@article{CuiSchlesingerSchoenhalsetal.2016, author = {Cui, Huanhuan and Schlesinger, Jenny and Schoenhals, Sophia and Toenjes, Martje and Dunkel, Ilona and Meierhofer, David and Cano, Elena and Schulz, Kerstin and Berger, Michael F. and Haack, Timm and Abdelilah-Seyfried, Salim and Bulyk, Martha L. and Sauer, Sascha and Sperling, Silke R.}, title = {Phosphorylation of the chromatin remodeling factor DPF3a induces cardiac hypertrophy through releasing HEY repressors from DNA}, series = {Nucleic acids research}, volume = {44}, journal = {Nucleic acids research}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {0305-1048}, doi = {10.1093/nar/gkv1244}, pages = {2538 -- 2553}, year = {2016}, abstract = {DPF3 (BAF45c) is a member of the BAF chromatin remodeling complex. Two isoforms have been described, namely DPF3a and DPF3b. The latter binds to acetylated and methylated lysine residues of histones. Here, we elaborate on the role of DPF3a and describe a novel pathway of cardiac gene transcription leading to pathological cardiac hypertrophy. Upon hypertrophic stimuli, casein kinase 2 phosphorylates DPF3a at serine 348. This initiates the interaction of DPF3a with the transcriptional repressors HEY, followed by the release of HEY from the DNA. Moreover, BRG1 is bound by DPF3a, and is thus recruited to HEY genomic targets upon interaction of the two components. Consequently, the transcription of downstream targets such as NPPA and GATA4 is initiated and pathological cardiac hypertrophy is established. In human, DPF3a is significantly up-regulated in hypertrophic hearts of patients with hypertrophic cardiomyopathy or aortic stenosis. Taken together, we show that activation of DPF3a upon hypertrophic stimuli switches cardiac fetal gene expression from being silenced by HEY to being activated by BRG1. Thus, we present a novel pathway for pathological cardiac hypertrophy, whose inhibition is a long-term therapeutic goal for the treatment of the course of heart failure.}, language = {en} } @misc{deVinuesaAbdelilahSeyfriedKnausetal.2016, author = {de Vinuesa, Amaya Garcia and Abdelilah-Seyfried, Salim and Knaus, Petra and Zwijsen, An and Bailly, Sabine}, title = {BMP signaling in vascular biology and dysfunction}, series = {New journal of physics : the open-access journal for physics}, volume = {27}, journal = {New journal of physics : the open-access journal for physics}, publisher = {Elsevier}, address = {Oxford}, issn = {1359-6101}, doi = {10.1016/j.cytogfr.2015.12.005}, pages = {65 -- 79}, year = {2016}, abstract = {The vascular system is critical for developmental growth, tissue homeostasis and repair but also for tumor development. Bone morphogenetic protein (BMP) signaling has recently emerged as a fundamental pathway of the endothelium by regulating cardiovascular and lymphatic development and by being causative for several vascular dysfunctions. Two vascular disorders have been directly linked to impaired BMP signaling: pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia. Endothelial BMP signaling critically depends on the cellular context, which includes among others vascular heterogeneity, exposure to flow, and the intertwining with other signaling cascades (Notch, WNT, Hippo and hypoxia). The purpose of this review is to highlight the most recent findings illustrating the clear need for reconsidering the role of BMPs in vascular biology. (C) 2015 Elsevier Ltd. All rights reserved.}, language = {en} } @misc{HaackAbdelilahSeyfried2016, author = {Haack, Timm and Abdelilah-Seyfried, Salim}, title = {The force within: endocardial development, mechanotransduction and signalling during cardiac morphogenesis}, series = {Development : Company of Biologists}, volume = {143}, journal = {Development : Company of Biologists}, publisher = {Company of Biologists Limited}, address = {Cambridge}, issn = {0950-1991}, doi = {10.1242/dev.131425}, pages = {373 -- 386}, year = {2016}, abstract = {Endocardial cells are cardiac endothelial cells that line the interior of the heart tube. Historically, their contribution to cardiac development has mainly been considered from a morphological perspective. However, recent studies have begun to define novel instructive roles of the endocardium, as a sensor and signal transducer of biophysical forces induced by blood flow, and as an angiocrine signalling centre that is involved in myocardial cellular morphogenesis, regeneration and reprogramming. In this Review, we discuss how the endocardium develops, how endocardial-myocardial interactions influence the developing embryonic heart, and how the dysregulation of blood flowresponsive endocardial signalling can result in pathophysiological changes.