Skip to main content

Research Repository

Advanced Search

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

Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis Thumbnail


Authors

Chunbo Yang

Yaobo Xu

Min Yu

David Lee

Sameer Alharti

Nicola Hellen

Noor Ahmad Shaik

Babajan Banaganapalli

Hussein Sheikh Ali Mohamoud

Ramu Elango

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

Files

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