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

Yang, Chunbo and Xu, Yaobo and Yu, Min and Lee, David and Alharti, Sameer and Hellen, Nicola and Ahmad Shaik, Noor and Banaganapalli, Babajan and Sheikh Ali Mohamoud, Hussein and Elango, Ramu and Przyborski, Stefan and Tenin, Gennadiy and Williams, Simon and O’Sullivan, John and Al-Radi, Osman O. and Atta, Jameel and Harding, Sian E. and Keavney, Bernard and Lako, Majlinda and Armstrong, Lyle (2017) 'Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.', Human molecular genetics., 26 (16). pp. 3031-3045.

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

Item Type:Article
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1093/hmg/ddx140
Publisher statement:© 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.
Date accepted:06 April 2017
Date deposited:04 July 2017
Date of first online publication:17 May 2017
Date first made open access:No date available

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