ArticleHuman molecular genetics2017
Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 68 citations in OpenAlex.
- Review
- Transformative Potential of Induced Pluripotent Stem Cells in Congenital Heart Disease Research and Treatment.Children (Basel, Switzerland) · 2025Review
- Current advances in human-induced pluripotent stem cell-based models and therapeutic approaches for congenital heart disease.Molecular and cellular biochemistry · 2025Review
- The molecular mechanisms of cardiac development and related diseases.Signal transduction and targeted therapy · 2024Review
- In Vivo and In Vitro Approaches to Modeling Hypoplastic Left Heart Syndrome.Current cardiology reports · 2024Review
- iPSC-Derived Cardiomyocytes as a Disease Model to Understand the Biology of Congenital Heart Defects.Cells · 2024Review
- Deciphering Congenital Heart Disease Using Human Induced Pluripotent Stem Cells.Advances in experimental medicine and biology · 2024Article
- Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead.International journal of molecular sciences · 2023Review
- Article
- Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases.Current cardiology reports · 2023Review
- Unlocking the potential of induced pluripotent stem cells for neonatal disease modeling and drug development.Seminars in perinatology · 2023Review
- Use of Frogs as a Model to Study the Etiology of HLHS.Journal of cardiovascular development and disease · 2023Article
- Endocardium in Hypoplastic Left Heart Syndrome: Implications from In Vitro Study.Journal of cardiovascular development and disease · 2022Article
- Systems analysis of de novo mutations in congenital heart diseases identified a protein network in the hypoplastic left heart syndrome.Cell systems · 2022Article
- iPSCs derived from esophageal atresia patients reveal SOX2 dysregulation at the anterior foregut stage.Disease models & mechanisms · 2022Article
- Translational potential of hiPSCs in predictive modeling of heart development and disease.Birth defects research · 2022Review
- Probing single ventricle heart defects with patient-derived induced pluripotent stem cells and emerging technologies.Birth defects research · 2022Review
- Flow-Mediated Factors in the Pathogenesis of Hypoplastic Left Heart Syndrome.Journal of cardiovascular development and disease · 2022Review
- Significance of α-Myosin Heavy Chain (Journal of cardiovascular development and disease · 2022Article
- Delving into the Molecular World of Single Ventricle Congenital Heart Disease.Current cardiology reports · 2022Review
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Authors and funding
20 authors at 7 institutions in 2 countries.
Funding
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.
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