Pathogenic variants in the FBN1 gene, which encodes the extracellular matrix protein fibrillin-1, cause Marfan syndrome (MFS), which affects multiple organ systems, including the cardiovascular system. Myocardial dysfunction has been observed in a subset of patients with MFS and in several MFS mouse models. However, there is limited understanding of the intrinsic consequences of FBN1 variants on cardiomyocytes (CMs). To elucidate the CM-specific contribution in Marfan's cardiomyopathy, cardiosphere cultures of CMs and cardiac fibroblasts (CFs) are used. CMs and CFs were derived by human induced pluripotent stem cell (iPSC) differentiation from MFS iPSCs with a pathogenic variant in FBN1 (c.3725G>A; p.Cys1242Tyr) and the corresponding CRISPR-corrected iPSC line (Cor).

Cardiospheres containing MFS CMs show decreased FBN1, COL1A2 and GJA1 expression. MFS CMs cultured in cardiospheres have fewer binucleated CMs in comparison with Cor CMs. 13% of MFS CMs in cardiospheres are binucleated and 15% and 16% in cardiospheres that contain co-cultures with respectively MFS CFs and Cor CFs, compared to Cor CMs, that revealed up to 23% binucleation when co-cultured with CFs. The sarcomere length of CMs, as a marker of development, is significantly increased in MFS CMs interacting with Cor CF or MFS CF, as compared to monocultured MFS CMs. Nuclear blebbing was significantly more frequent in MFS CFs, which correlated with increased stiffness of the nuclear area compared to Cor CFs.

Our cardiosphere model for Marfan-related cardiomyopathy identified a contribution of CFs in Marfan-related cardiomyopathy and suggests that abnormal early development of CMs may play a role in the disease mechanism.

FBN1基因（编码细胞外基质蛋白fibrillin-1）的致病性变异会导致马凡综合征 (MFS)，影响多个器官系统，包括心血管系统。在部分 MFS 患者和几种 MFS 小鼠模型中观察到心肌功能障碍。然而，人们对FBN1变异对心肌细胞 (CM)的内在影响的了解有限。为了阐明 CM 特异性在马凡氏心肌病中的作用，使用了 CM 和心脏成纤维细胞 (CF) 的心脏球培养物。CM 和 CF 是通过人诱导多能干细胞 (iPSC) 从 MFS iPSC 分化而来，其中FBN1 (c.3725G> A ; p.Cys1242Tyr) 中存在致病性变异，以及相应的 CRISPR 校正 iPSC 系 (Cor)。

含有 MFS CM 的心球显示FBN1、COL1A2和GJA1表达降低。与 Cor CM 相比，在心球中培养的 MFS CM 具有更少的双核 CM。心球中 13% 的 MFS CM 是双核的，而分别与 MFS CF 和 Cor CF 共培养的心球中，这一比例为 15% 和 16%，而 Cor CM 与 CF 共培养时双核率高达 23%。与单一培养的 MFS CM 相比，与 Cor CF 或 MFS CF 相互作用的 MFS CM 的 CM 肌节长度（作为发育标志）显着增加。与 Cor CF 相比，MFS CF 中的核起泡明显更频繁，这与核区域的硬度增加相关。

我们的马凡相关心肌病心脏圈模型确定了 CF 在马凡相关心肌病中的作用，并表明 CM 的异常早期发育可能在疾病机制中发挥作用。