Effects of fibrillin mutations on the behavior of heart muscle cells in Marfan syndrome.

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Aalders, Jeffrey 
Léger, Laurens 
Van der Meeren, Louis 
Van den Vreken, Natasja 
Skirtach, Andre G 

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Myocardial dysfunction has been demonstrated in MFS patients and mouse models, but little is known about the intrinsic effect on the cardiomyocytes (CMs). In this study, both induced pluripotent stem cells derived from a MFS-patient and the line with the corrected FBN1 mutation were differentiated to CMs. Several functional analyses are performed on this model to study MFS related cardiomyopathy. Atomic force microscopy revealed that MFS CMs are stiffer compared to corrected CMs. The contraction amplitude of MFS CMs is decreased compared to corrected CMs. Under normal culture conditions, MFS CMs show a lower beat-to-beat variability compared to corrected CMs using multi electrode array. Isoproterenol-induced stress or cyclic strain demonstrates lack of support from the matrix in MFS CMs. This study reports the first cardiac cell culture model for MFS, revealing abnormalities in the behavior of MFS CMs that are related to matrix defects. Based on these results, we postulate that impaired support from the extracellular environment plays a key role in the improper functioning of CMs in MFS.

Adult, Cell Differentiation, Fibrillins, Humans, Induced Pluripotent Stem Cells, Marfan Syndrome, Mutation, Myocytes, Cardiac
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Springer Science and Business Media LLC
Medical Research Council (MC_PC_12009)
British Heart Foundation (RG/17/5/32936)
British Heart Foundation (FS/18/46/33663)
Medical Research Council (MC_PC_17230)