| RRC ID |
64995
|
| Author |
Yasutake H, Lee JK, Hashimoto A, Masuyama K, Li J, Kuramoto Y, Higo S, Hikoso S, Hidaka K, Naito AT, Miyagawa S, Sawa Y, Komuro I, Sakata Y.
|
| Title |
Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes.
|
| Journal |
Sci Rep
|
| 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.
|
| Volume |
11(1)
|
| Pages |
10351
|
| Published |
2021-5-14
|
| DOI |
10.1038/s41598-021-89603-8
|
| PII |
10.1038/s41598-021-89603-8
|
| PMID |
33990626
|
| PMC |
PMC8121946
|
| MeSH |
Adaptor Proteins, Signal Transducing / deficiency*
Adaptor Proteins, Signal Transducing / genetics
Adult
CRISPR-Cas Systems / genetics
Cardiomyopathy, Dilated / genetics
Cardiomyopathy, Dilated / pathology*
Cell Proliferation
Cells, Cultured
Gene Editing
Humans
Induced Pluripotent Stem Cells / metabolism*
Male
Mechanotransduction, Cellular
Muscular Dystrophy, Duchenne / complications*
Muscular Dystrophy, Duchenne / genetics
Muscular Dystrophy, Duchenne / pathology
Myocytes, Cardiac / pathology*
Primary Cell Culture
Transcription Factors / deficiency*
Transcription Factors / genetics
YAP-Signaling Proteins
|
| IF |
3.998
|
| Resource |
| Human and Animal Cells |
201B7(HPS0063) |
