cell-derived cardiomyocyte calcium handling by manipulating SR uptake and SERCA2a expression via direct physical contact, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 776-776, ISSN: 0195-668X
Ibrahim M, Nader A, Yacoub MH, et al., 2015, Manipulation of sarcoplasmic reticulum Ca<SUP>2+</SUP> release in heart failure through mechanical intervention, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 593, Pages: 3253-3259, ISSN: 0022-3751
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- Citations: 10
Zaman JAB, Al-Aidarous S, Alayoubi S, et al., 2015, Orthogonal pacing reveals anisotropy in isolated rat atria and direction dependence of novel electrogram markers on a hitherto unprecedented scale, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 216-216, ISSN: 0195-668X
Trantidou T, Terracciano CM, Kontziampasis D, et al., 2015, Biorealistic cardiac cell culture platforms with integrated monitoring of extracellular action potentials, Scientific Reports, Vol: 5, ISSN: 2045-2322
Current platforms for in vitro drug development utilize confluent, unorganized monolayers of heart cells to study the effect on action potential propagation. However, standard cell cultures are of limited use in cardiac research, as they do not preserve important structural and functional properties of the myocardium. Here we present a method to integrate a scaffolding technology with multi-electrode arrays and deliver a compact, off-the-shelf monitoring platform for growing biomimetic cardiac tissue. Our approach produces anisotropic cultures with conduction velocity (CV) profiles that closer resemble native heart tissue; the fastest impulse propagation is along the long axis of the aligned cardiomyocytes (CVL) and the slowest propagation is perpendicular (CVT), in contrast to standard cultures where action potential propagates isotropically (CVL ≈ CVT). The corresponding anisotropy velocity ratios (CVL/CVT = 1.38 – 2.22) are comparable with values for healthy adult rat ventricles (1.98 – 3.63). The main advantages of this approach are that (i) it provides ultimate pattern control, (ii) it is compatible with automated manufacturing steps and (iii) it is utilized through standard cell culturing protocols. Our platform is compatible with existing read-out equipment and comprises a prompt method for more reliable CV studies.
Terracciano CM, Navaratnarajah M, Bello SOZ, et al., 2015, Does Size Matter? In search of a physiological definition of myocardial atrophy, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 65, Pages: 2154-2156, ISSN: 0735-1097
Cartledge JE, Kane C, Dias P, et al., 2015, Functional crosstalk between cardiac fibroblasts and adult cardiomyocytes by soluble mediators, CARDIOVASCULAR RESEARCH, Vol: 105, Pages: 260-270, ISSN: 0008-6363
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- Citations: 110
Du DTM, Hellen N, Kane C, et al., 2015, Action potential morphology of human induced pluripotent stem cell-derived cardiomyocytes does not predict cardiac chamber specificity and is dependent on cell density., Biophys J, Vol: 108, Pages: 1-4
Previous studies investigating human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have proposed the distinction of heart chamber-specific (atrial, ventricular, pacemaker) electrophysiological phenotypes based on action potential (AP) morphology. This suggestion has been based on data acquired using techniques that allow measurements from only a small number of cells and at low seeding densities. It has also been observed that density of culture affects the properties of iPSC-CMs. Here we systematically analyze AP morphology from iPSC-CMs at two seeding densities: 60,000 cells/well (confluent monolayer) and 15,000 cells/well (sparsely-seeded) using a noninvasive optical method. The confluent cells (n = 360) demonstrate a series of AP morphologies on a normally distributed spectrum with no evidence for specific subpopulations. The AP morphologies of sparsely seeded cells (n = 32) displayed a significantly different distribution, but even in this case there is no clear evidence of chamber-specificity. Reduction in gap junction conductance using carbenoxolone only minimally affected APD distribution in confluent cells. These data suggest that iPSC-CMs possess a sui generis AP morphology, and when observed in different seeding densities may encompass any shape including those resembling chamber-specific subtypes. These results may be explained by different functional maturation due to culture conditions.
