Ebert, Antje Dagmar

[["dc.bibliographiccitation.artnumber","209"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Dai, Yuanyuan"],["dc.contributor.author","Amenov, Asset"],["dc.contributor.author","Ignatyeva, Nadezda"],["dc.contributor.author","Koschinski, Andreas"],["dc.contributor.author","Xu, Hang"],["dc.contributor.author","Soong, Poh Loong"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Linke, Wolfgang A."],["dc.contributor.author","Zaccolo, Manuela"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Ebert, Antje"],["dc.date.accessioned","2020-04-14T14:41:47Z"],["dc.date.available","2020-04-14T14:41:47Z"],["dc.date.issued","2020"],["dc.description.abstract","The sarcomeric troponin-tropomyosin complex is a critical mediator of excitation-contraction coupling, sarcomeric stability and force generation. We previously reported that induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with a dilated cardiomyopathy (DCM) mutation, troponin T (TnT)-R173W, display sarcomere protein misalignment and impaired contractility. Yet it is not known how TnT mutation causes dysfunction of sarcomere microdomains and how these events contribute to misalignment of sarcomeric proteins in presence of DCM TnT-R173W. Using a human iPSC-CM model combined with CRISPR/Cas9-engineered isogenic controls, we uncovered that TnT-R173W destabilizes molecular interactions of troponin with tropomyosin, and limits binding of PKA to local sarcomere microdomains. This attenuates troponin phosphorylation and dysregulates local sarcomeric microdomains in DCM iPSC-CMs. Disrupted microdomain signaling impairs MYH7-mediated, AMPK-dependent sarcomere-cytoskeleton filament interactions and plasma membrane attachment. Small molecule-based activation of AMPK can restore TnT microdomain interactions, and partially recovers sarcomere protein misalignment as well as impaired contractility in DCM TnT-R173W iPSC-CMs. Our findings suggest a novel therapeutic direction targeting sarcomere- cytoskeleton interactions to induce sarcomere re-organization and contractile recovery in DCM."],["dc.identifier.doi","10.1038/s41598-019-56597-3"],["dc.identifier.pmid","31937807"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/64087"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/336"],["dc.language.iso","en"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A12: Alternative molekulare Signaltransduktionswege durch Kardiomyopathie-verursachende Troponin-Mutationen"],["dc.relation.issn","2045-2322"],["dc.relation.workinggroup","RG Ebert (Cardiovascular Cell Biology and Systems Medicine)"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Linke (Kardiovaskuläre Physiologie)"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY 4.0"],["dc.title","Troponin destabilization impairs sarcomere-cytoskeleton interactions in iPSC-derived cardiomyocytes from dilated cardiomyopathy patients"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","5"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","117"],["dc.contributor.author","Jung, Philipp"],["dc.contributor.author","Seibertz, Fitzwilliam"],["dc.contributor.author","Fakuade, Funsho E."],["dc.contributor.author","Ignatyeva, Nadezda"],["dc.contributor.author","Sampathkumar, Shrivatsan"],["dc.contributor.author","Ritter, Melanie"],["dc.contributor.author","Li, Housen"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Ebert, Antje"],["dc.contributor.author","Voigt, Niels"],["dc.date.accessioned","2022-05-24T06:53:38Z"],["dc.date.available","2022-05-24T06:53:38Z"],["dc.date.issued","2022-05-02"],["dc.description.abstract","Dilated cardiomyopathy (DCM) is a major risk factor for heart failure and is associated with the development of life-threatening cardiac arrhythmias. Using a patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model harbouring a mutation in cardiac troponin T (R173W), we aim to examine the cellular basis of arrhythmogenesis in DCM patients with this mutation. iPSC from control (Ctrl) and DCM-TnT-R173W donors from the same family were differentiated into iPSC-CM and analysed through optical action potential (AP) recordings, simultaneous measurement of cytosolic calcium concentration ([Ca2+]i) and membrane currents and separately assayed using field stimulation to detect the threshold for AP- and [Ca2+]i-alternans development. AP duration was unaltered in TnT-R173W iPSC-CM. Nevertheless, TnT-R173W iPSC-CM showed a strikingly low stimulation