73 results found
Lyon A, Babalis D, Morley-Smith AC, et al., 2020, Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device – the SERCA-LVAD TRIAL, Gene Therapy, ISSN: 0969-7128
The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. Enrolled subjects were randomised to receive a single intracoronary infusion of 1x1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort, which may help guide future trial design.
Gara E, Zucchelli E, Jakus Z, et al., 2020, Building functional vascular grafts from human pluripotent stem cells-derived endothelial cells, Publisher: ELSEVIER SCI LTD, Pages: S10-S10, ISSN: 1465-3249
Zucchelli E, Majid QA, Foldes G, 2019, New artery of knowledge: 3D models of angiogenesis, Vascular Biology, Vol: 1, Pages: H135-H143, ISSN: 2516-5658
Angiogenesis and vasculogenesis are complex processes by which new blood vessels are formed and expanded. They play a pivotal role not only in physiological development and growth and tissue and organ repair, but also in a range of pathological conditions, from tumour formation to chronic inflammation and atherosclerosis. Understanding the multistep cell-differentiation programmes and identifying the key molecular players of physiological angiogenesis/vasculogenesis are critical to tackle pathological mechanisms. While many questions are yet to be answered, increasingly sophisticated in vitro, in vivo and ex vivo models of angiogenesis/vasculogenesis, together with cutting-edge imaging techniques, allowed for recent major advances in the field. This review aims to summarise the three-dimensional models available to study vascular network formation and to discuss advantages and limitations of the current systems.
Berecz T, Husvéth-Tóth M, Mioulane M, et al., 2019, Generation and analysis of pluripotent stem cell-derived cardiomyocytes and endothelial cells for high content screening purposes, Imaging and Tracking Stem Cells, Editors: Turksen, Publisher: Humana Press, Pages: 57-77
Human-induced pluripotent stem cells (hiPSCs) and their differentiated derivatives became a new, promising source for in vitro screening techniques. Cell lines derived from healthy individuals can be applied for drug safety testing, while patient-derived cells provide a platform to model diseases in vitro and can be used as a tool for personalized medicine including specific drug efficacy testing and identification of new pharmacological targets as well as for tailoring pharmacological therapies. Efficient differentiation protocols yielding cardiomyocytes or endothelial cells derived from iPSCs have been developed recently. Phenotypic characterization and gene expression profiling of these derivatives can reveal clues for developmental and pathological questions. Moreover, functional analysis and cell-based assays using automated fluorescence imaging platform and high content analysis characterize cell type-specific profiles of hiPSC-derived cardiomyocytes (hiPSC-CM) and endothelial cells (hiPSC-EC) at the cellular and subcellular levels. This can be utilized in a platform which can provide multiple endpoint profiles of candidate compounds.
Madeddu P, Foldes G, 2019, Editorial: Multicellularity in the cardiovascular system, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X
Sweeney M, Foldes G, 2018, Takes two: endothelial-perivascular cell cross-talk in vascular development and disease, Frontiers in Cardiovascular Medicine, Vol: 5, ISSN: 2297-055X
The formation of new blood vessels is a crucial step in the development of any new tissue both during embryogenesis and in vitro models as without sufficient perfusion the tissue will be unable to grow beyond the size where nutrition and oxygenation can be managed by diffusion alone. Endothelial cells are the primary building block of blood vessels and are capable of forming tube like structures independently however they are unable to independently form functional vasculature which is capable of conducting blood flow. This requires support from other structures including supporting perivascular cells and the extracellular matrix. The crosstalk between endothelial cells and perivascular cells is vital in regulating vasculogenesis and angiogenesis and the consequences when this is disrupted can be seen in a variety of congenital and acquired disease states. This review details the mechanisms of vasculogenesis in vivo during embryogenesis and compares this to currently employed in vitro techniques. It also highlights clinical consequences of defects in the endothelial cell—pericyte cross-talk and highlights therapies which are being developed to target this pathway. Improving the understanding of the intricacies of endothelial—pericyte signaling will inform pathophysiology of multiple vascular diseases and allow the development of effective in vitro models to guide drug development and assist with approaches in tissue engineering to develop functional vasculature for regenerative medicine applications.
