Effects of fibrillin mutations on the behavior of heart muscle cells in Marfan syndrome.
Effects of fibrillin mutations on the behavior of heart muscle cells in Marfan syndrome.
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DOI：
10.1038/s41598-020-73802-w
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发表时间：
2020-10-07
影响因子：
4.6
通讯作者：
van Hengel J
中科院分区：
文献类型：
--
作者：
Aalders J;Léger L;Van der Meeren L;Van den Vreken N;Skirtach AG;Sinha S;De Backer J;van Hengel J
马凡氏综合征（MFS）是一种由纤维蛋白1 （FBN1）基因致病性变异引起的结缔组织全身性疾病。心肌功能障碍已在MFS患者和小鼠模型中得到证实，但对心肌细胞（CMs）的内在影响知之甚少。在这项研究中，来自mfs患者的诱导多能干细胞和经过纠正的FBN1突变的细胞系都分化为CMs。我们对该模型进行了一些功能分析，以研究MFS相关的心肌病。原子力显微镜显示MFS CMs比校正CMs更硬。与校正cm相比，MFS cm的收缩幅度减小。在正常培养条件下，与使用多电极阵列的校正CMs相比，MFS CMs显示出更低的节拍-节拍变异性。异丙肾上腺素诱导的应力或循环应变表明在MFS CMs中缺乏基质的支持。本研究报道了MFS的第一个心脏细胞培养模型，揭示了与基质缺陷相关的MFS CMs行为异常。基于这些结果，我们假设来自细胞外环境的支持受损在MFS中CMs功能不正常中起关键作用。
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.
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影响因子：
37.8
作者：
Mandel Y;Weissman A;Schick R;Barad L;Novak A;Meiry G;Goldberg S;Lorber A;Rosen MR;Itskovitz-Eldor J;Binah O
通讯作者：
Binah O
影响因子：
18.2
作者：
Alpendurada, Francisco;Wong, Joyce;Mohiaddin, Raad H.
通讯作者：
Mohiaddin, Raad H.
影响因子：
3.4
作者：
Hetzer, Roland;Siegel, Guenter;Walter, Eva Maria Delmo
通讯作者：
Walter, Eva Maria Delmo
DOI：
10.1007/s11626-019-00413-9
发表时间：
2019-10-29
影响因子：
2.1
作者：
Aalders, Jeffrey;Van den Vreken, Natasja;van Hengel, Jolanda
通讯作者：
van Hengel, Jolanda
影响因子：
5.9
作者：
Bedada, Fikru B.;Chan, Sunny S-K.;Metzger, Stefania K.;Zhang, Liying;Zhang, Jianyi;Garry, Daniel J.;Kamp, Timothy J.;Kyba, Michael;Metzger, Joseph M.
通讯作者：
Metzger, Joseph M.