Zimmermann, Wolfram-Hubertus

[["dc.bibliographiccitation.firstpage","219"],["dc.bibliographiccitation.lastpage","239"],["dc.contributor.author","Fujita, Buntaro"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Ensminger, Stephan"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.editor","Ieda, Masaki"],["dc.contributor.editor","Zimmermann, Wolfram-Hubertus"],["dc.date.accessioned","2019-02-27T13:40:08Z"],["dc.date.available","2019-02-27T13:40:08Z"],["dc.date.issued","2017"],["dc.description.abstract","Heart muscle restoration with in vitro engineered tissue constructs is an exciting and rapidly advancing field. Feasibility, safety, and efficacy data have been obtained in animal models. First clinical trials are on the way to explore the therapeutic utility of cell-free and non-contractile cell-containing grafts. Engineering of contractile patches according to current good manufacturing practice (cGMP) for bona fide myocardial re-muscularization and scalability to address clinical demands remains challenging. Proof-of-concept for solutions to address obvious technical hurdles exists, and it can be anticipated that the first generation of clinically applicable engineered heart muscle (EHM) grafts will become available in the near future. Foreseeable, but likely manageable risks include arrhythmia induction and teratoma formation. Remaining biomedical challenges pertain to the requirement of immune suppression and the strategic approach to optimize immune suppression without subjecting the target patient population to an unacceptable risk. This chapter summarizes the current state of tissue-engineered heart repair with a special emphasis on knowledge gained from in vitro and in vivo studies as well as issues pertaining to transplant immunology and cGMP process development."],["dc.identifier.doi","10.1007/978-3-319-56106-6_10"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57646"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/185"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.publisher","Springer"],["dc.publisher.place","Cham, Switzerland"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation.crisseries","Cardiac and Vascular Biology"],["dc.relation.doi","10.1007/978-3-319-56106-6"],["dc.relation.isbn","978-3-319-56104-2"],["dc.relation.isbn","978-3-319-56106-6"],["dc.relation.ispartof","Cardiac Regeneration"],["dc.relation.ispartofseries","Cardiac and Vascular Biology"],["dc.relation.issn","2509-7830"],["dc.relation.issn","2509-7849"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.title","State-of-the-Art in Tissue-Engineered Heart Repair"],["dc.type","book_chapter"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","975"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Journal of the American College of Cardiology"],["dc.bibliographiccitation.lastpage","991"],["dc.bibliographiccitation.volume","70"],["dc.contributor.author","Borchert, Thomas"],["dc.contributor.author","Hübscher, Daniela"],["dc.contributor.author","Guessoum, Celina I."],["dc.contributor.author","Lam, Tuan-Dinh D."],["dc.contributor.author","Ghadri, Jelena R."],["dc.contributor.author","Schellinger, Isabel N."],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Liaw, Norman Y."],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Haas, Jan"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Huber, Mia A."],["dc.contributor.author","Cyganek, Lukas"],["dc.contributor.author","Jacobshagen, Claudius"],["dc.contributor.author","Dressel, Ralf"],["dc.contributor.author","Raaz, Uwe"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.contributor.author","Guan, Kaomei"],["dc.contributor.author","Thiele, Holger"],["dc.contributor.author","Meder, Benjamin"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Lüscher, Thomas F."],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Templin, Christian"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.date.accessioned","2018-04-23T11:48:11Z"],["dc.date.available","2018-04-23T11:48:11Z"],["dc.date.issued","2017"],["dc.description.abstract","Background Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis. Objectives The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS. Methods Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function. Results Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate–dependent protein kinase A–mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function. Conclusions Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype."],["dc.identifier.doi","10.1016/j.jacc.2017.06.061"],["dc.identifier.gro","3142333"],["dc.identifier.pmid","28818208"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16489"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13468"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/204"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation","SFB 1002 | D02: Neue Mechanismen der genomischen Instabilität bei Herzinsuffizienz"],["dc.relation.issn","0735-1097"],["dc.relation.workinggroup","RG Cyganek (Stem Cell Unit)"],["dc.relation.workinggroup","RG Dressel"],["dc.relation.workinggroup","RG Guan (Application of patient-specific induced pluripotent stem cells in disease modelling)"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Wollnik"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","51"],["dc.bibliographiccitation.journal","Progress in Biophysics and Molecular