| 1. |
- Asp, Michaela, et al.
(författare)
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A Spatiotemporal Organ-Wide Gene Expression and Cell Atlas of the Developing Human Heart
- 2019
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Ingår i: Cell. - : CELL PRESS. - 0092-8674 .- 1097-4172. ; 179:7, s. 1647-
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Tidskriftsartikel (refereegranskat)abstract
- The process of cardiac morphogenesis in humans is incompletely understood. Its full characterization requires a deep exploration of the organ-wide orchestration of gene expression with a single-cell spatial resolution. Here, we present a molecular approach that reveals the comprehensive transcriptional landscape of cell types populating the embryonic heart at three developmental stages and that maps cell-type-specific gene expression to specific anatomical domains. Spatial transcriptomics identified unique gene profiles that correspond to distinct anatomical regions in each developmental stage. Human embryonic cardiac cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of embryonic cardiac gene expression. In situ sequencing was then used to refine these results and create a spatial subcellular map for the three developmental phases. Finally, we generated a publicly available web resource of the human developing heart to facilitate future studies on human cardiogenesis.
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| 2. |
- Asp, Michaela, et al.
(författare)
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An organ‐wide gene expression atlas of the developing human heart
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The human developing heart holds a greater proportion of stem-cell-like cells than the adult heart. However, it is not completely understood how these stem cells differentiate into various cardiac cell types. We have performed an organ-wide transcriptional landscape analysis of the developing heart to advance our understanding of cardiac morphogenesis in humans. Comprehensive spatial gene expression analyses identified distinct profiles that correspond not only to individual chamber compartments, but also distinctive regions within the outflow tract. Furthermore, the generated spatial expression reference maps facilitated the assignment of 3,787 human embryonic cardiac cells obtained from single-cell RNA-sequencing to an in situlocation. Through this approach we reveal that the outflow tract contains a wider range of cell types than the chambers, and that the epicardium expression profile can be traced to several cell types that are activated at different stages of development. We also provide a 3D spatial model of human embryonic cardiac cells to enable further studies of the developing human heart.
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| 3. |
- Chen, Hongjiang, 1965-
(författare)
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Studies on Cell Injury Induced by Hypoxia-Reoxygenation and Oxidized Low Density Lipoprotein : With Special Reference to the Protectiove Effect of Mixed Tocopherols, Omega-3 Fatty Acids and Transforming Growth Factor-beta1
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hypoxia-reoxygenation (H-R) injury is an important clinical phenomenon in patients with coronary artery disease (CAD). Endothelial injury is a critical step in the initiation and progression of atherosclerosis. Therefore, endothelial and cardiomyocyte protection has been considered an effective step in prevention and treatment of CAD.To investigate the cardioprotective effect of tocopherols, omega-3 fatty acid [eicosapentaenoic acid (EPA)] and transforming growth factor-β1 (TGF-β1) during H-R, calcium tolerant myocytes isolated from adult rats were cultured and subjected to hypoxia for 24 hrs followed by reoxygenation of 3 hrs. All strategies, including tocopherol preparations, EPA and TGF-β1, showed attenuation of H-R-induced myocyte injury indicated by reduction of lactate dehydrogenase (LDH) release. Both a-tocopherol and a mixed- tocopherols (α-, γ-, and δ-) decreased the effects of H-R on iNOS expression and SOD activity in cultured myocytes. The mixed-tocopherols was more potent than a-tocopherol alone. EPA inhibited H-R-induced lipid peroxidation, MMP-1 expression and p38MAPK phosphorylation. TGF-β1 blocked the increase in iNOS and PKB phosphorylation as well as the decrease in eNOS expression in cultured myocytes exposed to H-R. To further investigate the protective effect of omega-3 fatty acids [docosahexaenoic acid (DHA) and EPA] and TGF-β1, the cultured endothelial cells were exposed to oxidant injury mediated by oxidized low-density lipoprotein (ox-LDL). Ox-LDL markedly reduced TGF-β1 release, increased the expression of TGF-β1 receptors, upregulated the expression of adhesion molecules, P-selectin and ICAM-1, enhanced the adhesion of monocytes to endothelial cells, and decreased protein kinase B (PKB) activation. Both DHA and EPA blocked these effects of ox-LDL on endothelial cells. Exogenous recombinant TGF-β1 also ameliorated ox-LDL-induced expression of adhesion molecules and monocytes adhesion, which were blocked by antibodies to the TGF-β1 type 2, but not to the type 3 receptor.These observations provide mechanistic insights into H-R and oxidant injury and tissue protection by three different strategies.
