Publications
464 results found
Todorova VB, Baxan N, Delahaye M, et al., 2023, Drug-based mobilisation of mesenchymal stem/stromal cells improves cardiac function post myocardial infarction, Disease Models and Mechanisms, Vol: 16, Pages: 1-28, ISSN: 1754-8403
There is an unmet need for treatments that prevent the progressive cardiac dysfunction following myocardial infarction. Mesenchymal stem/stromal cells (MSCs) are under investigation for cardiac repair; however, culture expansion prior to transplantation is hindering their homing and reparative abilities. Pharmacological mobilisation could be an alternative to MSC transplantation. Here, we report that endogenous MSCs mobilise into the circulation at day 5 post myocardial infarction in male Lewis rats. This mobilisation can be significantly increased by using a combination of the FDA-approved drugs mirabegron (β3-adrenoceptor agonist) and AMD3100 (CXCR4 antagonist). Blinded cardiac magnetic resonance imaging analysis showed the treated group to have increased left ventricular ejection fraction and decreased end systolic volume at 5 weeks post myocardial infarction. The mobilised group had a significant decrease in plasma IL-6 and TNF-α levels, a decrease in interstitial fibrosis, and an increase in the border zone blood vessel density. Conditioned medium from blood-derived MSCs supported angiogenesis in vitro, as shown by tube formation and wound healing assays. Our data suggest a novel pharmacological strategy that enhances myocardial infarction-induced MSC mobilisation and improves cardiac function after myocardial infarction.
Dark N, Cosson M-V, Tsansizi LI, et al., 2023, Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells, Cell Reports: Methods, Vol: 3, ISSN: 2667-2375
Decreased left ventricle (LV) function caused by genetic mutations or injury often leads to debilitating and fatal cardiovascular disease. LV cardiomyocytes are, therefore, a potentially valuable therapeutical target. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are neither homogeneous nor functionally mature, which reduces their utility. Here, we exploit cardiac development knowledge to instruct differentiation of hPSCs specifically toward LV cardiomyocytes. Correct mesoderm patterning and retinoic acid pathway blocking are essential to generate near-homogenous LV-specific hPSC-CMs (hPSC-LV-CMs). These cells transit via first heart field progenitors and display typical ventricular action potentials. Importantly, hPSC-LV-CMs exhibit increased metabolism, reduced proliferation, and improved cytoarchitecture and functional maturity compared with age-matched cardiomyocytes generated using the standard WNT-ON/WNT-OFF protocol. Similarly, engineered heart tissues made from hPSC-LV-CMs are better organized, produce higher force, and beat more slowly but can be paced to physiological levels. Together, we show that functionally matured hPSC-LV-CMs can be obtained rapidly without exposure to current maturation regimes.
Fassina D, Costa CM, Bishop M, et al., 2023, Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models, COMPUTERS IN BIOLOGY AND MEDICINE, Vol: 154, ISSN: 0010-4825
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- Citations: 1
Dvinskikh L, Sparks H, Brito L, et al., 2023, Remote-refocusing light-sheet fluorescence microscopy enables 3D imaging of electromechanical coupling of hiPSC-derived and adult cardiomyocytes in co-culture, Scientific Reports, Vol: 13, Pages: 1-14, ISSN: 2045-2322
Improving cardiac function through stem-cell regenerative therapy requires functional and structural integration of the transplanted cells with the host tissue. Visualizing the electromechanical interaction between native and graft cells necessitates 3D imaging with high spatio-temporal resolution and low photo-toxicity. A custom light-sheet fluorescence microscope was used for volumetric imaging of calcium dynamics in co-cultures of adult rat left ventricle cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes. Aberration-free remote refocus of the detection plane synchronously to the scanning of the light sheet along the detection axis enabled fast dual-channel 3D imaging at subcellular resolution without mechanical sample disturbance at up to 8 Hz over a ∼300 µm × 40 µm × 50 µm volume. The two cell types were found to undergo electrically stimulated and spontaneous synchronized calcium transients and contraction. Electromechanical coupling improved with co-culture duration, with 50% of adult-CM coupled after 24 h of co-culture, compared to 19% after 4 h (p = 0.0305). Immobilization with para-nitroblebbistatin did not prevent calcium transient synchronization, with 35% and 36% adult-CM coupled in control and treated samples respectively (p = 0.91), indicating that electrical coupling can be maintained independently of mechanotransduction.
