Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy.
TNNI3
engineered heart tissue
induced pluripotent stem cells
relaxation impairment
restrictive cardiomyopathy
Journal
Development, growth & differentiation
ISSN: 1440-169X
Titre abrégé: Dev Growth Differ
Pays: Japan
ID NLM: 0356504
Informations de publication
Date de publication:
09 Jan 2024
09 Jan 2024
Historique:
revised:
20
12
2023
received:
10
12
2023
accepted:
24
12
2023
medline:
9
1
2024
pubmed:
9
1
2024
entrez:
9
1
2024
Statut:
aheadofprint
Résumé
Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease-specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive cardiomyopathy (RCM), a rare and intractable cardiomyopathy, remains at the experimental stage because there is currently no established method to replicate the hallmark phenotype of RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs from a patient with early childhood-onset RCM harboring the TNNI3 R170W mutation (R170W-iPSCs). The properties of R170W-iPSC-derived cardiomyocytes (CMs) and EHTs were evaluated and compared with an isogenic iPSC line in which the mutation was corrected. Our results indicated altered calcium kinetics in R170W-iPSC-CMs, including prolonged tau, and an increased ratio of relaxation force to contractile force in R170W-EHTs. These properties were reversed in the isogenic line, suggesting that our model recapitulates impaired relaxation of RCM, i.e., diastolic dysfunction in clinical practice. Furthermore, overexpression of wild-type TNNI3 in R170W-iPSC-CMs and -EHTs effectively rescued impaired relaxation. These results highlight the potential efficacy of EHT, a modality that can accurately recapitulate diastolic dysfunction in vitro, to elucidate the pathophysiology of RCM, as well as the possible benefits of gene therapies for patients with RCM.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP18K15120
Organisme : Japan Society for the Promotion of Science
ID : JP18KK0461
Organisme : Japan Agency for Medical Research and Development
ID : 22bm0804008h0006
Organisme : Japan Agency for Medical Research and Development
ID : 22bm0804035h0001
Organisme : Japan Agency for Medical Research and Development
ID : 23bm1123035h0001
Organisme : Japan Agency for Medical Research and Development
ID : 23ek0109684h0001
Informations de copyright
© 2024 The Authors. Development, Growth & Differentiation published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Developmental Biologists.
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