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| 4. |
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| 5. |
- Danielsson, Christian, et al.
(författare)
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Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism
- 2013
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP): Policy B. - 0008-6363 .- 1755-3245. ; 97:1, s. 23-32
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Tidskriftsartikel (refereegranskat)abstract
- Several drugs blocking the rapidly activating potassium (K-r) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species. less thanbrgreater than less thanbrgreater thanPatch-clamp and quantitative-mRNA measurements of K-r and slowly activating K (K-s) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K-r channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K-r-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K-r-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K-s channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit. less thanbrgreater than less thanbrgreater thanThis first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K-r-channel blocker in human, rat, and rabbit embryos provides evidence of K-r-channel inhibition as a common mechanism for embryonic malformations and death.
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| 6. |
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| 7. |
- Grinnemo, Karl-Henrik, et al.
(författare)
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Costimulation blockade induces tolerance to HESC transplanted to the testis and induces regulatory T-cells to HESC transplanted into the heart
- 2008
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 26:7, s. 1850-1857
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Tidskriftsartikel (refereegranskat)abstract
- In order to study the ability of costimulation blockade to induce tolerance to human embryonic stem cells (HESC), severe combined immunodeficient (SCID), and immunocompetent C57BL/6 mice treated with costimulation blockade received intratesticular and intramyocardial HESC transplants. All SCID mice with intratesticular HESC transplants developed teratoma. When SCID mice were transplanted intramyocardially, only two of five mice developed teratoma-like tumors. C57BL/6 mice transplanted intratesticularly and treated with costimulation blockade all developed teratoma and were surrounded by CD4(+)CD25(+)Foxp3(+) T-cells, while isotype control treated recipients rejected their grafts. Most C57BL/6 mice transplanted intramyocardially and treated with costimulation blockade demonstrated lymphocytic infiltrates 1 month after transplantation, whereas one maintained its graft. Isolation of regulatory T-cells from intramyocardial transplanted recipients treated with costimulation blockade demonstrated specificity toward undifferentiated HESC and down-regulated naive T-cell activation toward HESC. These results demonstrate that costimulation blockade is sufficiently robust to induce tolerance to HESC in the immune-privileged environment of the testis. HESC specific regulatory T-cells developed to HESC transplanted to the heart and the success of transplantation was similar to that seen in SCID mice.
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| 8. |
- Hao, Xiaojin, et al.
(författare)
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Angiogenic effects of sequential release of VEGF-A(165) and PDGF-BB with alginate hydrogels after myocardial infarction
- 2007
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 28, s. 612-612
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This study investigates whether local sequential delivery of vascular endothelial growth factor-A(165) (VEGF-A(165)) followed by platelet-derived growth factor-BB (PDGF-BB) with alginate hydrogels could induce an angiogenic effect and functional improvement greater than single factors after myocardial infarction. Methods: Alginate hydrogels were prepared by combining high and low molecular weight alginate. Growth factor release rates were monitored over time in vitro with I-125-labelled VEGF-A(165) and PDGF-BB included in the gels. One week after myocardial infarction was induced in Fisher rats, gels with VEGF-A(165), PDGF-BB, or both were given intra-myocardially along the border of the myocardial infarction. Vessel density was analysed in hearts and cardiac function was determined by Tissue Doppler Echocardiography. In addition, the angiogenic effect of sequenced delivery was studied in vitro in aortic rings from C57B1/6 mice. Results: Alginate gets were capable of delivering VEGF-A(165) and PDGF-BB in a sustainable manner, and PDGF-BB was released more slowly than VEGF-A(165). Sequential growth factor administration led to a higher density of alpha-actin positive vessels than single factors, whereas no further increment was found in capillary density. Sequential protein delivery increased the systolic velocity-time integral and displayed a superior effect than single factors. In the aortic ring model, sequential delivery led to a higher angiogenic effect than single factor administration. Conclusions: The alginate hydrogel is an effective and promising injectable delivery system in a myocardial infarction model. Sequential growth factor delivery of VEGF-A(165) and PDGF-BB induces mature vessels and improves cardiac function more than each factor singly. This may indicate clinical utility.
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| 9. |
- Hao, Xiaojin, et al.
