Murphy Sean A, Cho Gunsik, Limphong Pattraranee, Lee Dong I, Kwon Chulan
Division of Cardiology, Department of Medicine, Department of Cell Biology, Department of Biomedical Engineering, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Co-first.
bioRxiv. 2025 Aug 15:2025.08.11.669708. doi: 10.1101/2025.08.11.669708.
Muscle LIM protein (MLP) is a critical regulator of cardiomyocytes (CMs) cytoarchitecture, and its deficiency results in late-onset dilated cardiomyopathy (DCM) in both mice and human. However, recapitulating this phenotype using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) has been challenging largely due to their immature state. Here, we generated MLP knockout (MLP-KO) mouse iPSCs and differentiated them into CMs. We then employed both conventional and transplantation approach using immunocompromised rat hearts to promote cardiomyocytes maturation. Our results showed that while -matured MLP-KO iPSC-CMs failed to exhibit disease phenotypes, -matured MLP-KO iPSC-CMs successfully recapitulated the hallmarks of DCM, including disrupted sarcomeric architecture and upregulation of atrial natriuretic peptide (ANP), closely mirroring disease progression observed in MLP-deficient mice. These findings demonstrate that the maturation environment is essential for the maturation of iPSC-derived cardiomyocytes to better model genetic cardiac diseases like DCM and provide valuable insights for future therapeutic strategies.
肌肉LIM蛋白（MLP）是心肌细胞（CMs）细胞结构的关键调节因子，其缺乏会导致小鼠和人类出现迟发性扩张型心肌病（DCM）。然而，使用诱导多能干细胞衍生的心肌细胞（iPSC-CMs）重现这种表型一直具有挑战性，这主要是由于它们处于不成熟状态。在这里，我们生成了MLP基因敲除（MLP-KO）小鼠诱导多能干细胞，并将它们分化为心肌细胞。然后，我们采用传统方法和将其移植到免疫缺陷大鼠心脏的方法来促进心肌细胞成熟。我们的结果表明，未成熟的MLP-KO iPSC-CMs未能表现出疾病表型，而成熟的MLP-KO iPSC-CMs成功重现了DCM的特征，包括肌节结构破坏和心房利钠肽（ANP）上调，这与在MLP缺陷小鼠中观察到的疾病进展密切相似。这些发现表明，成熟环境对于iPSC衍生的心肌细胞成熟以更好地模拟像DCM这样的遗传性心脏病至关重要，并为未来的治疗策略提供了有价值的见解。
