@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{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} } @article{TangSullivanHongetal.2019, author = {Tang, Alan T. and Sullivan, Katie Rose and Hong, Courtney C. and Goddard, Lauren M. and Mahadevan, Aparna and Ren, Aileen and Pardo, Heidy and Peiper, Amy and Griffin, Erin and Tanes, Ceylan and Mattei, Lisa M. and Yang, Jisheng and Li, Li and Mericko-Ishizuka, Patricia and Shen, Le and Hobson, Nicholas and Girard, Romuald and Lightle, Rhonda and Moore, Thomas and Shenkar, Robert and Polster, Sean P. and Roedel, Claudia Jasmin and Li, Ning and Zhu, Qin and Whitehead, Kevin J. and Zheng, Xiangjian and Akers, Amy and Morrison, Leslie and Kim, Helen and Bittinger, Kyle and Lengner, Christopher J. and Schwaninger, Markus and Velcich, Anna and Augenlicht, Leonard and Abdelilah-Seyfried, Salim and Min, Wang and Marchuk, Douglas A. and Awad, Issam A. and Kahn, Mark L.}, title = {Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation}, series = {Science Translational Medicine}, volume = {11}, journal = {Science Translational Medicine}, number = {520}, publisher = {American Assoc. for the Advancement of Science}, address = {Washington}, issn = {1946-6234}, doi = {10.1126/scitranslmed.aaw3521}, pages = {14}, year = {2019}, abstract = {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.}, language = {en} } @article{LombardoHeiseMoghtadaeietal.2019, author = {Lombardo, Ver{\´o}nica A. and Heise, Melina and Moghtadaei, Motahareh and Bornhorst, Dorothee and M{\"a}nner, J{\"o}rg and Abdelilah-Seyfried, Salim}, title = {Morphogenetic control of zebrafish cardiac looping by Bmp signaling}, series = {Development : Company of Biologists}, volume = {146}, journal = {Development : Company of Biologists}, number = {22}, publisher = {The Company of Biologists Ltd}, address = {Cambridge}, issn = {0950-1991}, doi = {10.1242/dev.180091}, pages = {13}, year = {2019}, abstract = {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.}, language = {en} } @article{RoedelOttenDonatetal.2019, author = {R{\"o}del, Claudia Jasmin and Otten, Cecile and Donat, Stefan and Louren{\c{c}}o, Marta Sofia Rocha and Fischer, Dorothea and Kuropka, Benno and Paolini, Alessio and Freund, Christian and Abdelilah-Seyfried, Salim}, title = {Blood Flow Suppresses Vascular Anomalies in a Zebrafish Model of Cerebral Cavernous Malformations}, series = {Circulation Research}, volume = {125}, journal = {Circulation Research}, number = {10}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0009-7330}, doi = {10.1161/CIRCRESAHA.119.315076}, pages = {E43 -- E54}, year = {2019}, abstract = {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.}, language = {en} } @article{LisowskaRoedelManetetal.2018, author = {Lisowska, Justyna and R{\"o}del, Claudia Jasmin and Manet, Sandra and Miroshnikova, Yekaterina A. and Boyault, Cyril and Planus, Emmanuelle and De Mets, Richard and Lee, Hsiao-Hui and Destaing, Olivier and Mertani, Hichem and Boulday, Gwenola and Tournier-Lasserve, Elisabeth and Balland, Martial and Abdelilah-Seyfried, Salim and Albiges-Rizo, Corinne and Faurobert, Eva}, title = {The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity}, series = {Journal of cell science}, volume = {131}, journal = {Journal of cell science}, number = {15}, publisher = {Company biologists LTD}, address = {Cambridge}, issn = {0021-9533}, doi = {10.1242/jcs.216093}, pages = {15}, year = {2018}, abstract = {Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. This study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold, promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 (also known as KRIT1) produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1 and CCM2-depleted endothelial monolayers, and rescues the cardiovascular defects of ccm1 mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the ccm1 mutant phenotypes. Our study uncovers the role of the CCM1-CCM2 complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it solely identifies the ROCK1 isoform as a potential therapeutic target for the CCM disease.}, language = {en} }