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

Lookup NU author(s): Dr Chunbo Yang, Dr Yaobo Xu, Dr Min Yu, Dr David Lee, Dr John O'Sullivan, Professor Bernard Keavney, Professor Majlinda LakoORCiD, Professor Lyle Armstrong



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Yang C, Xu Y, Yu M, Lee D, Alharti S, Hellen N, Shaik NA, Banaganapalli B, Mohamoud H, Elango R, Przyborski S, Tenin G, Williams S, O'Sullivan J, Al-Radi OO, Atta J, Harding S, Keavney B, Lako M, Armstrong L

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2017

Volume: 26

Issue: 16

Pages: 3031-3045

Print publication date: 15/08/2017

Online publication date: 17/05/2017

Acceptance date: 06/04/2017

Date deposited: 16/05/2017

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddx140


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