Imperial College London

DrGaborFoldes

Faculty of MedicineNational Heart & Lung Institute

Research Fellow
 
 
 
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g.foldes

 
 
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ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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69 results found

Berecz T, Husvéth-Tóth M, Mioulane M, Merkely B, Apáti Á, Földes Get al., 2019, Generation and analysis of pluripotent stem cell-derived cardiomyocytes and endothelial cells for high content screening purposes, Methods in Molecular Biology, ISSN: 1940-6029

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.

Journal article

Madeddu P, Foldes G, 2019, Editorial: Multicellularity in the cardiovascular system, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X

Journal article

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.

Journal article

Karhu ST, Välimäki MJ, Jumppanen M, Kinnunen SM, Pohjolainen L, Leigh RS, Auno S, Földes G, Boije Af Gennäs G, Yli-Kauhaluoma J, Ruskoaho H, Talman Vet 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.

Journal article

Berecz T, Molnar A, Haltrich I, Homolya L, Harding S, Rethelyi J, Merkely B, Foldes G, Apati Aet 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

Conference paper

Foldes G, Lawlor K, Harding SE, Randi AMet 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

Conference paper

Husveth-Toth M, Gara E, Nemes A, Molnar AA, Csepi K, Radovits T, Harding SE, Merkely B, Foldes Get 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

Conference paper

Karhu ST, Valimaki M, Jumppanen M, Pohjolainen L, Leigh R, Foldes G, Af Gennas GB, Yli-Kauhaluoma J, Ruskoaho H, Talman Vet 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

Conference paper

Ricardo CP, Hellen N, Foldes G, Kodagoda T, Terracciano CM, Duchen MR, Harding SEet 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

Conference paper

Ontoria-Oviedo I, Dorronsoro A, Cervera AM, Foldes G, Tejedor S, Rueda J, Harding SE, McCreath KJ, Montero JA, Sepulveda Pet 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

Conference paper

Molnar AA, Gara E, Nemes A, Toth M, Kiraly S, Polos M, Merkely B, Foldes Get 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

Conference paper

Gara E, Molnar AA, Merkely B, Foeldes Get 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

Journal article

Foldes G, Gara E, Husveth-Toth M, Nemes A, Merkely B, Harding SEet 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

Conference paper

Gara E, Kiraly SZ, Kiszler G, Skopal J, Polos M, Merkely B, Harding SE, Foldes Get 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

Conference paper

Kosztin A, Széplaki G, Kovács A, Földes G, Szokodi I, Nagy KV, Kutyifa V, Fórizs É, Végh EM, Gellér L, Becker D, Aradi D, Merkely Bet 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.

Journal article

Williams DJ, Archer R, Archibald P, Bantounas I, Baptista R, Barker R, Barry J, Bietrix F, Blair N, Braybrook J, Campbell J, Canham M, Chandra A, Foldes G, Gilmanshin R, Girard M, Gorjup E, Hewitt Z, Hourd P, Hyllner J, Jesson H, Kee J, Kerby J, Kotsopoulou N, Kowalski S, Leidel C, Marshall D, Masi L, McCall M, McCann C, Medcalf N, Moore H, Ozawa H, Pan D, Parmar M, Plant AL, Reinwald Y, Sebastian S, Stacey G, Thomas RJ, Thomas D, Thurman-Newell J, Turner M, Vitillio L, Wall I, Wilson A, Wolfrum J, Yang Y, Zimmerman Het 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.

Journal article

Foldes G, Hellen N, Vittay O, Harding SEet 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

Conference paper

Merkely B, Gara E, Lendvai Z, Skopal J, Leja T, Zhou W, Kosztin A, Varady G, Mioulane M, Bagyura Z, Nemeth T, Harding SE, Foldes Get 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

Journal article

Abdelwahid E, Kalvelyte A, Stulpinas A, Teixeira de Carvalho KA, Guarita-Souza LC, Foldes Get 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.

Journal article

Dolatshad NF, Hellen N, Jabbour R, Harding SE, Foldes Get 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.

Journal article

Ebner N, Foeldes G, Schomburg L, Renko K, Springer J, Jankowska EA, Sharma R, Genth-Zotz S, Doehner W, Anker SD, von Haehling Set 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.

Journal article

Gara E, Merkely B, Skopal J, Polos M, Hartyanszky I, Harding SE, Foldes Get 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

Conference paper

Jacquet L, Neueder A, Földes G, Karagiannis P, Hobbs C, Jolinon N, Mioulane M, Sakai T, Harding SE, Ilic Det 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.

Journal article

Gara EE, Merkely B, Skopal J, Sampson R, Polos M, Hartyanszky I, Harding SE, Foldes Get 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

Journal article

Lawlor K, Harding S, Randi A, Foldes Get 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

Conference paper

Reed DM, Foldes G, Kirkby NS, Ahmetaj-Shala B, Mataragka S, Mohamed NA, Francis C, Gara E, Harding SE, Mitchell JAet 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

Journal article

Chahine MN, Mioulane M, Sikkel MB, O'Gara P, Dos Remedios CG, Pierce GN, Lyon AR, Foldes G, Harding SEet al., 2014, Nuclear pore rearrangements and nuclear trafficking in cardiomyocytes from rat and human failing hearts, Cardiovascular Research, Vol: 105, Pages: 31-43, ISSN: 1755-3245

Journal article

Foldes G, Matsa E, Kriston-Vizi J, Leja T, Amisten S, Kolker L, Kodagoda T, Dolatshad NF, Mioulane M, Vauchez K, Aranyi T, Ketteler R, Schneider MD, Denning C, Harding SEet al., 2014, Aberrant alpha-Adrenergic Hypertrophic Response in Cardiomyocytes from Human Induced Pluripotent Cells, Stem Cell Reports, Vol: 3, Pages: 905-914, ISSN: 2213-6711

Journal article

Semjeni M, Foldes G, Szigeti K, Kovacs N, Mathe Det al., 2014, ROLE OF IN VIVO IMAGING IN CARDIVASCULAR RESEARCH, DIAGNOSIS AND TREATMENT, 82nd Congress of the European-Atherosclerosis-Society (EAS), Publisher: ELSEVIER IRELAND LTD, Pages: E300-E300, ISSN: 0021-9150

Conference paper

Foldes G, Gara E, Lendvai Z, Mathe D, Skopal J, Leja T, Kosztin A, Merkely B, Harding SEet al., 2014, Signalling via pi3k/foxo1a pathway modulates formation and survival of human embryonic stem cell-derived endothelial cells, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363

Journal article

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