}, language = {en} } @article{ChapmanLantOhashietal.2019, author = {Chapman, Eric M. and Lant, Benjamin and Ohashi, Yota and Yu, Bin and Schertzberg, Michael and Go, Christopher and Dogra, Deepika and Koskimaki, Janne and Girard, Romuald and Li, Yan and Fraser, Andrew G. and Awad, Issam A. and Abdelilah-Seyfried, Salim and Gingras, Anne-Claude and Derry, William Brent}, title = {A conserved CCM complex promotes apoptosis non-autonomously by regulating zinc homeostasis}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, publisher = {Nature Publ. Group}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-019-09829-z}, pages = {15}, year = {2019}, abstract = {Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1(-/-) zebrafish, and SLC39 zinc transporters are mis-expressed in Cerebral Cavernous Malformations (CCM) patient tissues. This study provides new insights into the regulation of apoptosis by cross-tissue communication, and suggests a link between zinc localization and CCM disease.}, language = {en} } @article{DemalHeiseReizetal.2019, author = {Demal, Till Joscha and Heise, Melina and Reiz, Benedikt and Dogra, Deepika and Braenne, Ingrid and Reichenspurner, Hermann and M{\"a}nner, J{\"o}rg and Aherrahrou, Zouhair and Schunkert, Heribert and Erdmann, Jeanette and Abdelilah-Seyfried, Salim}, title = {A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A}, series = {Scientific reports}, volume = {9}, journal = {Scientific reports}, publisher = {Nature Publ. Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-019-39648-7}, pages = {12}, year = {2019}, abstract = {The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein's anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aap.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.}, language = {en} } @article{BornhorstXiaNakajimaetal.2019, author = {Bornhorst, Dorothee and Xia, Peng and Nakajima, Hiroyuki and Dingare, Chaitanya and Herzog, Wiebke and Lecaudey, Virginie and Mochizuki, Naoki and Heisenberg, Carl-Philipp and Yelon, Deborah and Abdelilah-Seyfried, Salim}, title = {Biomechanical signaling within the developing zebrafish heart attunes endocardial growth to myocardial chamber dimensions}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, publisher = {Nature Publ. Group}, address = {London}, issn = {2041-1723}, doi = {10.1038/s41467-019-12068-x}, pages = {10}, year = {2019}, abstract = {Intra-organ communication guides morphogenetic processes that are essential for an organ to carry out complex physiological functions. In the heart, the growth of the myocardium is tightly coupled to that of the endocardium, a specialized endothelial tissue that lines its interior. Several molecular pathways have been implicated in the communication between these tissues including secreted factors, components of the extracellular matrix, or proteins involved in cell-cell communication. Yet, it is unknown how the growth of the endocardium is coordinated with that of the myocardium. Here, we show that an increased expansion of the myocardial atrial chamber volume generates higher junctional forces within endocardial cells. This leads to biomechanical signaling involving VE-cadherin, triggering nuclear localization of the Hippo pathway transcriptional regulator Yap1 and endocardial proliferation. Our work suggests that the growth of the endocardium results from myocardial chamber volume expansion and ends when the tension on the tissue is relaxed.}, language = {en} } @misc{OlmerEngelsUsmanetal.2018, author = {Olmer, Ruth and Engels, Lena and Usman, Abdulai and Menke, Sandra and Malik, Muhammad Nasir Hayat and Pessler, Frank and G{\"o}hring, Gudrun and Bornhorst, Dorothee and Bolten, Svenja and Abdelilah-Seyfried, Salim and Scheper, Thomas and Kempf, Henning and Zweigerdt, Robert and Martin, Ulrich}, title = {Differentiation of Human Pluripotent Stem Cells into Functional Endothelial Cells in Scalable Suspension Culture}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch-Naturwissenschaftliche Reihe}, number = {5}, issn = {1866-8372}, doi = {10.25932/publishup-42709}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-427095}, pages = {18}, year = {2018}, abstract = {Endothelial cells (ECs) are involved in a variety of cellular responses. As multifunctional components of vascular structures, endothelial (progenitor) cells have been utilized in cellular therapies and are required as an important cellular component of engineered tissue constructs and in vitro disease models. Although primary ECs from different sources are readily isolated and expanded, cell quantity and quality in terms of functionality and karyotype stability is limited. ECs derived from human induced pluripotent stem cells (hiPSCs) represent an alternative and potentially superior cell source, but traditional culture approaches and 2D differentiation protocols hardly allow for production of large cell numbers. Aiming at the production of ECs, we have developed a robust approach for efficient endothelial differentiation of hiPSCs in scalable suspension culture. The established protocol results in relevant numbers of ECs for regenerative approaches and industrial applications that show in vitro proliferation capacity and a high degree of chromosomal stability.