Camelliti P, Al-Ayoubi S, Terracciano C, 2014, MAPPING REGIONAL REPOLARISATION GRADIENTS IN THE FAILING HUMAN VENTRICLE USING CARDIAC SLICES, Autumn Meeting of the British-Society-for-Cardiovascular-Research (BSCR) on Cardiovascular Signalling in Health and Disease, Publisher: BMJ PUBLISHING GROUP, ISSN: 1355-6037
Navaratnarajah M, Siedlecka U, Ibrahim M, et al., 2014, Impact of Combined Clenbuterol and Metoprolol Therapy on Reverse Remodelling during Mechanical Unloading, PLOS One, Vol: 9, ISSN: 1932-6203
Background: Clenbuterol (Cl), a b2 agonist, is associated with enhanced myocardial recovery during left ventricular assistdevice (LVAD) support, and exerts beneficial remodelling effects during mechanical unloading (MU) in rodent heart failure(HF). However, the specific effects of combined Cl+b1 blockade during MU are unknown.Methods and Results: We studied the chronic effects (4 weeks) of b2-adrenoceptor (AR) stimulation via Cl (2 mg/kg/day)alone, and in combination with b1-AR blockade using metoprolol ((Met), 250 mg/kg/day), on whole heart/cell structure,function and excitation-contraction (EC) coupling in failing (induced by left coronary artery (LCA) ligation), and unloaded(induced by heterotopic abdominal heart transplantation (HATx)) failing rat hearts. Combined Cl+Met therapy displayedfavourable effects in HF: Met enhanced Cl’s improvement in ejection fraction (EF) whilst preventing Cl-induced hypertrophyand tachycardia. During MU combined therapy was less beneficial than either mono-therapy. Met, not Cl, prevented MUinducedmyocardial atrophy, with increased atrophy occurring during combined therapy. MU-induced recovery of Ca2+transient amplitude, speed of Ca2+ release and sarcoplasmic reticulum Ca2+ content was enhanced equally by Cl or Metmono-therapy, but these benefits, together with Cl’s enhancement of sarcomeric contraction speed, and MU-inducedrecovery of Ca2+ spark frequency, disappeared during combined therapy.Conclusions: Combined Cl+Met therapy shows superior functional effects to mono-therapy in rodent HF, but appearsinferior to either mono-therapy in enhancing MU-induced recovery of EC coupling. These results suggest that combined b2-AR simulation +b1-AR blockade therapy is likely to be a safe and beneficial therapeutic HF strategy, but is not as effective asmono-therapy in enhancing myocardial recovery during LVAD support.
Fernandez-Fuente M, Terracciano CM, Martin-Duque P, et al., 2014, Calcium homeostasis in myogenic differentiation factor 1 (MyoD)-transformed, virally-transduced, skin-derived equine myotubes, PLoS ONE, Vol: 9, ISSN: 1932-6203
Dysfunctional skeletal muscle calcium homeostasis plays a central role in the pathophysiology of several human and animalskeletal muscle disorders, in particular, genetic disorders associated with ryanodine receptor 1 (RYR1) mutations, such asmalignant hyperthermia, central core disease, multiminicore disease and certain centronuclear myopathies. In addition,aberrant skeletal muscle calcium handling is believed to play a pivotal role in the highly prevalent disorder of Thoroughbredracehorses, known as Recurrent Exertional Rhabdomyolysis. Traditionally, such defects were studied in human and equinesubjects by examining the contractile responses of biopsied muscle strips exposed to caffeine, a potent RYR1 agonist.However, this test is not widely available and, due to its invasive nature, is potentially less suitable for valuable animals intraining or in the human paediatric setting. Furthermore, increasingly, RYR1 gene polymorphisms (of unknownpathogenicity and significance) are being identified through next generation sequencing projects. Consequently, we haveinvestigated a less invasive test that can be used to study calcium homeostasis in cultured, skin-derived fibroblasts that areconverted to the muscle lineage by viral transduction with a MyoD (myogenic differentiation 1) transgene. Similar modelshave been utilised to examine calcium homeostasis in human patient cells, however, to date, there has been no detailedassessment of the cells’ calcium homeostasis, and in particular, the responses to agonists and antagonists of RYR1. Here wedescribe experiments conducted to assess calcium handling of the cells and examine responses to treatment withdantrolene, a drug commonly used for prophylaxis of recurrent exertional rhabdomyolysis in horses and malignanthyperthermia in humans.
