@article{MuenchAbdelilahSeyfried2021, author = {M{\"u}nch, Juliane and Abdelilah-Seyfried, Salim}, title = {Sensing and responding of cardiomyocytes to changes of tissue stiffness in the diseased heart}, series = {Frontiers in cell developmental biology}, volume = {9}, journal = {Frontiers in cell developmental biology}, publisher = {Frontiers Media}, address = {Lausanne}, issn = {2296-634X}, doi = {10.3389/fcell.2021.642840}, pages = {13}, year = {2021}, abstract = {Cardiomyocytes are permanently exposed to mechanical stimulation due to cardiac contractility. Passive myocardial stiffness is a crucial factor, which defines the physiological ventricular compliance and volume of diastolic filling with blood. Heart diseases often present with increased myocardial stiffness, for instance when fibrotic changes modify the composition of the cardiac extracellular matrix (ECM). Consequently, the ventricle loses its compliance, and the diastolic blood volume is reduced. Recent advances in the field of cardiac mechanobiology revealed that disease-related environmental stiffness changes cause severe alterations in cardiomyocyte cellular behavior and function. Here, we review the molecular mechanotransduction pathways that enable cardiomyocytes to sense stiffness changes and translate those into an altered gene expression. We will also summarize current knowledge about when myocardial stiffness increases in the diseased heart. Sophisticated in vitro studies revealed functional changes, when cardiomyocytes faced a stiffer matrix. Finally, we will highlight recent studies that described modulations of cardiac stiffness and thus myocardial performance in vivo. Mechanobiology research is just at the cusp of systematic investigations related to mechanical changes in the diseased heart but what is known already makes way for new therapeutic approaches in regenerative biology.}, language = {en} } @article{BornhorstAbdelilahSeyfried2021, author = {Bornhorst, Dorothee and Abdelilah-Seyfried, Salim}, title = {Strong as a Hippo's Heart: Biomechanical Hippo Signaling During Zebrafish Cardiac Development}, series = {Frontiers in Cell and Developmental Biology}, volume = {9}, journal = {Frontiers in Cell and Developmental Biology}, publisher = {Frontiers Media}, address = {Lausanne, Schweiz}, issn = {2296-634X}, doi = {10.3389/fcell.2021.731101}, pages = {1 -- 10}, year = {2021}, abstract = {The heart is comprised of multiple tissues that contribute to its physiological functions. During development, the growth of myocardium and endocardium is coupled and morphogenetic processes within these separate tissue layers are integrated. Here, we discuss the roles of mechanosensitive Hippo signaling in growth and morphogenesis of the zebrafish heart. Hippo signaling is involved in defining numbers of cardiac progenitor cells derived from the secondary heart field, in restricting the growth of the epicardium, and in guiding trabeculation and outflow tract formation. Recent work also shows that myocardial chamber dimensions serve as a blueprint for Hippo signaling-dependent growth of the endocardium. Evidently, Hippo pathway components act at the crossroads of various signaling pathways involved in embryonic zebrafish heart development. Elucidating how biomechanical Hippo signaling guides heart morphogenesis has direct implications for our understanding of cardiac physiology and pathophysiology.}, language = {en} } @article{RoedelAbdelilahSeyfried2021, author = {R{\"o}del, Claudia Jasmin and Abdelilah-Seyfried, Salim}, title = {A zebrafish toolbox for biomechanical signaling in cardiovascular development and disease}, series = {Current opinion in hematology}, volume = {28}, journal = {Current opinion in hematology}, number = {3}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {1065-6251}, doi = {10.1097/MOH.0000000000000648}, pages = {198 -- 207}, year = {2021}, abstract = {Purpose of review The zebrafish embryo has emerged as a powerful model organism to investigate the mechanisms by which biophysical forces regulate vascular and cardiac cell biology during development and disease. A versatile arsenal of methods and tools is available to manipulate and analyze biomechanical signaling. This review aims to provide an overview of the experimental strategies and tools that have been utilized to study biomechanical signaling in cardiovascular developmental processes and different vascular disease models in the zebrafish embryo. Within the scope of this review, we focus on work published during the last two years. Recent findings Genetic and pharmacological tools for the manipulation of cardiac function allow alterations of hemodynamic flow patterns in the zebrafish embryo and various types of transgenic lines are available to report endothelial cell responses to biophysical forces. These tools have not only revealed the impact of biophysical forces on cardiovascular development but also helped to establish more accurate models for cardiovascular diseases including cerebral cavernous malformations, hereditary hemorrhagic telangiectasias, arteriovenous malformations, and lymphangiopathies. Summary The zebrafish embryo is a valuable vertebrate model in which in-vivo manipulations of biophysical forces due to cardiac contractility and blood flow can be performed. These analyses give important insights into biomechanical signaling pathways that control endothelial and endocardial cell behaviors. The technical advances using this vertebrate model will advance our understanding of the impact of biophysical forces in cardiovascular pathologies.