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

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 dys...

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Autores principales:	Hideki Yasutake, Jong-Kook Lee, Akihito Hashimoto, Kiyoshi Masuyama, Jun Li, Yuki Kuramoto, Shuichiro Higo, Shungo Hikoso, Kyoko Hidaka, Atsuhiko T. Naito, Shigeru Miyagawa, Yoshiki Sawa, Issei Komuro, Yasushi Sakata
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9bdcceb878174d0dad5ab80684f07298
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spelling	oai:doaj.org-article:9bdcceb878174d0dad5ab80684f072982021-12-02T15:43:23ZDecreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes10.1038/s41598-021-89603-82045-2322https://doaj.org/article/9bdcceb878174d0dad5ab80684f072982021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89603-8https://doaj.org/toc/2045-2322Abstract 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.Hideki YasutakeJong-Kook LeeAkihito HashimotoKiyoshi MasuyamaJun LiYuki KuramotoShuichiro HigoShungo HikosoKyoko HidakaAtsuhiko T. NaitoShigeru MiyagawaYoshiki SawaIssei KomuroYasushi SakataNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hideki Yasutake Jong-Kook Lee Akihito Hashimoto Kiyoshi Masuyama Jun Li Yuki Kuramoto Shuichiro Higo Shungo Hikoso Kyoko Hidaka Atsuhiko T. Naito Shigeru Miyagawa Yoshiki Sawa Issei Komuro Yasushi Sakata Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes
description	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.
format	article
author	Hideki Yasutake Jong-Kook Lee Akihito Hashimoto Kiyoshi Masuyama Jun Li Yuki Kuramoto Shuichiro Higo Shungo Hikoso Kyoko Hidaka Atsuhiko T. Naito Shigeru Miyagawa Yoshiki Sawa Issei Komuro Yasushi Sakata
author_facet	Hideki Yasutake Jong-Kook Lee Akihito Hashimoto Kiyoshi Masuyama Jun Li Yuki Kuramoto Shuichiro Higo Shungo Hikoso Kyoko Hidaka Atsuhiko T. Naito Shigeru Miyagawa Yoshiki Sawa Issei Komuro Yasushi Sakata
author_sort	Hideki Yasutake
title	Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes
title_short	Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes
title_full	Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes
title_fullStr	Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes
title_full_unstemmed	Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes
title_sort	decreased yap activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9bdcceb878174d0dad5ab80684f07298
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Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes

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