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An induced pluripotent stem cell model of hypoplastic left heart syndrome (HLHS) reveals multiple expression and functional differences in HLHS-derived cardiac myocytes.

ABSTRACT: Hypoplastic left heart syndrome (HLHS) is a serious congenital cardiovascular malformation resulting in hypoplasia or atresia of the left ventricle, ascending aorta, and aortic and mitral valves. Diminished flow through the left side of the heart is clearly a key contributor to the condition, but any myocardial susceptibility component is as yet undefined. Using recent advances in the field of induced pluripotent stem cells (iPSCs), we have been able to generate an iPSC model of HLHS malformation and characterize the properties of cardiac myocytes (CMs) differentiated from these and control-iPSC lines. Differentiation of HLHS-iPSCs to cardiac lineages revealed changes in the expression of key cardiac markers and a lower ability to give rise to beating clusters when compared with control-iPSCs and human embryonic stem cells (hESCs). HLHS-iPSC-derived CMs show a lower level of myofibrillar organization, persistence of a fetal gene expression pattern, and changes in commitment to ventricular versus atrial lineages, and they display different calcium transient patterns and electrophysiological responses to caffeine and ?-adrenergic antagonists when compared with hESC- and control-iPSC-derived CMs, suggesting that alternative mechanisms to release calcium from intracellular stores such as the inositol trisphosphate receptor may exist in HLHS in addition to the ryanodine receptor thought to function in control-iPSC-derived CMs. Together our findings demonstrate that CMs derived from an HLHS patient demonstrate a number of marker expression and functional differences to hESC/control iPSC-derived CMs, thus providing some evidence that cardiomyocyte-specific factors may influence the risk of HLHS.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC3973710 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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An induced pluripotent stem cell model of hypoplastic left heart syndrome (HLHS) reveals multiple expression and functional differences in HLHS-derived cardiac myocytes.

Jiang Yan Y Habibollah Saba S Tilgner Katarzyna K Collin Joseph J Barta Tomas T Al-Aama Jumana Yousuf JY Tesarov Lenka L Hussain Rafiqul R Trafford Andrew W AW Kirkwood Graham G Sernagor Evelyne E Eleftheriou Cyril G CG Przyborski Stefan S Stojković Miodrag M Lako Majlinda M Keavney Bernard B Armstrong Lyle L

Stem cells translational medicine 20140303 4

Hypoplastic left heart syndrome (HLHS) is a serious congenital cardiovascular malformation resulting in hypoplasia or atresia of the left ventricle, ascending aorta, and aortic and mitral valves. Diminished flow through the left side of the heart is clearly a key contributor to the condition, but any myocardial susceptibility component is as yet undefined. Using recent advances in the field of induced pluripotent stem cells (iPSCs), we have been able to generate an iPSC model of HLHS malformatio ...[more]

PMID: 24591732

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Project description:BackgroundComplex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role.MethodsTo identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls.ResultsGene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues.ConclusionsOur results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

Dataset Information

An induced pluripotent stem cell model of hypoplastic left heart syndrome (HLHS) reveals multiple expression and functional differences in HLHS-derived cardiac myocytes.

Publications

An induced pluripotent stem cell model of hypoplastic left heart syndrome (HLHS) reveals multiple expression and functional differences in HLHS-derived cardiac myocytes.

Similar Datasets

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