Humphrey E, Trantidou T, Kane C, et al., 2014, Improved calcium cycling is associated with microtubule reorganisation in anisotropic cardiomyocyte cultures, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Kane C, Dias P, Helen N, et al., 2014, Direct contact between human cardiac fibroblasts and human induced pluripotent stem cell-derived cardiomyocytes counteracts changes in calcium cycling induced by soluble mediators, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Hellen N, Wheeler JX, Ricardo CP, et al., 2014, Effect of T3 on human induced pluripotent stem cell-derived cardiomyocyte maturation, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
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- Citations: 4
Alayoubi S, Al-Aidarous S, Ricardo CP, et al., 2014, Slowed conduction velocity in spontaneously hypertensive rat hearts is due to disease related remodelling, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Trantidou T, Tariq M, Terracciano CM, et al., 2014, Parylene C-Based Flexible Electronics for pH Monitoring Applications, Sensors, Vol: 14, Pages: 11629-11639, ISSN: 1424-8239
Emerging materials in the field of implantable sensors should meet the needs for biocompatibility; transparency; flexibility and integrability. In this work; we present an integrated approach for implementing flexible bio-sensors based on thin Parylene C films that serve both as flexible support substrates and as active H+ sensing membranes within the same platform. Using standard micro-fabrication techniques; a miniaturized 40-electrode array was implemented on a 5 μm-thick Parylene C film. A thin capping film (1 μm) of Parylene on top of the array was plasma oxidized and served as the pH sensing membrane. The sensor was evaluated with the use of extended gate discrete MOSFETs to separate the chemistry from the electronics and prolong the lifetime of the sensor. The chemical sensing array spatially maps the local pH levels; providing a reliable and rapid-response (<5 s) system with a sensitivity of 23 mV/pH. Moreover; it preserves excellent encapsulation integrity and low chemical drifts (0.26–0.38 mV/min). The proposed approach is able to deliver hybrid flexible sensing platforms that will facilitate concurrent electrical and chemical recordings; with application in real-time physiological recordings of organs and tissues.
Trantidou T, Rao C, Barrett H, et al., 2014, Selective hydrophilic modification of Parylene C films: a new approach to cell micro-patterning for synthetic biology applications, Biofabrication, Vol: 6, ISSN: 1758-5090
We demonstrate a simple, accurate and versatile method to manipulate Parylene C, a material widely known for its high biocompatibility, and transform it to a substrate that can effectively control the cellular microenvironment and consequently affect the morphology and function of the cells in vitro. The Parylene C scaffolds are fabricated by selectively increasing the material's surface water affinity through lithography and oxygen plasma treatment, providing free bonds for attachment of hydrophilic biomolecules. The micro-engineered constructs were tested as culture scaffolds for rat ventricular fibroblasts and neonatal myocytes (NRVM), toward modeling the unique anisotropic architecture of native cardiac tissue. The scaffolds induced the patterning of extracellular matrix compounds and therefore of the cells, which demonstrated substantial alignment compared to typical unstructured cultures. Ca2+ cycling properties of the NRVM measured at rates of stimulation 0.5–2 Hz were significantly modified with a shorter time to peak and time to 90% decay, and a larger fluorescence amplitude (p < 0.001). The proposed technique is compatible with standard cell culturing protocols and exhibits long-term pattern durability. Moreover, it allows the integration of monitoring modalities into the micro-engineered substrates for a comprehensive interrogation of physiological parameters.
Ibrahim M, Edlin JCE, Nader A, et al., 2014, Recovery of the failing heart: emerging approaches and mechanisms in excitation-contraction coupling, F1000prime reports, Vol: 6, ISSN: 2051-7599
Heart failure (HF) is a growing cause of morbidity and mortality globally. All clinical therapies that reduce mortality have been shown to induce reverse remodeling. In this article, we discuss a conceptual approach to the evolving treatment of HF using emerging treatment modalities for the drug-refractory patient. This approach is based on the combinatorial, integrated application of therapies shown to influence reverse remodeling in the laboratory.
Shintani Y, Drexler HCA, Kioka H, et al., 2014, Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2, EMBO Reports, Vol: 15, Pages: 438-445, ISSN: 1469-221X
Toll-like receptor 9 (TLR9) has a key role in the recognition of pathogen DNA in the context of infection and cellular DNA that is released from damaged cells. Pro-inflammatory TLR9 signalling pathways in immune cells have been well investigated, but we have recently discovered an alternative pathway in which TLR9 temporarily reduces energy substrates to induce cellular protection from stress in cardiomyocytes and neurons. However, the mechanism by which TLR9 stimulation reduces energy substrates remained unknown. Here, we identify the calcium-transporting ATPase, SERCA2 (also known as Atp2a2), as a key molecule for the alternative TLR9 signalling pathway. TLR9 stimulation reduces SERCA2 activity, modulating Ca(2+) handling between the SR/ER and mitochondria, which leads to a decrease in mitochondrial ATP levels and the activation of cellular protective machinery. These findings reveal how distinct innate responses can be elicited in immune and non-immune cells--including cardiomyocytes--using the same ligand-receptor system.