Biology"],["dc.bibliographiccitation.lastpage","60"],["dc.bibliographiccitation.volume","144"],["dc.contributor.author","Schlick, Susanne F."],["dc.contributor.author","Spreckelsen, Florian"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Iyer, Lavanya M."],["dc.contributor.author","Meyer, Tim"],["dc.contributor.author","Zelarayan, Laura C."],["dc.contributor.author","Luther, Stefan"],["dc.contributor.author","Parlitz, Ulrich"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Rehfeldt, Florian"],["dc.date.accessioned","2020-12-10T15:20:42Z"],["dc.date.available","2020-12-10T15:20:42Z"],["dc.date.issued","2019"],["dc.description.abstract","Cardiomyocyte and stroma cell cross-talk is essential for the formation of collagen-based engineered heart muscle, including engineered human myocardium (EHM). Fibroblasts are a main component of the myocardial stroma. We hypothesize that fibroblasts, by compacting the surrounding collagen network, support the self-organization of cardiomyocytes into a functional syncytium. With a focus on early self-organization processes in EHM, we studied the molecular and biophysical adaptations mediated by defined populations of fibroblasts and embryonic stem cell-derived cardiomyocytes in a collagen type I hydrogel. After a short phase of cell-independent collagen gelation (30 min), tissue compaction was progressively mediated by fibroblasts. Fibroblast-mediated tissue stiffening was attenuated in the presence of cardiomyocytes allowing for the assembly of stably contracting, force-generating EHM within 4 weeks. Comparative RNA-sequencing data corroborated that fibroblasts are particularly sensitive to the tissue compaction process, resulting in the fast activation of transcription profiles, supporting heart muscle development and extracellular matrix synthesis. Large amplitude oscillatory shear (LAOS) measurements revealed nonlinear strain stiffening at physiological strain amplitudes (>2%), which was reduced in the presence of cells. The nonlinear stress-strain response could be characterized by a mathematical model. Collectively, our study defines the interplay between fibroblasts and cardiomyocytes during human heart muscle self-organization in vitro and underscores the relevance of fibroblasts in the biological engineering of a cardiomyogenesis-supporting viscoelastic stroma. We anticipate that the established mathematical model will facilitate future attempts to optimize EHM for in vitro (disease modelling) and in vivo applications (heart repair)."],["dc.identifier.doi","10.1016/j.pbiomolbio.2018.11.011"],["dc.identifier.pmid","30553553"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/72769"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/248"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | S01: In vivo und in vitro Krankheitsmodelle"],["dc.relation.workinggroup","RG Luther (Biomedical Physics)"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY 4.0"],["dc.title","Agonistic and antagonistic roles of fibroblasts and cardiomyocytes on viscoelastic stiffening of engineered human myocardium"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Acta Physiologica"],["dc.bibliographiccitation.volume","216"],["dc.contributor.author","Jatho, Aline"],["dc.contributor.author","Hartmann, S."],["dc.contributor.author","Kittana, Naim"],["dc.contributor.author","Muegge, F."],["dc.contributor.author","Wuertz, Christina"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Katschinski, Doerthe Magdalena"],["dc.contributor.author","Lutz, S."],["dc.date.accessioned","2018-11-07T10:17:27Z"],["dc.date.available","2018-11-07T10:17:27Z"],["dc.date.issued","2016"],["dc.identifier.isi","000372285400124"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/41230"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.publisher.place","Hoboken"],["dc.relation.issn","1748-1716"],["dc.relation.issn","1748-1708"],["dc.title","RhoA ambivalently controls prominent myofibroblast characteristics by involving distinct signaling routes"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Naunyn-Schmiedeberg s Archives of Pharmacology"],["dc.bibliographiccitation.volume","389"],["dc.contributor.author","Schlick, S."],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Zeidler, S."],["dc.contributor.author","Lutz, S."],["dc.contributor.author","Wingender, Edgar"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.date.accessioned","2018-11-07T10:19:01Z"],["dc.date.available","2018-11-07T10:19:01Z"],["dc.date.issued","2016"],["dc.format.extent","S12"],["dc.identifier.isi","000398368200040"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/41573"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.conference","82nd Annual Meeting of the German-Society-for-Exerimental-and-Clinical-Pharmacology-and-Toxicology (DGPT) / 18th Annual Meeting of the Network-Clinical-Pharmacology-Germany (VKliPha)"],["dc.relation.eventlocation","Berlin, GERMANY"],["dc.relation.issn","1432-1912"],["dc.relation.issn","0028-1298"],["dc.title","Hyaluronic acid deposition determines engineered heart muscle characteristics and can be pharmacologically targeted to enhance function"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e0137519"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Jatho, Aline"],["dc.contributor.author","Hartmann, Svenja"],["dc.contributor.author","Kittana, Naim"],["dc.contributor.author","Muegge, Felicitas"],["dc.contributor.author","Wuertz, Christina