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

Human Molecular Genetics
Chunbo YangLyle 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 confirmi...Continue Reading

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Citations

Feb 7, 2020·American Journal of Medical Genetics. Part a·Hagit DaumTamar Harel
Jun 4, 2019·Journal of Cardiovascular Translational Research·Ampadu O JacksonKai Yin
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Jun 21, 2020·Current Cardiology Reports·Arun Sharma
Nov 27, 2020·Stem Cell Research & Therapy·Christoph HallerMichael A Laflamme
Jan 13, 2021·Journal of the American Heart Association·Lauren E Parker, Andrew P Landstrom
Aug 17, 2019·Journal of Molecular and Cellular Cardiology·Anita SarafChunhui Xu
Feb 16, 2021·Frontiers in Cell and Developmental Biology·Hui LinMing-Tao Zhao
Dec 11, 2019·Cold Spring Harbor Perspectives in Biology·Uddalak MajumdarVidu Garg
Jun 3, 2021·International Journal of Molecular Sciences·Summer A HelmiDerrick E Rancourt

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