Rao C, 2014, The Effect of Biomimetic Tissue Engineering Constructs on the Phenotype of Immature Cardiomyocytes
Several studies have suggested that induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) are sufficiently comparable to adult myocardium to facilitate application in a wide range of toxicology, drug development and disease modelling applications. Evidence from the literature is however, inconstant. We tested the hypothesis that iPSC-CM and hESC-CM have a predictable and consistent response to pharmacological manipulation, finding in many instances this was not true. We then focused on methods to improve the maturity of iPSC-CM, in particular, on the effect of cell alignment on intra-cellular Ca2+ cycling. For much of the exploratory work and validation of the techniques we used neonatal rat ventricular myocytes (NRVM). They are more readily available than iPSC-CM and have similar properties. We hypothesized that cell alignment of immature cardiomyocytes, in a fashion analogous to the adult myocardium, would improve the speed of intra-cellular Ca2+ cycling. We found that structured culture modulated Ca2+ cycling in iPSC-CM, and that this was probably due to improvements in sarcoplasmic reticulum Ca2+ release mechanisms. In contrast to NRVM, structured culture did not appear to have a significant effect on Ca2+ extrusion mechanisms in iPSC-CM. Furthermore, we found that the physical properties of the constructs made it difficult to fully explore the mechanisms underlying these experimental findings. Consequently, we developed and validated novel constructs which would facilitate exploration of the mechanisms underlying the association between cell-alignment and the functional properties of immature cardiomyocytes. These findings suggest that tissue engineering approaches are likely to be relevant to in vitro modelling with iPSC-CM. An important next step will be to conclusively demonstrate that these techniques overcome the limitations of iPSC-CM highlighted in the first part of this thesis, and
Rao C, Barratt H, Prodromakis T, et al., 2014, Tissue Engineering Techniques in Cardiac Repair and Disease Modelling, CURRENT PHARMACEUTICAL DESIGN, Vol: 20, Pages: 2048-2056, ISSN: 1381-6128
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- Citations: 3
Fernandez-Fuente M, Martin-Duque P, Vassaux G, et al., 2014, Adenovirus-mediated expression of myogenic differentiation factor 1 (MyoD) in equine and human dermal fibroblasts enables their conversion to caffeine-sensitive myotubes, NEUROMUSCULAR DISORDERS, Vol: 24, Pages: 250-258, ISSN: 0960-8966
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- Citations: 6
Alayoubi S, Ricardo CP, Zaman J, et al., 2014, Electrophysiological and Structural Left Ventricle Remodelling in Spontaneously Hypertensive Rat Hearts: A Multicellular Study, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 122A-122A, ISSN: 0006-3495
Candasamy AJ, Haworth RS, Cuello F, et al., 2014, Phosphoregulation of the Titin-cap Protein Telethonin in Cardiac Myocytes, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 1282-1293
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- Citations: 32
Kane C, Cartledge J, Dias P, et al., 2014, CARDIOMYOCYTES INFLUENCE FIBROBLAST PROLIFERATION AND α-SMOOTH MUSCLE ACTIN EXPRESSION VIA THE SECRETION OF PARACRINE MEDIATORS, 40th Anniversary Celebration of the BSCR on Cardiovascular Research - Bench to Bedside and Back Again, Publisher: BMJ PUBLISHING GROUP, Pages: A6-A7, ISSN: 1355-6037
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- Citations: 1
Dias P, Navaratnarajah M, Alayoubi S, et al., 2014, IVABRADINE ALTERS FIBROBLAST NUMBER AND TRANSFORMING GROWTH FACTOR BETA 1 EXPRESSION IN HEART FAILURE, HEART, Vol: 100, Pages: A4-A4, ISSN: 1355-6037
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- Citations: 1
Kane C, Hellen N, Trantidou T, et al., 2014, Direct Contact Between Human Cardiac Fibroblasts and Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Counteracts Changes in Calcium Cycling Induced by Soluble Mediators, Publisher: Elsevier, Pages: 730a-730a
Trantidou T, Tariq M, Pinto K, et al., 2014, A lab-on-chip approach for monitoring the electrochemical activity of biorealistic cell cultures, IEEE International Symposium on Circuits and Systems (ISCAS), Publisher: IEEE, Pages: 642-645, ISSN: 0271-4302
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