M."],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Katschinski, Dörthe M."],["dc.contributor.author","Lutz, Susanne"],["dc.date.accessioned","2017-09-07T11:43:28Z"],["dc.date.available","2017-09-07T11:43:28Z"],["dc.date.issued","2015"],["dc.description.abstract","Introduction RhoA has been shown to be beneficial in cardiac disease models when overexpressed in cardiomyocytes, whereas its role in cardiac fibroblasts (CF) is still poorly understood. During cardiac remodeling CF undergo a transition towards a myofibroblast phenotype thereby showing an increased proliferation and migration rate. Both processes involve the remodeling of the cytoskeleton. Since RhoA is known to be a major regulator of the cytoskeleton, we analyzed its role in CF and its effect on myofibroblast characteristics in 2 D and 3D models. Results Downregulation of RhoA was shown to strongly affect the actin cytoskeleton. It decreased the myofibroblast marker alpha-sm-actin, but increased certain fibrosis-associated factors like TGF-beta and collagens. Also, the detailed analysis of CTGF expression demonstrated that the outcome of RhoA signaling strongly depends on the involved stimulus. Furthermore, we show that proliferation of myofibroblasts rely on RhoA and tubulin acetylation. In assays accessing three different types of migration, we demonstrate that RhoA/ROCK/Dia1 are important for 2D migration and the repression of RhoA and Dia1 signaling accelerates 3D migration. Finally, we show that a downregulation of RhoA in CF impacts the viscoelastic and contractile properties of engineered tissues. Conclusion RhoA positively and negatively influences myofibroblast characteristics by differential signaling cascades and depending on environmental conditions. These include gene expression, migration and proliferation. Reduction of RhoA leads to an increased viscoelasticity and a decrease in contractile force in engineered cardiac tissue."],["dc.description.sponsorship","Open-Access Publikationsfonds 2015"],["dc.identifier.doi","10.1371/journal.pone.0137519"],["dc.identifier.gro","3141809"],["dc.identifier.isi","000362511000003"],["dc.identifier.pmid","26448568"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12214"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1312"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/118"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C02: RhoGTPasen und ihre Bedeutung für die Last-abhängige Myokardfibrose"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | C06: Mechanismen und Regulation der koronaren Gefäßneubildung"],["dc.relation.issn","1932-6203"],["dc.relation.workinggroup","RG Lutz (G Protein-Coupled Receptor Mediated Signaling)"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","435"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Future Cardiology"],["dc.bibliographiccitation.lastpage","445"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Eschenhagen, Thomas"],["dc.date.accessioned","2017-09-07T11:54:28Z"],["dc.date.available","2017-09-07T11:54:28Z"],["dc.date.issued","2011"],["dc.description.abstract","Engineered myocardium may be used to repair myocardial defects. Although not clinically applicable yet, initial studies in rodents have demonstrated the feasibility of tissue engineering based myocardial repair in vivo. In order for restorative treatment to evolve into a functional treatment modality, tissue engineers have to generate human myocardium of sufficient size and with relevant contractile function to replace/repair myocardial defects. This requires the identification of a scalable and ideally autologous cardiomyocyte source as well as the development of strategies to overcome size limitations. We will further address pivotal issues pertaining to the allocation of suitable human cells for myocardial tissue engineering and discuss the translation of present myocardial tissue engineering concepts into preclinical, as well as clinical, trials."],["dc.identifier.doi","10.2217/14796678.3.4.435"],["dc.identifier.gro","3145184"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2892"],["dc.language.iso","en"],["dc.notes.intern","Crossref Import"],["dc.notes.status","final"],["dc.relation.issn","1479-6678"],["dc.title","Cardiac tissue engineering: a clinical perspective"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Naunyn-Schmiedeberg s Archives of Pharmacology"],["dc.bibliographiccitation.volume","387"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Engel, Guenther"],["dc.contributor.author","Sanders, Sonka-Johanna"],["dc.contributor.author","Sowa, Thomas"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.date.accessioned","2018-11-07T09:44:51Z"],["dc.date.available","2018-11-07T09:44:51Z"],["dc.date.issued","2014"],["dc.format.extent","S20"],["dc.identifier.isi","000359538500077"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34487"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.eventlocation","Hannover, GERMANY"],["dc.relation.issn","1432-1912"],["dc.relation.issn","0028-1298"],["dc.title","Ryanodine receptor calcium leak contributes to statin-induced myopathy"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","9"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","21"],["dc.bibliographiccitation.volume","113"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Fomin, Andrey"],["dc.contributor.author","Luo, Xiaojing"],["dc.contributor.author","Li, Wener"],["dc.contributor.author","Fischer, Claudia"],["dc.contributor.author","Özcelik, Cemil"],["dc.contributor.author","Perrot, Andreas"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Haas, Jan"],["dc.contributor.author","Vidal, Ramon