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

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

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

Abstract: 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

Maturation of human pluripotent stem cell-derived cardiomyocytes

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The effect of a photopolymerizable poly(ε-caprolactone-co-glycolide) matrix on the cement reactions of tetracalcium phosphate and tetracalcium phosphate-monocalcium phosphate monohydrate mixtures

In this study, the influence of a biodegradable polymer matrix on the conversion of tetracalcium phosphate (TTCP) or TTCP-monocalcium phosphate monohydrate (MCPM) powders was investigated. As a reference, the properties of three calcium phosphate cements (CPCs) based on TTCP or TTCP-MCPM mixtures were discussed. Additionally, the influence of these calcium phosphate (CP) reacting powders on the polymer degradation was studied. Composites were formulated by mixing cross-linkable dimethacrylates of the 3-caprolactone/glycolide co-polymer with hydroxyethylmethacrylate, a photo-initiator and TTCP or TTCP-MCPM. The composite samples were set by visible light irradiation. CPC and composite samples were immersed in HEPES at 37 degrees C. The CPC based on TTCP converted to a carbonated apatite. Adding MCPM to the TTCP powder improved the conversion of TTCP. By varying the MCPM/TTCP ratio it was possible to tailor the conversion reactions so that an apatitic phase could be formed via intermediate products like DPC, DCPD and OCP. In the composites, a mutual interaction between the CP reacting powders and the polymer was observed. The co-polymer and its degradation products influenced the conversion reactions of the CP reacting powders. The degradation products tend to enhance the TTCP conversion after a long immersion time. The conversion of the TTCP-MCPM mixtures was retarded by the polymer matrix although the intermediate products were not altered. The basicity or acidity of the CP reacting powders and their conversion reactions were the main cause for the retarded polymer degradation, which was more pronounced when the basicity of the CP reacting powders increased