(författare)
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Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model
- 2007
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 73:3, s. 481-487
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To compare gene transfer of plasmid (P) and adenovirus (Ad) encoding human vascular endothelial growth factor-A(165) (hVEGF-A(165)) angiogenic efficacy and adverse effects as regards apoptosis and ectopic expression of the transgene in a rat myocardial infarction model. Methods: Myocardial infarction was provoked in Fisher rats. One week later, PhVEGF-A(165), PLacZ, AdhVEGF-A(165), or AdLacZ was transferred intramyocardially along the border of the myocardial infarction. hVEGF-A expression was detected with ELISA. Myocardial vessel density was analyzed 1 and 4 weeks after gene transfer. Apoptosis was detected by TUNEL staining. Cardiac function was assessed with Tissue Doppler Velocity Imaging. Results: Although AdhVEGF-A(165) had substantially higher myocardial hVEGF-A expression than PhVEGF-A(165), AdhVEGF-A(165) and PhVEGF-A(165) induced angiogenic effects to a similar extent with maintained increased arteriolar density after 4 weeks of gene transfer (p < 0.05). The two treatments also improved left ventricular function similarly. Adenoviral gene transfer induced a higher number of TUNEL positive cells than plasmid (p < 0.02). Ectopic expression of the transgene was present with both vectors but substantially higher after adenoviral gene transfer. Conclusions: AdhVEGF-A165 has no obvious angiogenic advantage over PhVEGF-A165 but more side effects at least in a rat myocardial infarction model. This indicates that PhVEGF-A(165) might be more applicable for therapeutic angiogenesis than AdhVEGF-A(165).
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| 10. |
- Lázár, Enikő, et al.
(författare)
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Spatial Dynamics of the Developing Human Heart
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Heart development relies on a topologically defined interplay between a diverse array of cardiac cells. We finely curated spatial and single-cell measurements with subcellular imaging-based transcriptomics validation to explore spatial dynamics during early human cardiogenesis. Analyzing almost 80,000 individual cells and 70,000 spatially barcoded tissue regions between the 5.5th and 14th postconceptional weeks, we identified 31 coarse- and 72 fine-grained cell states and mapped them to highly resolved cardiac cellular niches. We provide novel insight into the development of the cardiac pacemaker-conduction system, heart valves, and atrial septum, and decipher heterogeneity of the hitherto elusive cardiac fibroblast population. Furthermore, we describe the formation of cardiac autonomic innervation and present the first spatial account of chromaffin cells in the fetal human heart. In summary, our study delineates the cellular and molecular landscape of the developing heart’s architecture, offering links to genetic causes of heart disease.
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| 11. |
- Marco Salas, Sergio, et al.
(författare)
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De novo spatiotemporal modelling of cell-type signatures in the developmental human heart using graph convolutional neural networks
- 2022
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 18:8
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Tidskriftsartikel (refereegranskat)abstract
- With the emergence of high throughput single cell techniques, the understanding of the molecular and cellular diversity of mammalian organs have rapidly increased. In order to understand the spatial organization of this diversity, single cell data is often integrated with spatial data to create probabilistic cell maps. However, targeted cell typing approaches relying on existing single cell data achieve incomplete and biased maps that could mask the true diversity present in a tissue slide. Here we applied a de novo technique to spatially resolve and characterize cellular diversity of in situ sequencing data during human heart development. We obtained and made accessible well defined spatial cell-type maps of fetal hearts from 4.5 to 9 post conception weeks, not biased by probabilistic cell typing approaches. With our analysis, we could characterize previously unreported molecular diversity within cardiomyocytes and epicardial cells and identified their characteristic expression signatures, comparing them with specific subpopulations found in single cell RNA sequencing datasets. We further characterized the differentiation trajectories of epicardial cells, identifying a clear spatial component on it. All in all, our study provides a novel technique for conducting de novo spatial-temporal analyses in developmental tissue samples and a useful resource for online exploration of cell-type differentiation during heart development at sub-cellular image resolution.
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| 12. |
- Masarapu, Yuvarani, et al.
(författare)
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Spatially resolved multiomics on the neuronal effects induced by spaceflight in mice
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Impairment of the central nervous system (CNS) poses a significant health risk for astronauts during long-duration space missions. In this study, we employed an innovative approach by integrating single-cell multiomics (transcriptomics and chromatin accessibility) with spatial transcriptomics to elucidate the impact of spaceflight on the mouse brain in female mice. Our comparative analysis between ground control and spaceflight-exposed animals revealed significant alterations in essential brain processes including neurogenesis, synaptogenesis and synaptic transmission, particularly affecting the cortex, hippocampus, striatum and neuroendocrine structures. Additionally, we observed astrocyte activation and signs of immune dysfunction. At the pathway level, some spaceflight-induced changes in the brain exhibit similarities with neurodegenerative disorders, marked by oxidative stress and protein misfolding. Our integrated spatial multiomics approach serves as a stepping stone towards understanding spaceflight-induced CNS impairments at the level of individual brain regions and cell types, and provides a basis for comparison in future spaceflight studies. For broader scientific impact, all datasets from this study are available through an interactive data portal, as well as the National Aeronautics and Space Administration (NASA) Open Science Data Repository (OSDR).