Todorova V, Baxan N, Delahaye M, et al., 2022, Mechanism of improved cardiac function after pharmacological, 24th World Congress of the International-Society-for-Heart-Research, Publisher: ELSEVIER SCI LTD, Pages: S54-S56, ISSN: 0022-2828
Mohammadi N, Sanchez-Alonso J, Harding S, et al., 2022, Investigating the functional communication between sympathetic neurons and HiPSC-CMs in vitro, 24th World Congress of the International-Society-for-Heart-Research, Publisher: ELSEVIER SCI LTD, Pages: S110-S110, ISSN: 0022-2828
Tranter MH, Redfors B, Wright PT, et al., 2022, Hyperthermia as a trigger for Takotsubo syndrome in a rat model (vol 9, 869585, 2022), FRONTIERS IN CARDIOVASCULAR MEDICINE, Vol: 9, ISSN: 2297-055X
Tranter MH, Redfors B, Wright PT, et al., 2022, Hyperthermia as a trigger for Takotsubo syndrome in a rat model, Frontiers in Cardiovascular Medicine, Vol: 9, Pages: 1-9
Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40–41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.
Couch LS, Fiedler J, Chick G, et al., 2022, Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure, Cardiovascular Research, Vol: 118, Pages: 1758-1770, ISSN: 0008-6363
AIMS: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and absence of coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. METHODS AND RESULTS: miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal) cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4) and G-protein subunit Gβ (GNB1) as underlying these effects. CONCLUSION: miR-16 and miR-26a sensitise the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future. TRANSLATIONAL PERSPECTIVE: TTS-associated miRs have the potential to be active players predisposing to TTS. Feasibly, their measurement in recovered TTS patients during subsequent peri
Fassina D, Costa CM, Longobardi S, et al., 2022, Modelling the interaction between stem cells derived cardiomyocytes patches and host myocardium to aid non-arrhythmic engineered heart tissue design, PLOS COMPUTATIONAL BIOLOGY, Vol: 18, ISSN: 1553-734X
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- Citations: 6
Roy I, Dubey P, Majid Q, et al., 2022, POLYHYDROXYALKANOATES, NATURAL MATERIALS OF BACTERIAL ORIGIN, IDEAL FOR CARDIAC TISSUE ENGINEERING, Publisher: MARY ANN LIEBERT, INC, Pages: S36-S37, ISSN: 1937-3341
Pitoulis FG, Nunez-Toldra R, Xiao K, et al., 2022, Remodelling of adult cardiac tissue subjected to physiological and pathological mechanical load in vitro, Cardiovascular Research, Vol: 118, Pages: 814-827, ISSN: 0008-6363
Aims:Cardiac remodelling is the process by which the heart adapts to its environment. Mechanical load is a major driver of remodelling. Cardiac tissue culture has been frequently employed for in vitro studies of load-induced remodelling; however, current in vitro protocols (e.g. cyclic stretch, isometric load, and auxotonic load) are oversimplified and do not accurately capture the dynamic sequence of mechanical conformational changes experienced by the heart in vivo. This limits translational scope and relevance of findings.Methods and results:We developed a novel methodology to study chronic load in vitro. We first developed a bioreactor that can recreate the electromechanical events of in vivo pressure–volume loops as in vitro force–length loops. We then used the bioreactor to culture rat living myocardial slices (LMS) for 3 days. The bioreactor operated based on a 3-Element Windkessel circulatory model enabling tissue mechanical loading based on physiologically relevant parameters of afterload and preload. LMS were continuously stretched/relaxed during culture simulating conditions of physiological load (normal preload and afterload), pressure-overload (normal preload and high afterload), or volume-overload (high preload & normal afterload). At the end of culture, functional, structural, and molecular assays were performed to determine load-induced remodelling. Both pressure- and volume-overloaded LMS showed significantly decreased contractility that was more pronounced in the latter compared with physiological load (P < 0.0001). Overloaded groups also showed cardiomyocyte hypertrophy; RNAseq identified shared and unique genes expressed in each overload group. The PI3K-Akt pathway was dysregulated in volume-overload while inflammatory pathways were mostly associated with remodelling in pressure-overloaded LMS.Conclusion:We have developed a proof-of-concept platform and methodology to recreate remodelling under pathophysiol
Berecz T, Yiu A, Vittay O, et al., 2022, Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy, ESC HEART FAILURE, Vol: 9, Pages: 224-235, ISSN: 2055-5822
