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Article: Isogenic Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes Reveal Activation of Wnt Signaling Pathways Underlying Intrinsic Cardiac Abnormalities in Rett Syndrome

TitleIsogenic Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes Reveal Activation of Wnt Signaling Pathways Underlying Intrinsic Cardiac Abnormalities in Rett Syndrome
Authors
Keywordsintrinsic cardiac abnormality
MeCP2 mutation
Rett syndrome
Wnt/β-catenin signaling pathway
Issue Date9-Dec-2022
PublisherMDPI
Citation
International Journal of Molecular Sciences, 2022, v. 23, n. 24 How to Cite?
Abstract

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by MeCP2 mutations. Nonetheless, the pathophysiological roles of MeCP2 mutations in the etiology of intrinsic cardiac abnormality and sudden death remain unclear. In this study, we performed a detailed functional studies (calcium and electrophysiological analysis) and RNA-sequencing-based transcriptome analysis of a pair of isogenic RTT female patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) that expressed either MeCP2wildtype or MeCP2mutant allele and iPSC-CMs from a non-affected female control. The observations were further confirmed by additional experiments, including Wnt signaling inhibitor treatment, siRNA-based gene silencing, and ion channel blockade. Compared with MeCP2wildtype and control iPSC-CMs, MeCP2mutant iPSC-CMs exhibited prolonged action potential and increased frequency of spontaneous early after polarization. RNA sequencing analysis revealed up-regulation of various Wnt family genes in MeCP2mutant iPSC-CMs. Treatment of MeCP2mutant iPSC-CMs with a Wnt inhibitor XAV939 significantly decreased the β-catenin protein level and CACN1AC expression and ameliorated their abnormal electrophysiological properties. In summary, our data provide novel insight into the contribution of activation of the Wnt/β-catenin signaling cascade to the cardiac abnormalities associated with MeCP2 mutations in RTT.


Persistent Identifierhttp://hdl.handle.net/10722/338432
ISSN
2023 Impact Factor: 4.9
2023 SCImago Journal Rankings: 1.179
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNg, KM-
dc.contributor.authorDing, Q-
dc.contributor.authorTse, YL-
dc.contributor.authorChou, OHI-
dc.contributor.authorLai, WH-
dc.contributor.authorAu, KW-
dc.contributor.authorLau, YM-
dc.contributor.authorJi, Y-
dc.contributor.authorSiu, CW-
dc.contributor.authorTang, CSM-
dc.contributor.authorColman, A-
dc.contributor.authorTsang, SY-
dc.contributor.authorTse, HF-
dc.date.accessioned2024-03-11T10:28:51Z-
dc.date.available2024-03-11T10:28:51Z-
dc.date.issued2022-12-09-
dc.identifier.citationInternational Journal of Molecular Sciences, 2022, v. 23, n. 24-
dc.identifier.issn1661-6596-
dc.identifier.urihttp://hdl.handle.net/10722/338432-
dc.description.abstract<p>Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by MeCP2 mutations. Nonetheless, the pathophysiological roles of MeCP2 mutations in the etiology of intrinsic cardiac abnormality and sudden death remain unclear. In this study, we performed a detailed functional studies (calcium and electrophysiological analysis) and RNA-sequencing-based transcriptome analysis of a pair of isogenic RTT female patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) that expressed either MeCP2wildtype or MeCP2mutant allele and iPSC-CMs from a non-affected female control. The observations were further confirmed by additional experiments, including Wnt signaling inhibitor treatment, siRNA-based gene silencing, and ion channel blockade. Compared with MeCP2wildtype and control iPSC-CMs, MeCP2mutant iPSC-CMs exhibited prolonged action potential and increased frequency of spontaneous early after polarization. RNA sequencing analysis revealed up-regulation of various Wnt family genes in MeCP2mutant iPSC-CMs. Treatment of MeCP2mutant iPSC-CMs with a Wnt inhibitor XAV939 significantly decreased the β-catenin protein level and CACN1AC expression and ameliorated their abnormal electrophysiological properties. In summary, our data provide novel insight into the contribution of activation of the Wnt/β-catenin signaling cascade to the cardiac abnormalities associated with MeCP2 mutations in RTT.</p>-
dc.languageeng-
dc.publisherMDPI-
dc.relation.ispartofInternational Journal of Molecular Sciences-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectintrinsic cardiac abnormality-
dc.subjectMeCP2 mutation-
dc.subjectRett syndrome-
dc.subjectWnt/β-catenin signaling pathway-
dc.titleIsogenic Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes Reveal Activation of Wnt Signaling Pathways Underlying Intrinsic Cardiac Abnormalities in Rett Syndrome-
dc.typeArticle-
dc.identifier.doi10.3390/ijms232415609-
dc.identifier.scopuseid_2-s2.0-85144541563-
dc.identifier.volume23-
dc.identifier.issue24-
dc.identifier.eissn1422-0067-
dc.identifier.isiWOS:000911934200001-
dc.identifier.issnl1422-0067-

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