threshold for AP- and [Ca2+]i-alternans. Myofilaments are known to play a role as intracellular Ca2+ buffers and here we show increased Ca2+ affinity of intracellular buffers in TnT-R173W cells, indicating increased myofilament sensitivity to Ca2+. Similarly, EMD57033, a myofilament Ca2+ sensitiser, replicated the abnormal [Ca2+]i dynamics observed in TnT-R173W samples and lowered the threshold for alternans development. In contrast, application of a Ca2+ desensitiser (blebbistatin) to TnT-R173W iPSC-CM was able to phenotypically rescue Ca2+ dynamics, normalising Ca2+ transient profile and minimising the occurrence of Ca2+ alternans at physiological frequencies. This finding suggests that increased Ca2+ buffering likely plays a major arrhythmogenic role in patients with DCM, specifically in those with mutations in cardiac troponin T. In addition, we propose that modulation of myofilament Ca2+ sensitivity could be an effective anti-arrhythmic target for pharmacological management of this disease."],["dc.identifier.doi","10.1007/s00395-022-00912-z"],["dc.identifier.pmid","35499658"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/108251"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/430"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/482"],["dc.language.iso","en"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1435-1803"],["dc.relation.issn","0300-8428"],["dc.relation.workinggroup","RG Ebert (Cardiovascular Cell Biology and Systems Medicine)"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.rights","CC BY 4.0"],["dc.title","Increased cytosolic calcium buffering contributes to a cellular arrhythmogenic substrate in iPSC-cardiomyocytes from patients with dilated cardiomyopathy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","32669"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Lee, Jaecheol"],["dc.contributor.author","Jung, Seung Min"],["dc.contributor.author","Ebert, Antje D."],["dc.contributor.author","Wu, Haodi"],["dc.contributor.author","Diecke, Sebastian"],["dc.contributor.author","Kim, Youngkyun"],["dc.contributor.author","Yi, Hyoju"],["dc.contributor.author","Park, S. H. P."],["dc.contributor.author","Ju, Ji Hyeon"],["dc.date.accessioned","2018-11-07T10:08:38Z"],["dc.date.available","2018-11-07T10:08:38Z"],["dc.date.issued","2016"],["dc.description.abstract","Cardiovascular disease is a leading cause of morbidity in rheumatoid arthritis (RA) patients. This study aimed to generate and characterise cardiomyocytes from induced pluripotent stem cells (iPSCs) of RA patients. Fibroblast-like synoviocytes (FLSs) from patients with RA and osteoarthritis (OA) were successfully reprogrammed into RA-iPSCs and OA-iPSCs, respectively. The pluripotency of iPSCs was confirmed by quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining. Established iPSCs were differentiated into cardiomyocytes using a small molecule-based monolayer differentiation protocol. Within 12 days of cardiac differentiation from patient-specific and control-iPSCs, spontaneously beating cardiomyocytes (iPSC-CMs) were observed. All iPSC-CMs exhibited a reliable sarcomeric structure stained with antibodies against cardiac markers and similar expression profiles of cardiac-specific genes. Intracellular calcium signalling was recorded to compare calcium-handling properties among cardiomyocytes differentiated from the three groups of iPSCs. RA-iPSC-CMs had a lower amplitude and a shorter duration of calcium transients than the control groups. Peak tangential stress and the maximum contractile rate were also decreased in RA-iPSC-CMs, suggesting that contractility was reduced. This study demonstrates the successful generation of functional cardiomyocytes from pathogenic synovial cells in RA patients through iPSC reprogramming. Research using RA-iPSC-CMs might provide an opportunity to investigate the pathophysiology of cardiac involvement in RA."],["dc.identifier.doi","10.1038/srep32669"],["dc.identifier.isi","000382779200001"],["dc.identifier.pmid","27609119"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13750"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39500"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","2045-2322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Generation of Functional Cardiomyocytes from the Synoviocytes of Patients with Rheumatoid Arthritis via Induced Pluripotent Stem Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]