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| 13. |
- Sadigh, Bita, et al.
(författare)
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The ischemic preconditioning effect of adenosine in patients with ischemic heart disease
- 2009
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Ingår i: Cardiovascular Ultrasound. - : Springer Science and Business Media LLC. - 1476-7120. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: In vivo and in vitro evidence suggests that adenosine and its agonists play key roles in the process of ischemic preconditioning. The effects of low-dose adenosine infusion on ischemic preconditioning have not been thoroughly studied in humans. AIMS: We hypothesised that a low-dose adenosine infusion could reduce the ischemic burden evoked by physical exercise and improve the regional left ventricular (LV) systolic function. MATERIALS AND METHODS: We studied nine severely symptomatic male patients with severe coronary artery disease. Myocardial ischemia was induced by exercise on two separate occasions and quantified by Tissue Doppler Echocardiography. Prior to the exercise test, intravenous low-dose adenosine or placebo was infused over ten minutes according to a randomized, double blind, cross-over protocol. The LV walls were defined as ischemic if a reduction, no increment, or an increment of < 15% in peak systolic velocity (PSV) was observed during maximal exercise compared to the baseline values observed prior to placebo-infusion. Otherwise, the LV walls were defined as non-ischemic. RESULTS: PSV increased from baseline to maximal exercise in non-ischemic walls both during placebo (P = 0.0001) and low-dose adenosine infusion (P = 0.0009). However, in the ischemic walls, PSV increased only during low-dose adenosine infusion (P = 0.001), while no changes in PSV occurred during placebo infusion (P = NS). CONCLUSION: Low-dose adenosine infusion reduced the ischemic burden and improved LV regional systolic function in the ischemic walls of patients with exercise-induced myocardial ischemia, confirming that adenosine is a potential preconditioning agent in humans.
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| 14. |
- Shahrara, Shiva, et al.
(författare)
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Characterization of AT-1 Cardiomyocytes as a Model for Studies of T3 Effects on Cardiac Cells
- 1997
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 237:2, s. 303-306
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Tidskriftsartikel (refereegranskat)abstract
- AT-1 cardiomyocyte derive from atrial tumors in transgenic mice. Earlier studies have indicated a highly differentiated, contracting, cardiac phenotype in primary cultures and the AT-1 cardiomyocyte may thus be an excellent in vitro model in cardiac research. Thyroid hormone (T3) has positive inotropic and chronotropic effects and is clinically known to be relevant in various pathological heart conditions. Thyroid Hormone Receptors (TR) are ligand regulated transcriptional activators who mediate the effects of T3. The aim of this study was to determine whether AT-1 cardiomyocytes express TR. Regular binding competition assays showed a Kd of 370 +/- 105 for 125I-T3 binding to TR. Reverse transcription-PCR in mouse showed that TRalpha1, alpha2, beta1 and beta2 mRNA were expressed in AT-1 cardiomyocytes and mouse myocardium. Western blot with polyclonal rabbit antibodies against human TR revealed the presence of TRalpha1, beta2 and low levels of TRbeta1 while TRalpha2 was not detectable. Generally, for the detected subtypes the intensities of the bands were weaker for AT-1 cardiomyocytes in comparison to mouse heart. We conclude that the AT-1 cardiomyocytes express both protein and mRNA for TR and may provide a useful model for studying T3 effects in cultured cardiac myocytes.
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| 15. |
- Sylven, Christer, et al.
(författare)
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High cardiomyocyte diversity in human early prenatal heart development
- 2023
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Ingår i: ISCIENCE. - : Elsevier BV. - 2589-0042. ; 26:1, s. 105857-
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Tidskriftsartikel (refereegranskat)abstract
- Cardiomyocytes play key roles during cardiogenesis, but have poorly understood features, especially in prenatal stages. Here, we characterized human prenatal cardiomyocytes, 6.5-7 weeks post-conception, by integrating single-cell RNA sequencing, spatial transcriptomics, and ligand-receptor interaction information. Using a computational workflow developed to dissect cell type heterogeneity, localize cell types, and explore their molecular interactions, we identified eight types of developing cardiomyocyte, more than double compared to the ones identified in the Human Developmental Cell Atlas. These have high variability in cell cycle activity, mitochondrial content, and connexin gene expression, and are differentially distributed in the ventricles, including outflow tract, and atria, including sinoatrial node. Moreover, cardiomyocyte ligand-receptor crosstalk is mainly with non-cardiomyocyte cell types, encompassing cardiogenesis-related pathways. Thus, early prenatal human cardiomyocytes are highly heterogeneous and develop unique location-dependent properties, with complex ligand-receptor crosstalk. Further elucidation of their developmental dynamics may give rise to new therapies.