Karhu ST, Välimäki MJ, Jumppanen M, et al., 2018, Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds, Archives of Toxicology, Vol: 92, Pages: 2897-2911, ISSN: 0340-5761
Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure-toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4. By screening the effects of eight compounds at concentrations ranging from 10 nM up to 30 µM on the viability of eight different cell types, we identified significant cell type- and structure-dependent toxicity profiles. We further characterized two compounds in more detail using high-content analysis. The results highlight the importance of cell type selection for toxicity screening and indicate that stem cells represent the most sensitive screening model, which can detect toxicity that may otherwise remain unnoticed. Furthermore, our structure-toxicity analysis reveals a characteristic dihedral angle in the GATA4-targeted compounds that causes stem cell toxicity and thus helps to direct further drug development efforts towards non-toxic derivatives.
Foldes G, Lawlor K, Harding SE, et al., 2018, STAT3 mediates differentiation and maintenance of human pluripotent stem-derived endothelial cells, 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S39-S39, ISSN: 0008-6363
Background: High plasticity derivatives of human pluripotent stem cells (hPSC) such as embryonic stem cells (hESC) are being intensively developed for their use in endothelial replacement.Methods/Results: In this study, we found that transient addition of Activin A, followed by culture with VEGF165, BMP4 and FGF2 was an effective mechanism to induce differentiation of hESC toward the endothelial lineage. Indeed, human GeneChip microarray analysis revealed that endothelial gene regulatory networks were gradually increased during 12 days of differentiation. Isolated hESC-derived endothelial cells (hESC-EC) expressed mature endothelial-associated genes, including CD31, NRP1, VE-cadherin, Tie2, VWF and ICAM2, reaching levels comparable with human umbilical cord vascular endothelial cells by day 19. We found that a network of CD31+ tubes comprising endothelial precursor cells had formed in culture from 10 days after start of differentiation of hESC. As assessed by automated high content microscopy, the alignment and tube formation of the newly formed CD31+ vascular network were markedly decreased in response to C188-9, a novel small molecule inhibitor of STAT3 transcription factor (tube length: 57%, connected tube area: 22% of those in control, both p<0.001). Human ESC-EC were capable of transdifferentiating into mesenchymal cells in long-term cultures. Endothelial-mesenchymal transition was characterised by gradual loss of endothelial marker expression and increased mesenchymal marker FSP1 expression. We found that inhibition of STAT3 tyr705 phosphorylation by C188-9 resulted in a decreased proliferation of FSP1+ mesenchymal cells (2-fold decrease in Ki67%-positive population, p<0.001), and subsequently reduced number of FSP+ cells (36% reduction, p<0.05). At the same time, C188-9 increased the number of CD31+ hESC-EC by 30% (p=0.05, n=6). Viability remained unchanged in C188-9-treated cells (Topro3 necrosis marker, p=0.32, n=3).Conclusions: These results sugge
Berecz T, Molnar A, Haltrich I, et al., 2018, Cardiomyocytes derived from induced pluripotent stem cells of patient with DiGeorge syndrome show slower beating frequency and higher irregularity, 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, Publisher: Oxford University Press (OUP), Pages: S19-S19, ISSN: 1755-3245
Husveth-Toth M, Gara E, Nemes A, et al., 2018, Human pluripotent stem cell-derived endothelial cells are vasoactive in vitro and capable of engineering 3D vascular grafts, 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, Publisher: Oxford University Press (OUP), Pages: S111-S111, ISSN: 1755-3245
Karhu ST, Valimaki M, Jumppanen M, et al., 2018, Toxicity profiling of cardiac transcription factor-targeted compounds in various cardiac and stem cell types reveals cell type-and compound-dependent toxicity, 5th Congress of the ESC-Council-on-Basic-Cardiovascular-Science on Frontiers in Cardio Vascular Biology, Publisher: Oxford University Press (OUP), Pages: S75-S75, ISSN: 1755-3245
