Publications
464 results found
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.
Gouadon E, Moore-Morris T, Smit NW, et al., 2015, Concise Review: Pluripotent Stem Cell-Derived Cardiac Cells, A Promising Cell Source for Therapy of Heart Failure: Where Do We Stand?, Stem Cells, Vol: 34, Pages: 34-43, ISSN: 1549-4918
Heart failure is still a major cause of hospitalization and mortality in developed countries. Many clinical trials have tested the use of multipotent stem cells as a cardiac regenerative medicine. The benefit for the patients of this therapeutic intervention has remained limited. Herein, we review the pluripotent stem cells as a cell source for cardiac regeneration. We more specifically address the various challenges of this cell therapy approach. We question the cell delivery systems, the immune tolerance of allogenic cells, the potential proarrhythmic effects, various drug mediated interventions to facilitate cell grafting and, finally, we describe the pathological conditions that may benefit from such an innovative approach. As members of a transatlantic consortium of excellence of basic science researchers and clinicians, we propose some guidelines to be applied to cell types and modes of delivery in order to translate pluripotent stem cell cardiac derivatives into safe and effective clinical trials.
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
Derda AA, O'Gara P, Tranter MH, et al., 2015, Characterization of cardiac stress (Takotsubo syndrome)-related miRNAs ex vivo, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 1208-1209, ISSN: 0195-668X
Dyer BT, Elder JM, Lagarto J, et al., 2015, Application of label-free autofluorescence lifetime in vivo to measure changes in myocardial fibrosis and metabolism in a doxorubicin cardiomyopathy heart failure model, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 151-151, ISSN: 0195-668X
Dyer BT, Elder JM, Lagarto J, et al., 2015, LABEL-FREE AUTOFLUORESCENCE LIFETIME TO ASSESS CHANGES IN MYOCARDIAL FIBROSIS AND METABOLISM <i>IN VIVO</i> IN A DOXORUBICIN CARDIOMYOPATHY HEART FAILURE MODEL, British-Cardiac-Society (BCS) Annual Conference on Hearts and Genes, Publisher: BMJ PUBLISHING GROUP, Pages: A94-A94, ISSN: 1355-6037
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.
Noseda M, Harada M, McSweeney S, et al., 2015, PDGFRα demarcates the cardiogenic clonogenic Sca1(+) stem/progenitor cell in adult murine myocardium, Nature Communications, Vol: 6, ISSN: 2041-1723
Cardiac progenitor/stem cells in adult hearts represent an attractive therapeutic target for heart regeneration, though (inter)-relationships among reported cells remain obscure. Using single-cell qRT-PCR and clonal analyses, here we define four subpopulations of cardiac progenitor/stem cells in adult mouse myocardium all sharing stem cell antigen-1 (Sca1), based on side population (SP) phenotype, PECAM-1 (CD31) and platelet-derived growth factor receptor-α (PDGFRα) expression. SP status predicts clonogenicity and cardiogenic gene expression (Gata4/6, Hand2 and Tbx5/20), properties segregating more specifically to PDGFRα(+) cells. Clonal progeny of single Sca1(+) SP cells show cardiomyocyte, endothelial and smooth muscle lineage potential after cardiac grafting, augmenting cardiac function although durable engraftment is rare. PDGFRα(-) cells are characterized by Kdr/Flk1, Cdh5, CD31 and lack of clonogenicity. PDGFRα(+)/CD31(-) cells derive from cells formerly expressing Mesp1, Nkx2-5, Isl1, Gata5 and Wt1, distinct from PDGFRα(-)/CD31(+) cells (Gata5 low; Flk1 and Tie2 high). Thus, PDGFRα demarcates the clonogenic cardiogenic Sca1(+) stem/progenitor cell.
Roca-Alonso L, Castellano L, Mills A, et al., 2015, Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in beta-adrenergic signaling and enhances apoptosis, Cell Death & Disease, Vol: 6, ISSN: 2041-4889
The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks ofcardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typicallyprogresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development ofcardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles inboth cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellularprocesses downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application toisolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts followingmyocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating theβ-adrenergic pathway, where preferential β1- and β2-adrenoceptor (β1AR and β2AR) direct inhibition is combined with Giα-2targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, wedemonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygenspecies generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. Inconclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotectiveand anti-tumorigenic strategy for anthracyclines.
