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Title

Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21

Authors
Sartiani, Laura
Del Lungo, Martina
Kuziakiv, Rostyslav
Tohonen, Virpi
Zucchelli, Marco
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Published in Stem Cells. 2015, vol. 33, no. 5, p. 1434-1446
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.
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PMID: 25645121
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Article (Published version) (1.1 MB) - public document Free access
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Research groups Mécanismes de différentiation cellulaire des cellules cardiaques (536)
Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248)
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BOSMAN, Alexis et al. Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21. In: Stem Cells, 2015, vol. 33, n° 5, p. 1434-1446. https://archive-ouverte.unige.ch/unige:76397

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Deposited on : 2015-10-23

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