}, language = {en} } @article{OttenKnoxBouldayetal.2018, author = {Otten, Cecile and Knox, Jessica and Boulday, Gwenola and Eymery, Mathias and Haniszewski, Marta and Neuenschwander, Martin and Radetzki, Silke and Vogt, Ingo and Haehn, Kristina and De Luca, Coralie and Cardoso, Cecile and Hamad, Sabri and Igual Gil, Carla and Roy, Peter and Albiges-Rizo, Corinne and Faurobert, Eva and von Kries, Jens P. and Campillos, Monica and Tournier-Lasserve, Elisabeth and Derry, William Brent and Abdelilah-Seyfried, Salim}, title = {Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations}, series = {EMBO molecular medicine}, volume = {10}, journal = {EMBO molecular medicine}, number = {10}, publisher = {Wiley}, address = {Hoboken}, issn = {1757-4676}, doi = {10.15252/emmm.201809155}, pages = {17}, year = {2018}, abstract = {Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to CCM mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish CCM2 mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of CCM2 and CCM3 and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.}, language = {en} } @misc{MerksSwinarskiMeyeretal.2018, author = {Merks, Anne Margarete and Swinarski, Marie and Meyer, Alexander Matthias and M{\"u}ller, Nicola Victoria and {\"O}zcan, Ismail and Donat, Stefan and Burger, Alexa and Gilbert, Stephen and Mosimann, Christian and Abdelilah-Seyfried, Salim and Pan{\´a}kov{\´a}, Daniela}, title = {Planar cell polarity signalling coordinates heart tube remodelling through tissue-scale polarisation of actomyosin activity}, series = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe}, number = {849}, issn = {1866-8372}, doi = {10.25932/publishup-42702}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-427026}, pages = {17}, year = {2018}, abstract = {Development of a multiple-chambered heart from the linear heart tube is inherently linked to cardiac looping. Although many molecular factors regulating the process of cardiac chamber ballooning have been identified, the cellular mechanisms underlying the chamber formation remain unclear. Here, we demonstrate that cardiac chambers remodel by cell neighbour exchange of cardiomyocytes guided by the planar cell polarity (PCP) pathway triggered by two non-canonical Wnt ligands, Wnt5b and Wnt11. We find that PCP signalling coordinates the localisation of actomyosin activity, and thus the efficiency of cell neighbour exchange. On a tissue-scale, PCP signalling planar-polarises tissue tension by restricting the actomyosin contractility to the apical membranes of outflow tract cells. The tissue-scale polarisation of actomyosin contractility is required for cardiac looping that occurs concurrently with chamber ballooning. Taken together, our data reveal that instructive PCP signals couple cardiac chamber expansion with cardiac looping through the organ-scale polarisation of actomyosin-based tissue tension.}, language = {en} } @article{AbdelilahSeyfriedIruelaArispePenningeretal.2022, author = {Abdelilah-Seyfried, Salim and Iruela-Arispe, M. Luisa and Penninger, Josef M. and Tournier-Lasserve, Elisabeth and Vikkula, Miikka and Cleaver, Ondine}, title = {Recalibrating vascular malformations and mechanotransduction by pharmacological intervention}, series = {Journal of clinical investigation}, volume = {132}, journal = {Journal of clinical investigation}, number = {8}, publisher = {American Society for Clinical Investigation}, address = {Ann Arbor}, issn = {0021-9738}, doi = {10.1172/JCI160227}, pages = {4}, year = {2022}, language = {en} } @article{GrdseloffBouldayRoedeletal.2023, author = {Grdseloff, Nastasja and Boulday, Gwenola and Roedel, Claudia J. and Otten, Cecile and Vannier, Daphne Raphaelle and Cardoso, Cecile and Faurobert, Eva and Dogra, Deepika and Tournier-Lasserve, Elisabeth and Abdelilah-Seyfried, Salim}, title = {Impaired retinoic acid signaling in cerebral cavernous malformations}, series = {Scientific reports}, volume = {13}, journal = {Scientific reports}, number = {1}, publisher = {Nature Portfolio}, address = {Berlin}, issn = {2045-2322}, doi = {10.1038/s41598-023-31905-0}, pages = {11}, year = {2023}, abstract = {The capillary-venous pathology cerebral cavernous malformation (CCM) is caused by loss of CCM1/Krev interaction trapped protein 1 (KRIT1), CCM2/MGC4607, or CCM3/PDCD10 in some endothelial cells. Mutations of CCM genes within the brain vasculature can lead to recurrent cerebral hemorrhages. Pharmacological treatment options are urgently needed when lesions are located in deeply-seated and in-operable regions of the central nervous system. Previous pharmacological suppression screens in disease models of CCM led to the discovery that treatment with retinoic acid improved CCM phenotypes. This finding raised a need to investigate the involvement of retinoic acid in CCM and test whether it has a curative effect in preclinical mouse models. Here, we show that components of the retinoic acid synthesis and degradation pathway are transcriptionally misregulated across disease models of CCM. We complemented this analysis by pharmacologically modifying retinoic acid levels in zebrafish and human endothelial cell models of CCM, and in acute and chronic mouse models of CCM. Our pharmacological intervention studies in CCM2-depleted human umbilical vein endothelial cells (HUVECs) and krit1 mutant zebrafish showed positive effects when retinoic acid levels were increased. However, therapeutic approaches to prevent the development of vascular lesions in adult chronic murine models of CCM were drug regiment-sensitive, possibly due to adverse developmental effects of this hormone. A treatment with high doses of retinoic acid even worsened CCM lesions in an adult chronic murine model of CCM. This study provides evidence that retinoic acid signaling is impaired in the CCM pathophysiology and suggests that modification of retinoic acid levels can alleviate CCM phenotypes.}, language = {en} }