Chunbo Yang
Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis
Yang, Chunbo; Xu, Yaobo; Yu, Min; Lee, David; Alharti, Sameer; Hellen, Nicola; Ahmad Shaik, Noor; Banaganapalli, Babajan; Sheikh Ali Mohamoud, Hussein; Elango, Ramu; Przyborski, Stefan; Tenin, Gennadiy; Williams, Simon; O’Sullivan, John; Al-Radi, Osman O.; Atta, Jameel; Harding, Sian E.; Keavney, Bernard; Lako, Majlinda; Armstrong, Lyle
Authors
Yaobo Xu
Min Yu
David Lee
Sameer Alharti
Nicola Hellen
Noor Ahmad Shaik
Babajan Banaganapalli
Hussein Sheikh Ali Mohamoud
Ramu Elango
Professor Stefan Przyborski stefan.przyborski@durham.ac.uk
Deputy Provost
Gennadiy Tenin
Simon Williams
John O’Sullivan
Osman O. Al-Radi
Jameel Atta
Sian E. Harding
Bernard Keavney
Majlinda Lako
Lyle Armstrong
Abstract
Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development
Citation
Yang, C., Xu, Y., Yu, M., Lee, D., Alharti, S., Hellen, N., …Armstrong, L. (2017). Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis. Human Molecular Genetics, 26(16), 3031-3045. https://doi.org/10.1093/hmg/ddx140
Journal Article Type | Article |
---|---|
Acceptance Date | Apr 6, 2017 |
Online Publication Date | May 17, 2017 |
Publication Date | Aug 15, 2017 |
Deposit Date | Jul 4, 2017 |
Publicly Available Date | Jul 4, 2017 |
Journal | Human Molecular Genetics |
Print ISSN | 0964-6906 |
Electronic ISSN | 1460-2083 |
Publisher | Oxford University Press |
Peer Reviewed | Peer Reviewed |
Volume | 26 |
Issue | 16 |
Pages | 3031-3045 |
DOI | https://doi.org/10.1093/hmg/ddx140 |
Public URL | https://durham-repository.worktribe.com/output/1375719 |
Files
Published Journal Article (Final published version)
(1.8 Mb)
PDF
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Copyright Statement
Final published version
Published Journal Article (Advance online version)
(2.2 Mb)
PDF
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Copyright Statement
Advance online version © The Author 2017. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
You might also like
Downloadable Citations
About Durham Research Online (DRO)
Administrator e-mail: dro.admin@durham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2025
Advanced Search