TY - JOUR A1 - Tang, Alan T. A1 - Sullivan, Katie Rose A1 - Hong, Courtney C. A1 - Goddard, Lauren M. A1 - Mahadevan, Aparna A1 - Ren, Aileen A1 - Pardo, Heidy A1 - Peiper, Amy A1 - Griffin, Erin A1 - Tanes, Ceylan A1 - Mattei, Lisa M. A1 - Yang, Jisheng A1 - Li, Li A1 - Mericko-Ishizuka, Patricia A1 - Shen, Le A1 - Hobson, Nicholas A1 - Girard, Romuald A1 - Lightle, Rhonda A1 - Moore, Thomas A1 - Shenkar, Robert A1 - Polster, Sean P. A1 - Roedel, Claudia Jasmin A1 - Li, Ning A1 - Zhu, Qin A1 - Whitehead, Kevin J. A1 - Zheng, Xiangjian A1 - Akers, Amy A1 - Morrison, Leslie A1 - Kim, Helen A1 - Bittinger, Kyle A1 - Lengner, Christopher J. A1 - Schwaninger, Markus A1 - Velcich, Anna A1 - Augenlicht, Leonard A1 - Abdelilah-Seyfried, Salim A1 - Min, Wang A1 - Marchuk, Douglas A. A1 - Awad, Issam A. A1 - Kahn, Mark L. T1 - Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation JF - Science Translational Medicine N2 - Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10. Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling. Y1 - 2019 U6 - https://doi.org/10.1126/scitranslmed.aaw3521 SN - 1946-6234 SN - 1946-6242 VL - 11 IS - 520 PB - American Assoc. for the Advancement of Science CY - Washington ER - TY - JOUR A1 - Rödel, Claudia Jasmin A1 - Otten, Cecile A1 - Donat, Stefan A1 - Lourenço, Marta Sofia Rocha A1 - Fischer, Dorothea A1 - Kuropka, Benno A1 - Paolini, Alessio A1 - Freund, Christian A1 - Abdelilah-Seyfried, Salim T1 - Blood Flow Suppresses Vascular Anomalies in a Zebrafish Model of Cerebral Cavernous Malformations JF - Circulation Research N2 - RATIONALE: Pathological biomechanical signaling induces vascular anomalies including cerebral cavernous malformations (CCM), which are caused by a clonal loss of CCM1/KRIT1 (Krev interaction trapped protein 1), CCM2/MGC4607, or CCM3/PDCD10. Why patients typically experience lesions only in lowly perfused venous capillaries of the cerebrovasculature is completely unknown. OBJECTIVE: In contrast, animal models with a complete loss of CCM proteins lack a functional heart and blood flow and exhibit vascular anomalies within major blood vessels as well. This finding raises the possibility that hemodynamics may play a role in the context of this vascular pathology. METHODS AND RESULTS: Here, we used a genetic approach to restore cardiac function and blood flow in a zebrafish model of CCM1. We find that blood flow prevents cardiovascular anomalies including a hyperplastic expansion within a large Ccm1-deficient vascular bed, the lateral dorsal aorta. CONCLUSIONS: This study identifies blood flow as an important physiological factor that is protective in the cause of this devastating vascular pathology. KW - animal models KW - cerebral cavernous malformations KW - endothelial cell KW - hemodynamics KW - zebrafish Y1 - 2019 U6 - https://doi.org/10.1161/CIRCRESAHA.119.315076 SN - 0009-7330 SN - 1524-4571 VL - 125 IS - 10 SP - E43 EP - E54 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Rödel, Claudia Jasmin A1 - Abdelilah-Seyfried, Salim T1 - A zebrafish toolbox for biomechanical signaling in cardiovascular development and disease JF - Current opinion in hematology N2 - 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. KW - angiogenesis KW - cardiovascular system KW - Danio rerio (zebrafish) KW - genetic KW - tools KW - mechanobiology Y1 - 2021 U6 - https://doi.org/10.1097/MOH.0000000000000648 SN - 1065-6251 SN - 1531-7048 VL - 28 IS - 3 SP - 198 EP - 207 PB - Lippincott Williams & Wilkins CY - Philadelphia ER - TY - JOUR A1 - Renz, Marc A1 - Otten, Cecile A1 - Faurobert, Eva A1 - Rudolph, Franziska A1 - Zhu, Yuan A1 - Boulday, Gwenola A1 - Duchene, Johan A1 - Mickoleit, Michaela A1 - Dietrich, Ann-Christin A1 - Ramspacher, Caroline A1 - Steed, Emily A1 - Manet-Dupe, Sandra A1 - Benz, Alexander A1 - Hassel, David A1 - Vermot, Julien A1 - Huisken, Jan A1 - Tournier-Lasserve, Elisabeth A1 - Felbor, Ute A1 - Sure, Ulrich A1 - Albiges-Rizo, Corinne A1 - Abdelilah-Seyfried, Salim T1 - Regulation of beta 1 Integrin-Klf2-Mediated angiogenesis by CCM proteins JF - Developmental cell N2 - 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. Y1 - 2015 U6 - https://doi.org/10.1016/j.devcel.2014.12.016 SN - 1534-5807 SN - 1878-1551 VL - 32 IS - 2 SP - 181 EP - 190 PB - Cell Press CY - Cambridge ER - TY - JOUR A1 - Paolini, Alessio A1 - Abdelilah-Seyfried, Salim T1 - The mechanobiology of zebrafish cardiac valve leaflet formation JF - Current opinion in cell biology : review articles, recommended reading, bibliography of the world literature N2 - Over a lifetime, rhythmic contractions of the heart provide a continuous flow of blood throughout the body. An essential morphogenetic process during cardiac development which ensures unidirectional blood flow is the formation of cardiac valves. These structures are largely composed of extracellular matrix and of endocardial cells, a specialized population of endothelial cells that line the interior of the heart and that are subjected to changing hemodynamic forces. Recent studies have significantly expanded our understanding of this morphogenetic process. They highlight the importance of the mechanobiology of cardiac valve formation and show how biophysical forces due to blood flow drive biochemical and electrical signaling required for the differentiation of cells to produce cardiac valves. Y1 - 2018 U6 - https://doi.org/10.1016/j.ceb.2018.05.007 SN - 0955-0674 SN - 1879-0410 VL - 55 SP - 52 EP - 58 PB - Elsevier CY - London ER - TY - JOUR A1 - Otten, Cecile A1 - Knox, Jessica A1 - Boulday, Gwenola A1 - Eymery, Mathias A1 - Haniszewski, Marta A1 - Neuenschwander, Martin A1 - Radetzki, Silke A1 - Vogt, Ingo A1 - Haehn, Kristina A1 - De Luca, Coralie A1 - Cardoso, Cecile A1 - Hamad, Sabri A1 - Igual Gil, Carla A1 - Roy, Peter A1 - Albiges-Rizo, Corinne A1 - Faurobert, Eva A1 - von Kries, Jens P. A1 - Campillos, Monica A1 - Tournier-Lasserve, Elisabeth A1 - Derry, William Brent A1 - Abdelilah-Seyfried, Salim T1 - Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations JF - EMBO molecular medicine N2 - 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. KW - angiogenesis KW - CCM KW - ERK5 KW - indirubin-3-monoxime KW - KLF2 Y1 - 2018 U6 - https://doi.org/10.15252/emmm.201809155 SN - 1757-4676 SN - 1757-4684 VL - 10 IS - 10 PB - Wiley CY - Hoboken ER - TY - JOUR A1 - Olmer, Ruth A1 - Engels, Lena A1 - Usman, Abdulai A1 - Menke, Sandra A1 - Malik, Muhammad Nasir Hayat A1 - Pessler, Frank A1 - Goehring, Gudrun A1 - Bornhorst, Dorothee A1 - Bolten, Svenja A1 - Abdelilah-Seyfried, Salim A1 - Scheper, Thomas A1 - Kempf, Henning A1 - Zweigerdt, Robert A1 - Martin, Ulrich T1 - Differentiation of Human Pluripotent Stem Cells into Functional Endothelial