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- Citations: 4
Boyalla V, Harling L, Snell A, et al., 2022, Biomarkers as predictors of recurrence of atrial fibrillation post ablation: an updated and expanded systematic review and meta-analysis, Clinical Research in Cardiology, Vol: 111, Pages: 680-691, ISSN: 0300-5860
BackgroundA high proportion of patients undergoing catheter ablation (CA) for atrial fibrillation (AF) experience recurrence of arrhythmia. This meta-analysis aims to identify pre-ablation serum biomarker(s) associated with arrhythmia recurrence to improve patient selection before CA.MethodsA systematic approach following PRISMA reporting guidelines was utilised in libraries (Pubmed/Medline, Embase, Web of Science, Scopus) and supplemented by scanning through bibliographies of articles. Biomarker levels were compared using a random-effects model and presented as odds ratio (OR). Heterogeneity was examined by meta-regression and subgroup analysis.ResultsIn total, 73 studies were identified after inclusion and exclusion criteria were applied. Nine out of 22 biomarkers showed association with recurrence of AF after CA. High levels of N-Terminal-pro-B-type-Natriuretic Peptide [OR (95% CI), 3.11 (1.80–5.36)], B-type Natriuretic Peptide [BNP, 2.91 (1.74–4.88)], high-sensitivity C-Reactive Protein [2.04 (1.28–3.23)], Carboxy-terminal telopeptide of collagen type I [1.89 (1.16–3.08)] and Interleukin-6 [1.83 (1.18–2.84)] were strongly associated with identifying patients with AF recurrence. Meta-regression highlighted that AF type had a significant impact on BNP levels (heterogeneity R2 = 55%). Subgroup analysis showed that high BNP levels were more strongly associated with AF recurrence in paroxysmal AF (PAF) cohorts compared to the addition of non-PAF patients. Egger’s test ruled out the presence of publication bias from small-study effects.ConclusionRanking biomarkers based on the strength of association with outcome provides each biomarker relative capacity to predict AF recurrence. This will provide randomised controlled trials, a guide to choosing a priori tool for identifying patients likely to revert to AF, which are required to substantiate these findings.
Gara E, Zucchelli E, Nemes A, et al., 2022, 3D culturing of human pluripotent stem cells-derived endothelial cells for vascular regeneration, THERANOSTICS, Vol: 12, Pages: 4684-4702, ISSN: 1838-7640
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- Citations: 2
Ontoria-Oviedo I, Foeldes G, Tejedor S, et al., 2021, Modeling Transposition of the Great Arteries with Patient-Specific Induced Pluripotent Stem Cells, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22
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- Citations: 3
Brito L, Mylonaki I, Grigsby CL, et al., 2021, Genetic Enhancement of Epicardial Paracrine Signalling for Cardiac Regeneration, Annual Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Wright PT, Gorelik J, Harding SE, 2021, Electrophysiological remodeling: cardiac t-tubules and β-adrenoceptors, Cells, Vol: 10, ISSN: 2073-4409
Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.
Fu L, Zhang H, Machuki JO, et al., 2021, Reply to: Estrogens for protection from an index and recurrent episodes of takotsubo syndrome? REPLY, JOURNAL OF ENDOCRINOLOGY, Vol: 250, Pages: L3-L3, ISSN: 0022-0795
Jabbour R, Owen T, Pandey P, et al., 2021, In vivo grafting of large engineered heart tissue patches for cardiac repair, JCI Insight, Vol: 6, Pages: 1-13, ISSN: 2379-3708
Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be anovel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more dataare needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5mm) consisting of up to 20 million human induced pluripotent stem cell–derived cardiomyocytes(hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarctionmodel was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs inEHTs became more aligned over 28 days and had improved contraction kinetics and faster calciumtransients. Blinded echocardiographic analysis revealed a significant improvement in function ininfarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularizationfrom the host to the patch was observed at week 1 and stable to week 4, but electrical couplingbetween patch and host heart was not observed. In vivo telemetry recordings and ex vivoarrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTsimproved function and reduced scar size without causing arrhythmia, which may be due to the lackof electrical coupling between patch and host heart.
