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YAP 活性降低可降低杜氏肌营养不良症诱导多能干细胞衍生的心肌细胞的增殖能力。

Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes.

机构信息

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan.

Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan.

出版信息

Sci Rep. 2021 May 14;11(1):10351. doi: 10.1038/s41598-021-89603-8.

DOI:10.1038/s41598-021-89603-8
PMID:33990626
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8121946/
Abstract

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration accompanied by dilated cardiomyopathy. Recently, abnormality of yes-associated protein (YAP) has been reported as the pathogenesis of muscle degeneration of DMD; however YAP activity remains unclear in dystrophic heart of DMD. Herein, we investigated YAP activity using disease-specific induced pluripotent stem cell (iPSC) derived cardiomyocytes (CMs) in DMD. DMD-iPSCs were generated from DMD patient with exon 48-54 deletion in DMD, and genome-edited (Ed)-DMD-iPSCs with in-frame (Ed-DMD-iPSCs) were created using CRISPR/Cas9. Nuclear translocation of YAP [nuclear (N)/cytoplasmic (C) ratio] was significantly lower in DMD-iPSC-CMs than in Ed-DMD-iPSC-CMs. In addition, Ki67 expression, indicating proliferative ability, was significantly lower in DMD-iPSC-CMs than Ed-DMD-iPSC-CMs. Therefore, immunofluorescent staining showed that actin stress fibers associated with YAP activity by mechanotransduction were disorganized in DMD-iPSC-CMs. Lysophosphatidic acid (LPA), a known lipid mediator on induction of actin polymerization, significantly increased YAP activity and actin dynamics in DMD-iPSC-CMs using live cell imaging. These results suggested that altered YAP activity due to impaired actin dynamics reduced proliferative ability in DMD-iPSC-CMs. Hence, decreased YAP activity in dystrophic heart may contribute to DMD-cardiomyopathy pathogenesis.

摘要

杜氏肌营养不良症（DMD）的特征是进行性肌肉退化，伴有扩张型心肌病。最近，研究发现 yes 相关蛋白（YAP）异常是 DMD 肌肉退化的发病机制；然而，DMD 病变心脏中的 YAP 活性尚不清楚。在此，我们使用 DMD 特异性诱导多能干细胞（iPSC）衍生的心肌细胞（CM）研究了 DMD 中的 YAP 活性。从 DMD 患者中生成了 DMD-iPSC，该患者的 DMD 中存在外显子 48-54 缺失，并用 CRISPR/Cas9 构建了框架内（Ed-DMD-iPSC）基因组编辑（Ed-DMD-iPSC）。YAP 的核易位[nuclear (N)/cytoplasmic (C) ratio]在 DMD-iPSC-CM 中明显低于 Ed-DMD-iPSC-CM。此外，Ki67 表达（增殖能力的指标）在 DMD-iPSC-CM 中明显低于 Ed-DMD-iPSC-CM。因此，免疫荧光染色显示，与 YAP 活性通过机械转导相关的肌动蛋白应激纤维在 DMD-iPSC-CM 中排列紊乱。溶血磷脂酸（LPA）是一种已知的诱导肌动蛋白聚合的脂质介质，通过活细胞成像，它可显著增加 DMD-iPSC-CM 中的 YAP 活性和肌动蛋白动力学。这些结果表明，由于肌动蛋白动力学受损导致的 YAP 活性改变降低了 DMD-iPSC-CM 的增殖能力。因此，DMD 病变心脏中 YAP 活性的降低可能导致 DMD 心肌病的发病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/b187747dd4b6/41598_2021_89603_Fig7_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/b187747dd4b6/41598_2021_89603_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/14393be57d7d/41598_2021_89603_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/f734db3aec94/41598_2021_89603_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/182f9ca24308/41598_2021_89603_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/758e136068b9/41598_2021_89603_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/ae1721a851d6/41598_2021_89603_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/cb687fefaa5e/41598_2021_89603_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a347/8121946/b187747dd4b6/41598_2021_89603_Fig7_HTML.jpg

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