}, language = {en} } @article{RenzOttenFaurobertetal.2015, author = {Renz, Marc and Otten, Cecile and Faurobert, Eva and Rudolph, Franziska and Zhu, Yuan and Boulday, Gwenola and Duchene, Johan and Mickoleit, Michaela and Dietrich, Ann-Christin and Ramspacher, Caroline and Steed, Emily and Manet-Dupe, Sandra and Benz, Alexander and Hassel, David and Vermot, Julien and Huisken, Jan and Tournier-Lasserve, Elisabeth and Felbor, Ute and Sure, Ulrich and Albiges-Rizo, Corinne and Abdelilah-Seyfried, Salim}, title = {Regulation of beta 1 Integrin-Klf2-Mediated angiogenesis by CCM proteins}, series = {Developmental cell}, volume = {32}, journal = {Developmental cell}, number = {2}, publisher = {Cell Press}, address = {Cambridge}, issn = {1534-5807}, doi = {10.1016/j.devcel.2014.12.016}, pages = {181 -- 190}, year = {2015}, abstract = {Mechanotransduction pathways are activated in response to biophysical stimuli during the development or homeostasis of organs and tissues. In zebrafish, the blood-flow-sensitive transcription factor Klf2a promotes VEGF-dependent angiogenesis. However, the means by which the Klf2a mechanotransduction pathway is regulated to prevent continuous angiogenesis remain unknown. Here we report that the upregulation of klf2 mRNA causes enhanced egfl7 expression and angiogenesis signaling, which underlies cardiovascular defects associated with the loss of cerebral cavernous malformation (CCM) proteins in the zebrafish embryo. Using CCM-protein-depleted human umbilical vein endothelial cells, we show that the misexpression of KLF2 mRNA requires the extracellular matrix-binding receptor beta 1 integrin and occurs in the absence of blood flow. Downregulation of beta 1 integrin rescues ccm mutant cardiovascular malformations in zebrafish. Our work reveals a beta 1 integrin-Klf2-Egfl7-signaling pathway that is tightly regulated by CCM proteins. This regulation prevents angiogenic overgrowth and ensures the quiescence of endothelial cells.}, language = {en} } @article{LombardoOttenAbdelilahSeyfried2015, author = {Lombardo, Veronica A. and Otten, Cecile and Abdelilah-Seyfried, Salim}, title = {Large-scale Zebrafish Embryonic Heart Dissection for Transcriptional Analysis}, series = {Journal of visualized experiments}, journal = {Journal of visualized experiments}, number = {95}, publisher = {JoVE}, address = {Cambridge}, issn = {1940-087X}, doi = {10.3791/52087}, pages = {7}, year = {2015}, abstract = {The zebrafish embryonic heart is composed of only a few hundred cells, representing only a small fraction of the entire embryo. Therefore, to prevent the cardiac transcriptome from being masked by the global embryonic transcriptome, it is necessary to collect sufficient numbers of hearts for further analyses. Furthermore, as zebrafish cardiac development proceeds rapidly, heart collection and RNA extraction methods need to be quick in order to ensure homogeneity of the samples. Here, we present a rapid manual dissection protocol for collecting functional/beating hearts from zebrafish embryos. This is an essential prerequisite for subsequent cardiac-specific RNA extraction to determine cardiac-specific gene expression levels by transcriptome analyses, such as quantitative real-time polymerase chain reaction (RT-qPCR). The method is based on differential adhesive properties of the zebrafish embryonic heart compared with other tissues; this allows for the rapid physical separation of cardiac from extracardiac tissue by a combination of fluidic shear force disruption, stepwise filtration and manual collection of transgenic fluorescently labeled hearts.}, language = {en} } @article{DietrichLombardoAbdelilahSeyfried2014, author = {Dietrich, Ann-Christin and Lombardo, Veronica A. and Abdelilah-Seyfried, Salim}, title = {Blood flow and Bmp signaling control endocardial chamber morphogenesis}, series = {Developmental cell}, volume = {30}, journal = {Developmental cell}, number = {4}, publisher = {Cell Press}, address = {Cambridge}, issn = {1534-5807}, doi = {10.1016/j.devcel.2014.06.020}, pages = {367 -- 377}, year = {2014}, abstract = {During heart development, the onset of heartbeat and blood flow coincides with a ballooning of the cardiac chambers. Here, we have used the zebrafish as a vertebrate model to characterize chamber ballooning morphogenesis of the endocardium, a specialized population of endothelial cells that line the interior of the heart. By combining functional manipulations, fate mapping studies, and high-resolution imaging, we show that endocardial growth occurs without an influx of external cells. Instead, endocardial cell proliferation is regulated, both by blood flow and by Bmp signaling, in a manner independent of vascular endothelial growth factor (VEGF) signaling. Similar to myocardial cells, endocardial cells obtain distinct chamber-specific and inner- versus outer-curvature-specific surface area sizes. We find that the hemodynamic-sensitive transcription factor Klf2a is involved in regulating endocardial cell morphology. These findings establish the endocardium as the flow-sensitive tissue in the heart with a key role in adapting chamber growth in response to the mechanical stimulus of blood flow.}, language = {en} }