Ricardo CP, Hellen N, Foldes G, et al., 2018, Low levels of the A3243G MTDNA mutation in human induced pluripotent stem cellcardiomyocytes do not cause functional or metabolic disturbances but increase with further passaging, Autumn Meeting of the British-Society-for-Cardiovascular-Research on Cardiac Metabolic Disorders and Mitochondrial Dysfunction, Publisher: BMJ Publishing Group, Pages: A8-A9, ISSN: 1355-6037
Ontoria-Oviedo I, Dorronsoro A, Cervera AM, et al., 2017, Characterisation of iPSCs from a patient with transposition of the great arteries, European-Society-of-Gene-and-Cell-Therapy (ESCGT) Congress, Publisher: Mary Ann Liebert, Pages: A50-A50, ISSN: 1043-0342
Molnar AA, Gara E, Nemes A, et al., 2017, Human pluripotent stem cells-derived endothelial cells for vascular tissue engineering, ESC Annual meeting, Publisher: Oxford University Press (OUP), Pages: 533-534, ISSN: 1522-9645
Gara E, Molnar AA, Merkely B, et al., 2017, Assessing the therapeutic readiness of stem cells for cardiovascular repair, Expert Opinion on Biological Therapy, Vol: 17, Pages: 911-914, ISSN: 1471-2598
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
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
Kosztin A, Széplaki G, Kovács A, et al., 2016, Impact of CT-apelin and NT-proBNP on identifying non-responders to cardiac resynchronization therapy, Biomarkers, Vol: 22, Pages: 279-286, ISSN: 1366-5804
CONTEXT: Assessment of response to cardiac resynchronization therapy (CRT) is essential. OBJECTIVE: To assess the predictive value of CT-apelin together with NT-proBNP in patients undergoing CRT. METHODS: Serum CT-apelin and NT-proBNP were measured by ELISA before, and 6-month after CRT. Primary endpoint was non-response (<4% increase in LVEF) after 6-month. RESULTS: From 81 patients, 15 proved to be non-responders. Six-month CT-apelin was superior compared to NT-proBNP in identifying non-responders by multivariate ROC (CT-apelin:p = 0.01, NT-proBNP:p = 0.13) and by logistic regression (CT-apelin:p = 0.01, NT-proBNP:p = 0.41) analyzes. CONCLUSION: Six-month CT-apelin might be valuable novel biomarker in identifying non-responders to CRT that was superior to NT-proBNP.
Williams DJ, Archer R, Archibald P, et al., 2016, Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14-15 September 2015, Regenerative Medicine, Vol: 11, Pages: 483-492, ISSN: 1746-076X
This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this 'may be difficult for cell-based medicinal products'. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates.
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
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
Abdelwahid E, Kalvelyte A, Stulpinas A, et al., 2015, Stem cell death and survival in heart regeneration and repair, Apoptosis, Vol: 21, Pages: 252-268, ISSN: 1573-675X
Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.
Dolatshad NF, Hellen N, Jabbour R, et al., 2015, G-Protein coupled receptor signalling in pluripotent stem cell-derived cardiovascular cells: Implications for disease modelling, Frontiers in Cell and Developmental Biology, Vol: 3, ISSN: 2296-634X
Human pluripotent stem cell derivatives show promise as an in vitro platform to study a range of human cardiovascular diseases. A better understanding of the biology of stem cells and their cardiovascular derivatives will help to understand the strengths and limitations of this new model system. G-protein coupled receptors (GPCRs) are key regulators of stem cell maintenance and differentiation and have an important role in cardiovascular cell signalling. In this review, we will therefore describe the state of knowledge concerning the regulatory role of GPCRs in both the generation and function of pluripotent stem cell derived-cardiomyocytes, -endothelial and -vascular smooth muscle cells. We will consider how far the in vitro disease models recapitulate authentic GPCR signalling and provide a useful basis for discovery of disease mechanisms or design of therapeutic strategies.
