title: Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21.
abstract: Congenital heart defects (CHD) occur in approximately 50% of patients with Down syndrome (DS); the mechanisms for this occurrence however remain unknown. In order to understand how these defects evolve in early development in DS, we focused on the earliest stages of cardiogenesis to ascertain perturbations in development leading to CHD. Using a trisomy 21 (T21) sibling human embryonic stem cell (hESC) model of DS, we show that T21-hESC display many significant differences in expression of genes and cell populations associated with mesodermal, and more notably, secondary heart field (SHF) development, in particular a reduced number of ISL1(+) progenitor cells. Furthermore, we provide evidence for two candidate genes located on chromosome 21, ETS2 and ERG, whose overexpression during cardiac commitment likely account for the disruption of SHF development, as revealed by downregulation or overexpression experiments. Additionally, we uncover an abnormal electrophysiological phenotype in functional T21 cardiomyocytes, a result further supported by mRNA expression data acquired using RNA-Seq. These data, in combination, revealed a cardiomyocyte-specific phenotype in T21 cardiomyocytes, likely due to the overexpression of genes such as RYR2, NCX, and L-type Ca(2+) channel. These results contribute to the understanding of the mechanisms involved in the development of CHD. Stem Cells 2015;33:1434-1446.
authors: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors: Alexis
authors: A
authors: Bosman
authors: Audrey
authors: A
authors: Letourneau
authors: Laura
authors: L
authors: Sartiani
authors: Martina
authors: M
authors: Del Lungo
authors: Flavio
authors: F
authors: Ronzoni
authors: Rostyslav
authors: R
authors: Kuziakiv
authors: Virpi
authors: V
authors: Tohonen
authors: Marco
authors: M
authors: Zucchelli
authors: Federico
authors: F
authors: Santoni
authors: Michel
authors: M
authors: Guipponi
authors: Biljana
authors: B
authors: Dumevska
authors: Outi
authors: O
authors: Hovatta
authors: Stylianos E
authors: SE
authors: Antonarakis
authors: Marisa E
authors: ME
authors: Jaconi
mesh_terms: D000200:Action Potentials; D002454:Cell Differentiation; D002460:Cell Line; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D006321:Heart / Q000196:embryology* / Q000503:physiopathology*; D006330:Heart Defects, Congenital / Q000235:genetics; D000066449:Human Embryonic Stem Cells / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059467:Transcriptome / Q000235:genetics
chemical_list: D012333:RNA, Messenger
keywords: Cardiac differentiation; Human embryonic stem cells; Transcriptome; Trisomy 21