title: 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 β-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.
authors.affiliation: Institute of Genetic Medicine and Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom; Soochow University, Su Zhou, China; Princess Al Jawhara Center of Excellence in Research, King Abdulaziz University, Jeddah, Saudi Arabia; Centre for Biomedical Image Analysis, Faculty of Informatics, Masaryk University, Brno, Czech Republic; Institute of Cardiovascular Science, Manchester Academic Health Science Centre, CoreTechnology Facility, Manchester, United Kingdom; School of Biomedical Sciences, University of Durham, Durham, United Kingdom; Department of Human Genetics, University of Kragujevac, Kragujevac, Serbia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Saba
authors.initials: S
authors.lastname: Habibollah
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Tilgner
authors.forename: Joseph
authors.initials: J
authors.lastname: Collin
authors.forename: Tomas
authors.initials: T
authors.lastname: Barta
authors.forename: Jumana Yousuf
authors.initials: JY
authors.lastname: Al-Aama
authors.forename: Lenka
authors.initials: L
authors.lastname: Tesarov
authors.forename: Rafiqul
authors.initials: R
authors.lastname: Hussain
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Trafford
authors.forename: Graham
authors.initials: G
authors.lastname: Kirkwood
authors.forename: Evelyne
authors.initials: E
authors.lastname: Sernagor
authors.forename: Cyril G
authors.initials: CG
authors.lastname: Eleftheriou
authors.forename: Stefan
authors.initials: S
authors.lastname: Przyborski
authors.forename: Miodrag
authors.initials: M
authors.lastname: Stojković
authors.forename: Majlinda
authors.initials: M
authors.lastname: Lako
authors.forename: Bernard
authors.initials: B
authors.lastname: Keavney
authors.forename: Lyle
authors.initials: L
authors.lastname: Armstrong
mesh_terms: D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000378:metabolism* / Q000473:pathology; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D009124:Muscle Proteins / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology
chemical_list: D009124:Muscle Proteins
keywords: Cardiac development; Cardiac myocytes; Hypoplastic left heart syndrome; Induced pluripotent stem cells; Pluripotent stem cell differentiation