Basnett P, Matharu RK, Taylor CS, et al., 2021, Harnessing Polyhydroxyalkanoates and Pressurized Gyration for Hard and Soft Tissue Engineering, ACS APPLIED MATERIALS & INTERFACES, Vol: 13, Pages: 32624-32639, ISSN: 1944-8244
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- Citations: 23
Cuello F, Knaust AE, Saleem U, et al., 2021, Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation, EMBO MOLECULAR MEDICINE, Vol: 13, ISSN: 1757-4676
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- Citations: 22
Fu L, Zhang H, Machuki JO, et al., 2021, GPER mediates estrogen cardioprotection against epinephrine-induced stress, JOURNAL OF ENDOCRINOLOGY, Vol: 249, Pages: 209-222, ISSN: 0022-0795
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- Citations: 12
Narodden S, 2021, Shockwave for the abrogation of heart failure in myocardial ischaemia-reperfusion injury
Dvinskikh L, Harding S, Sparks H, et al., 2021, High speed imaging of calcium dynamics in cardiomyocytes with a flexible light-sheet fluorescence microscope, Biophotonics Congress 2021
Kondrashov A, Mohd Yusof NAN, Hasan A, et al., 2021, CRISPR/Cas9-mediated generation and analysis of N terminus polymorphic models of β2AR in isogenic hPSC-derived cardiomyocytes, Molecular Therapy - Methods and Clinical Development, Vol: 20, Pages: 39-53, ISSN: 2329-0501
During normal- and patho-physiological situations, the behavior of the beta2-adrenoreceptor (β2AR) is influenced by polymorphic variants. The functional impact of such polymorphisms has been suggested from data derived from genetic association studies, in vitro experiments with primary cells, and transgenic overexpression models. However, heterogeneous genetic background and non-physiological transgene expression levels confound interpretation, leading to conflicting mechanistic conclusions. To overcome these limitations, we used CRISPR/Cas9 gene editing technology in human pluripotent stem cells (hPSCs) to create a unique suite of four isogenic homozygous variants at amino acid positions 16(G/R) and 27(G/Q), which reside in the N terminus of the β2AR. By producing cardiomyocytes from these hPSC lines, we determined that at a functional level β2AR signaling dominated over β1AR . Examining changes in beat rates and responses to isoprenaline, Gi coupling, cyclic AMP (cAMP) production, downregulation, and desensitization indicated that responses were often heightened for the GE variant, implying differential dominance of both polymorphic location and amino acid substitution. This finding was corroborated, since GE showed hypersensitivity to doxorubicin-induced cardiotoxicity relative to GQ and RQ variants. Thus, understanding the effect of β2AR polymorphisms on cardiac response to anticancer therapy may provide a route for personalized medicine and facilitate immediate clinical impact.
Kit-Anan W, Mazo M, Wang BX, et al., 2021, Multiplexing physical stimulation on single human induced pluripotent stem cell-derived cardiomyocytes for phenotype modulation, Biofabrication, Vol: 13, Pages: 1-16, ISSN: 1758-5082
Traditional in vitro bioengineering approaches whereby only individual biophysical cues are manipulated at any one time are highly inefficient, falling short when recapitulating the complexity of the cardiac environment. Multiple biophysical cues are present in the native myocardial niche and are essential during development, as well as in maintenance of adult cardiomyocyte (CM) phenotype in both health and disease. This study establishes a novel biofabrication workflow to study and manipulate hiPSC-CMs and to understand how these cells respond to a multiplexed biophysical environment, namely microscopic topography (3D shape resembling that of adult CM) and substrate stiffness, at a single cell level. Silicon masters were fabricated and developed to generate pillars of the desired 3D shapes, which would be used to mould the designed microwell arrays into a hydrogel. Polyacrylamide was modified with the incorporation of acrylic acid to provide a carboxylic group conjugation site for adhesion motifs, without comprising its capacity to modulate the stiffness. In this manner, individual parameters can be finely tuned independently within the hydrogel: the dimension of 3D shaped microwell and its stiffness. The design allows the platform to isolate single hiPSC-CMs to study solely biophysical cues in an absence of cell-cell physical interaction. Under physiologic-like physical conditions (3D shape resembling that of adult CM and 9.83 kPa substrate stiffness), isolated single hiPSC-CMs exhibit increased Cx-43 density, cell Peer reviewed version of the manuscript published in final form at Biofabrication (2020). membrane stiffness and calcium transient amplitude; co-expression of the subpopulation-related MYL2- MYL7 proteins; while displaying higher anisotropism in comparison to pathologic-like conditions (flat surface and 112 kPa substrate stiffness). This demonstrates that supplying a physiological or pathological microenvironment to an isolated single hiPSC-CM in absen
Leong KMW, Ng FS, Shun-Shin MJ, et al., 2021, Non-invasive detection of exercise-induced cardiac conduction abnormalities in sudden cardiac death survivors in the inherited cardiac conditions, EUROPACE, Vol: 23, Pages: 305-312, ISSN: 1099-5129
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- Citations: 7
Forte E, Panahi M, Baxan N, et al., 2021, Type 2 MI induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, Vol: 25, Pages: 229-243, ISSN: 1582-1838
Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol hydrochloride is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.
Crestani T, Steichen C, Neri E, et al., 2020, Electrical stimulation applied during differentiation drives the hiPSC-CMs towards a mature cardiac conduction-like cells, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 533, Pages: 376-382, ISSN: 0006-291X
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- Citations: 16
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