Cells in Scalable Suspension Culture JF - Stem Cell Reports N2 - 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. KW - virus infection KW - progenitor cells KW - in vitro KW - telomere dysfunction KW - cord blood KW - cardiomyogenic differentiation KW - angiogenesis KW - efficient KW - aberrations KW - expression Y1 - 2017 U6 - https://doi.org/10.1016/j.stemcr.2018.03.017 SN - 2213-6711 VL - 10 IS - 5 PB - Springer CY - New York ER - TY - JOUR A1 - Münch, Juliane A1 - Abdelilah-Seyfried, Salim T1 - Sensing and responding of cardiomyocytes to changes of tissue stiffness in the diseased heart JF - Frontiers in cell developmental biology N2 - 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. KW - mechanobiology KW - tissue stiffness KW - cardiomyocyte KW - heart regeneration KW - titin KW - collagen KW - agrin KW - extracellular matrix Y1 - 2020 U6 - https://doi.org/10.3389/fcell.2021.642840 SN - 2296-634X VL - 9 PB - Frontiers Media CY - Lausanne ER - TY - JOUR A1 - Merks, Anne Margarete A1 - Swinarski, Marie A1 - Meyer, Alexander Matthias A1 - Müller, Nicola Victoria A1 - Özcan, Ismail A1 - Donat, Stefan A1 - Burger, Alexa A1 - Gilbert, Stephen A1 - Mosimann, Christian A1 - Abdelilah-Seyfried, Salim A1 - Panakova, Daniela T1 - Planar cell polarity signalling coordinates heart tube remodelling through tissue-scale polarisation of actomyosin activity JF - Nature Communications N2 - 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. Y1 - 2018 U6 - https://doi.org/10.1038/s41467-018-04566-1 SN - 2041-1723 VL - 9 PB - Nature Publ. Group CY - London ER - TY - JOUR A1 - Lombardo, Verónica A. A1 - Heise, Melina A1 - Moghtadaei, Motahareh A1 - Bornhorst, Dorothee A1 - Männer, Jörg A1 - Abdelilah-Seyfried, Salim T1 - Morphogenetic control of zebrafish cardiac looping by Bmp signaling JF - Development : Company of Biologists N2 - Cardiac looping is an essential and highly conserved morphogenetic process that places the different regions of the developing vertebrate heart tube into proximity of their final topographical positions. High-resolution 4D live imaging of mosaically labelled cardiomyocytes reveals distinct cardiomyocyte behaviors that contribute to the deformation of the entire heart tube. Cardiomyocytes acquire a conical cell shape, which is most pronounced at the superior wall of the atrioventricular canal and contributes to S-shaped bending. Torsional deformation close to the outflow tract contributes to a torque-like winding of the entire heart tube between its two poles. Anisotropic growth of cardiomyocytes based on their positions reinforces S-shaping of the heart. During cardiac looping, bone morphogenetic protein pathway signaling is strongest at the future superior wall of the atrioventricular canal. Upon pharmacological or genetic inhibition of bone morphogenetic protein signaling, myocardial cells at the superior wall of the atrioventricular canal maintain cuboidal cell shapes and S-shaped bending is impaired. This description of cellular rearrangements and cardiac looping regulation may also be relevant for understanding the etiology of human congenital heart defects. KW - BMP KW - Wnt KW - Cardiac looping KW - Hemodynamics KW - Zebrafish Y1 - 2019 U6 - https://doi.org/10.1242/dev.180091 SN - 0950-1991 SN - 1477-9129 VL - 146 IS - 22 PB - The Company of Biologists Ltd CY - Cambridge ER -