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| 16. |
- Sylvén, Christer, et al.
(författare)
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Ventricular adenine nucleotide translocator mRNA is upregulated in dilated cardiomyopathy.
- 1993
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Ingår i: Cardiovascular research. - 0008-6363. ; 27:7, s. 1295-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: A disturbed energy transfer involving the adenine nucleotide translocator across the inner mitochondrial membrane has been suggested to be one specific pathogenetic mechanism in dilated cardiomyopathy. Pretranslational steady state expression of this protein in dilated cardiomyopathy was investigated. METHODS: Concentrations of adenine nucleotide translocator were quantified by solution hybridisation. The enzyme or protein expressions of citrate synthase, lactate dehydrogenase, and creatine kinase with isozymes were determined. Analysis was performed on specimens from the left and right ventricles from six organ donor hearts, six explanted hearts with dilated cardiomyopathy, two explanted hearts with ischaemic cardiomyopathy, and from papillary muscles from seven patients operated on for mitral regurgitation. RESULTS: The ejection fraction in patients with mitral regurgitation was 50(10)%, significantly higher (p < 0.001) than in patients with dilated cardiomyopathy (23(5))%. In mitral regurgitation and in ischaemic cardiomyopathy left ventricular adenine nucleotide translocator mRNA concentrations did not differ from those in donor hearts. In dilated cardiomyopathy, adenine nucleotide translocator mRNA concentrations were significantly increased (p < 0.001). Upregulation was more pronounced in right ventricular than in left ventricular myocardium (p < 0.01). The lactate dehydrogenase M subunit fraction was increased to a similar degree in dilated cardiomyopathy and in mitral regurgitation (p < 0.05). Citrate synthase activity was significantly decreased only in dilated cardiomyopathy (p < 0.005). On the other hand, the creatine kinase B subunit content was significantly higher in mitral regurgitation than in dilated cardiomyopathy (p < 0.001). CONCLUSIONS: Despite signs of increased anaerobic and depressed oxidative capacities, dilated cardiomyopathy was specifically characterised by pretranslational upregulation of adenine nucleotide translocator.
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| 17. |
- Szummer, Karolina, et al.
(författare)
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Relationship of plasma erythropoietin to long-term outcome in acute coronary syndrome
- 2010
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 143:2, s. 165-170
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Erythropoietin has been related to adverse prognosis in patients with heart failure, but it is unknown whether it adds prognostic information in acute coronary syndrome. METHODS: Plasma erythropoietin was measured on admission with enzyme-linked immunosorbent assay in 627 patients. Patients were divided into three groups depending on their erythropoietin level and followed for myocardial infarction (MI) (median 6 months) and mortality (median 39 months). Cox regression models were used to evaluate erythropoietin compared to clinical variables; age, gender, diabetes, smoking, prior MI, heart failure, hypertension and revascularization. In a second Cox regression model, laboratory markers were assessed; hemoglobin, estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), cardiac troponin T (cTnT) and N-terminal pro-brain-natriuretic peptide (NT-proBNP). RESULTS: Patients with the highest erythropoietin level (>8.8 mU/mL, n=205) had a 47% increased mortality (HR 1.47, 95% CI 1.04-2.06, p=0.028) when adjusted for clinical variables. Compared to laboratory risk markers, erythropoietin added prognostic information (HR 1.59, 95% CI 1.05-2.38, p=0.027) when adjusted for hemoglobin, eGFR and CRP. Erythropoietin (HR 1.21, 95% CI 0.79-1.86, p=0.387) was no longer significantly associated with mortality when cTnT and NT-proBNP were added. Erythropoietin was not related to the risk of future MI (HR 1.24, 95% CI 0.65-2.33, p=0.513). CONCLUSION: Elevated erythropoietin level was associated with increased mortality in patients admitted with possible ACS when adjusted for clinical variables, or for kidney function and hemoglobin. However, erythropoietin does not add prognostic information when markers of myocardial necrosis and dysfunction are available in ACS.
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| 18. |
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