Hayward C, Banner NR, Morley-Smith A, et al., 2015, The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective, HUMAN GENE THERAPY, Vol: 26, Pages: 293-304, ISSN: 1043-0342
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- Citations: 28
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
Tranter MH, Wright PT, Harding SE, et al., 2015, Development of therapeutic and preventative strategies for takotsubo syndrome, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 17, Pages: 30-30, 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
Fiedler LR, Jenkins M, Maifoshie E, et al., 2014, MAP4K4 MEDIATES CARDIOMYOCYTE CELL DEATH AND POTENTIATES A HEART FAILURE PHENOTYPE, Autumn Meeting of the British-Society-for-Cardiovascular-Research (BSCR) on Cardiovascular Signalling in Health and Disease, Publisher: BMJ PUBLISHING GROUP, ISSN: 1355-6037
Land S, Niederer SA, Louch WE, et al., 2014, Computational modeling of Takotsubo cardiomyopathy: effect of spatially varying β-adrenergic stimulation in the rat left ventricle, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 307, Pages: H1487-H1496, ISSN: 0363-6135
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- Citations: 20
Foldes G, Matsa E, Kriston-Vizi J, et 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
Cardiomyocytes from human embryonic stem cells (hESC-CMs) and induced pluripotent stem cells (hiPSC-CMs) represent new models for drug discovery. Although hypertrophy is a high-priority target, we found that hiPSC-CMs were systematically unresponsive to hypertrophic signals such as the α-adrenoceptor (αAR) agonist phenylephrine (PE) compared to hESC-CMs. We investigated signaling at multiple levels to understand the underlying mechanism of this differential responsiveness. The expression of the normal α1AR gene, ADRA1A, was reversibly silenced during differentiation, accompanied by ADRA1B upregulation in either cell type. ADRA1B signaling was intact in hESC-CMs, but not in hiPSC-CMs. We observed an increased tonic activity of inhibitory kinase pathways in hiPSC-CMs, and inhibition of antihypertrophic kinases revealed hypertrophic increases. There is tonic suppression of cell growth in hiPSC-CMs, but not hESC-CMs, limiting their use in investigation of hypertrophic signaling. These data raise questions regarding the hiPSC-CM as a valid model for certain aspects of cardiac disease.
Chahine MN, Mioulane M, Sikkel MB, et 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
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
Foldes G, Gara E, Lendvai Z, et 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
Gara E, Skopal J, Kosztin A, et al., 2014, Angiogenic potential of human pluripotent stem cell-derived arterial and venous endothelial cells, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Zhou W, Vilar R, Ying L, et al., 2014, Transcriptional regulatory roles of G-quadruplex DNA in promoters of genes involved in beta-adrenergic signaling pathway, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Roca-Alonso L, Castellano L, Mills A, et al., 2014, Myocardial miR-30 down-regulation caused by doxorubicin alters the beta-adrenergic system and mitochondrial death pathways, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Tranter MH, Wright PT, Lyon AR, et al., 2014, Ovariectomy increases epinephrine-induced mortality in a rat takotsubo cardiomyopathy model: the effects of estrogen supplementation, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
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- Citations: 1
Mills AM, Sikkel MB, Kumarswamy R, et al., 2014, miR-1: a link between SERCA2a and the Beta-Adrenoceptor in the failing heart?, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Harding SE, 2014, Large Stem Cell-Derived Cardiomyocyte Grafts: Cellular Ventricular Assist Devices?, MOLECULAR THERAPY, Vol: 22, Pages: 1240-1242, ISSN: 1525-0016
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- Citations: 1
Roca-Alonso L, Castellano L, Mills A, et al., 2014, Myocardial miR-30 down-regulation triggered by doxorubicin drives alterations in the beta-adrenergic pathway and enhances apoptosis, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 16, Pages: 115-115, ISSN: 1388-9842
Reed DM, Foldes G, Gatheral T, et al., 2014, Pathogen Sensing Pathways in Human Embryonic Stem Cell Derived-Endothelial Cells: Role of NOD1 Receptors, PLOS One, Vol: 9, ISSN: 1932-6203
Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage.
Foeldes G, Mioulane M, Kodagoda T, et al., 2014, Immunosuppressive Agents Modulate Function, Growth, and Survival of Cardiomyocytes and Endothelial Cells Derived from Human Embryonic Stem Cells, STEM CELLS AND DEVELOPMENT, Vol: 23, Pages: 467-476, ISSN: 1547-3287
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- Citations: 6
Wright PT, Nikolaev VO, O'Hara T, et al., 2014, Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 67, Pages: 38-48, ISSN: 0022-2828
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- Citations: 82
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