Three-dimensional co-culturing of stem cell-derived cardiomyocytes and cardiac fibroblasts reveals a role for both cell types in Marfan-related cardiomyopathy

IF 4.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jeffrey Aalders , Laurens Léger , Louis Van der Meeren , Sanjay Sinha , Andre G. Skirtach , Julie De Backer , Jolanda van Hengel
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引用次数: 0

Abstract

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.

干细胞衍生的心肌细胞和心脏成纤维细胞的三维共培养揭示了这两种细胞类型在马凡氏相关心肌病中的作用。
编码细胞外基质蛋白纤连蛋白-1 的 FBN1 基因中的致病变体会导致马凡综合征(MFS),影响包括心血管系统在内的多个器官系统。在一部分马凡综合征患者和几种马凡综合征小鼠模型中都观察到了心肌功能障碍。然而,人们对 FBN1 变体对心肌细胞(CMs)的内在影响了解有限。为了阐明马凡氏心肌病中 CM 的特异性贡献,我们使用了 CM 和心脏成纤维细胞(CF)的心球培养物。CMs和CFs通过人类诱导多能干细胞(iPSC)分化而来,这些诱导多能干细胞来自带有FBN1致病变体(c.3725G>A;p.Cys1242Tyr)的MFS iPSC和相应的CRISPR校正iPSC系(Cor)。含有 MFS CMs 的心球显示 FBN1、COL1A2 和 GJA1 表达减少。与 Cor CMs 相比,在心球中培养的 MFS CMs 的双核 CMs 更少。心球中 13% 的 MFS CMs 有双核,在分别与 MFS CFs 和 Cor CFs 共同培养的心球中,双核率分别为 15% 和 16%,而与 Cor CMs 共同培养时,双核率高达 23%。与单培养的 MFS CMs 相比,与 Cor CF 或 MFS CF 共同培养的 MFS CMs 中作为发育标志的 CMs 肉节长度明显增加。与 Cor CFs 相比,MFS CFs 中的核裂纹明显增加,这与核区硬度增加有关。我们的马凡氏相关心肌病心球模型确定了CFs在马凡氏相关心肌病中的作用,并表明CMs的早期发育异常可能在疾病机制中起作用。
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来源期刊
Matrix Biology
Matrix Biology 生物-生化与分子生物学
CiteScore
11.40
自引率
4.30%
发文量
77
审稿时长
45 days
期刊介绍: Matrix Biology (established in 1980 as Collagen and Related Research) is a cutting-edge journal that is devoted to publishing the latest results in matrix biology research. We welcome articles that reside at the nexus of understanding the cellular and molecular pathophysiology of the extracellular matrix. Matrix Biology focusses on solving elusive questions, opening new avenues of thought and discovery, and challenging longstanding biological paradigms.
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