Oliveira"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Khadjeh, Sara"],["dc.contributor.author","Meder, Benjamin"],["dc.contributor.author","Bonn, Stefan"],["dc.contributor.author","Linke, Wolfgang A."],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Guan, Kaomei"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.date.accessioned","2018-04-23T11:49:17Z"],["dc.date.available","2018-04-23T11:49:17Z"],["dc.date.issued","2017"],["dc.description.abstract","The ability to generate patient-specific induced pluripotent stem cells (iPSCs) provides a unique opportunity for modeling heart disease in vitro. In this study, we generated iPSCs from a patient with dilated cardiomyopathy (DCM) caused by a missense mutation S635A in RNA-binding motif protein 20 (RBM20) and investigated the functionality and cell biology of cardiomyocytes (CMs) derived from patient-specific iPSCs (RBM20-iPSCs). The RBM20-iPSC-CMs showed abnormal distribution of sarcomeric α-actinin and defective calcium handling compared to control-iPSC-CMs, suggesting disorganized myofilament structure and altered calcium machinery in CMs of the RBM20 patient. Engineered heart muscles (EHMs) from RBM20-iPSC-CMs showed that not only active force generation was impaired in RBM20-EHMs but also passive stress of the tissue was decreased, suggesting a higher visco-elasticity of RBM20-EHMs. Furthermore, we observed a reduced titin (TTN) N2B-isoform expression in RBM20-iPSC-CMs by demonstrating a reduction of exon skipping in the PEVK region of TTN and an inhibition of TTN isoform switch. In contrast, in control-iPSC-CMs both TTN isoforms N2B and N2BA were expressed, indicating that the TTN isoform switch occurs already during early cardiogenesis. Using next generation RNA sequencing, we mapped transcriptome and splicing target profiles of RBM20-iPSC-CMs and identified different cardiac gene networks in response to the analyzed RBM20 mutation in cardiac-specific processes. These findings shed the first light on molecular mechanisms of RBM20-dependent pathological cardiac remodeling leading to DCM. Our data demonstrate that iPSC-CMs coupled with EHMs provide a powerful tool for evaluating disease-relevant functional defects and for a deeper mechanistic understanding of alternative splicing-related cardiac diseases."],["dc.identifier.doi","10.1016/j.yjmcc.2017.09.008"],["dc.identifier.gro","3142517"],["dc.identifier.pmid","28941705"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16493"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13672"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/191"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A08: Translationale und posttranslationale Kontrolle trunkierter Titinproteine in Kardiomyozyten von Patienten mit dilatativer Kardiomyopathie"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.issn","0022-2828"],["dc.relation.workinggroup","RG Guan (Application of patient-specific induced pluripotent stem cells in disease modelling)"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Linke (Kardiovaskuläre Physiologie)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","8391"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Sharma, Parveen"],["dc.contributor.author","Abbasi, Cynthia"],["dc.contributor.author","Lazic, Savo"],["dc.contributor.author","Teng, Allen C. T."],["dc.contributor.author","Wang, Dingyan"],["dc.contributor.author","Dubois, Nicole"],["dc.contributor.author","Ignatchenko, Vladimir"],["dc.contributor.author","Wong, Victoria"],["dc.contributor.author","Liu, Jun"],["dc.contributor.author","Araki, Toshiyuki"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Ackerley, Cameron"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Hamilton, Robert"],["dc.contributor.author","Sun, Yu"],["dc.contributor.author","Liu, Peter P."],["dc.contributor.author","Keller, Gordon"],["dc.contributor.author","Stagljar, Igor"],["dc.contributor.author","Scott, Ian C."],["dc.contributor.author","Kislinger, Thomas"],["dc.contributor.author","Gramolini, Anthony O."],["dc.date.accessioned","2017-09-07T11:43:34Z"],["dc.date.available","2017-09-07T11:43:34Z"],["dc.date.issued","2015"],["dc.description.abstract","Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology. Molecular analyses suggest that Tmem65 interaction with connexin 43 (Cx43) is required for correct localization of Cx43 to the intercalated disc, since Tmem65 deletion results in marked internalization of Cx43, a shorter half-life through increased degradation, and loss of Cx43 function. Our data demonstrate that the membrane protein Tmem65 is an intercalated disc protein that interacts with and functionally regulates ventricular Cx43."],["dc.identifier.doi","10.1038/ncomms9391"],["dc.identifier.gro","3141832"],["dc.identifier.isi","000363137100006"],["dc.identifier.pmid","26403541"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1568"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/94"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation.issn","2041-1723"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.title","Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]