Ebner N, Foeldes G, Schomburg L, et al., 2015, Lipopolysaccharide responsiveness is an independent predictor of death in patients with chronic heart failure, Journal of Molecular and Cellular Cardiology, Vol: 87, Pages: 48-53, ISSN: 1095-8584
BackgroundThe origin of pro-inflammatory activation in chronic heart failure (HF) remains a matter of debate. Lipopolysaccharide (LPS) may enter the blood stream through the morphologically altered and leaky gut barrier. We hypothesized that lower LPS reactivity would be associated with worse survival as compared to normal or higher LPS reactivity.MethodsLPS responsiveness was studied in 122 patients with chronic HF (mean ± SD: age 67.3 ± 10.3 years, 24 female, New York Heart Association class [NYHA] class: 2.5 ± 0.8, left ventricular ejection fraction [LVEF]: 33.5 ± 12.5%) and 27 control subjects of similar age (63.7 ± 7.7 years, p > 0.05). Reference LPS was added at increasing doses to ex vivo whole blood samples and necrosis factor-α (TNFα) was measured. Patients were subgrouped into good- and poor-responder status according to their potential to react to increasing doses of LPS (delta TNFα secretion). The optimal cut-off value was calculated by receiver–operator characteristic curve (ROC) analysis.ResultsA total of 56 patients with chronic HF died from any cause during follow-up. At 24 months, cumulative mortality was 16.4% (95% confidence interval 16.0–16.7%). The delta TNFα value representing the optimal cut-off for the prediction of mortality was 1522 pg/mL (24 months) with a sensitivity of 49.3% (95% confidence interval 37.2–61.4%) and specificity of 81.5% (95% confidence interval 61.9–93.6%). LPS responder status remained an independent predictor of death after multivariable adjustment (hazard ratio 0.09 for good- vs. poor-responders, 95% confidence interval 0.01–0.67, p < 0.05).ConclusionsLPS responsiveness in patients with chronic HF is an independent predictor of death.
Gara E, Merkely B, Skopal J, et al., 2015, Endothelial derivatives of human pluripotent stem cells show antiplatelet effects in 3D culture -steps towards vascular tissue engineering, Congress of the European Society of Cardiology (ESC), Publisher: Oxford University Press, Pages: 947-948, ISSN: 1522-9645
Jacquet L, Neueder A, Földes G, et al., 2015, Three Huntington's Disease Specific Mutation-Carrying Human Embryonic Stem Cell Lines Have Stable Number of CAG Repeats upon In Vitro Differentiation into Cardiomyocytes., PLOS One, Vol: 10, Pages: e0126860-e0126860, ISSN: 1932-6203
Huntington disease (HD; OMIM 143100), a progressive neurodegenerative disorder, is caused by an expanded trinucleotide CAG (polyQ) motif in the HTT gene. Cardiovascular symptoms, often present in early stage HD patients, are, in general, ascribed to dysautonomia. However, cardio-specific expression of polyQ peptides caused pathological response in murine models, suggesting the presence of a nervous system-independent heart phenotype in HD patients. A positive correlation between the CAG repeat size and severity of symptoms observed in HD patients has also been observed in in vitro HD cellular models. Here, we test the suitability of human embryonic stem cell (hESC) lines carrying HD-specific mutation as in vitro models for understanding molecular mechanisms of cardiac pathology seen in HD patients. We have differentiated three HD-hESC lines into cardiomyocytes and investigated CAG stability up to 60 days after starting differentiation. To assess CAG stability in other tissues, the lines were also subjected to in vivo differentiation into teratomas for 10 weeks. Neither directed differentiation into cardiomyocytes in vitro nor in vivo differentiation into teratomas, rich in immature neuronal tissue, led to an increase in the number of CAG repeats. Although the CAG stability might be cell line-dependent, induced pluripotent stem cells generated from patients with larger numbers of CAG repeats could have an advantage as a research tool for understanding cardiac symptoms of HD patients.
Gara EE, Merkely B, Skopal J, et al., 2015, Optimised differentiation and 3D cell culture conditions modulate function and fate of human pluripotent stem cell-derived endothelial cells, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 17, Pages: 372-373, ISSN: 1388-9842
Lawlor K, Harding S, Randi A, et al., 2015, THE REGULATION OF ETS FACTORS IN THE DIFFERENTIATION AND MAINTENANCE OF PLURIPOTENT STEM CELL-DERIVED ENDOTHELIAL CELLS, Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 40-40, ISSN: 1018-1172
Reed DM, Foldes G, Kirkby NS, et al., 2014, Morphology and vasoactive hormone profiles from endothelial cells derived from stem cells of different sources, Biochemical and Biophysical Research Communications, Vol: 455, Pages: 172-177, ISSN: 1090-2104
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