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Understanding Heart Defects in Down's Syndrome using ESC Models

Review of “Perturbations of Heart Development and Function in Cardiomyocytes from hESC with Trisomy 21” from Stem Cells by Stuart P. Atkinson

Down's syndrome (DS) is caused by the presence of an extra human chromosome 21 [1] and amongst the common traits associated with this disease, congenital heart defects (CHDs) represent the leading cause of morbidity [2, 3].  Human stem cell models have attempted to understand the molecular underpinnings behind these defects, and while studies have uncovered a potential connection between DNA copy-number variations (CNVs) and heart defects [2, 4], much remains for to be understand.  Now, the laboratories of Marisa Jaconi (Geneva University) and Alexis Bosman (Victor Chang Cardiac Research Institute, Australia) have used “sibling” trisomy 21 (T21) human embryonic stem cells (hESC) lines to reduce inter‐line variability and facilitate the discovery of genes influencing early cardiac development.  Their studies have identified two chromosome 21 genes (ETS2 and ERG) which may play an important role in the development of CHDs, whilst also uncovering an abnormal electrophysiological phenotype in cardiomyocytes derived from the T21 hESCs [5].

The two T21 hESC lines used in this study (GEN021 and GEN053) initially displayed similar pluripotent characteristics in vitro and in vivo when compared to related euploid lines (GEN022 and GEN023 – siblings of GEN021).  However, upon differentiation towards beating cardiomyocyte clusters, the GEN021 T21 hESC line produced significantly more beating clusters than their euploid sibling cell lines. Thorough CNV and DNA methylation analysis demonstrated no overt differences, although expression analysis of hESC derived embryoid bodies (EBs) did uncover a dysregulated expression pattern of marker genes associated with early heart development in T21 hESCs. While searching for candidate causative genes present on chromosome 21, the group discovered that the Ets‐family transcription factors ETS2 and ERG were both overexpressed in T21 cells compared to euploid controls. Artificial perturbation of ETS2 and ERG on euploid hESC-EBs produced a dysregulated mesoderm/early heart development-associated gene expression pattern, and this dysregulation was further correlated to the reduced expression of TWIST1, a transcription factor expressed in certain areas of the primordial heart and functions in valve development and epithelial‐mesenchymal transition (EMT). 

Electrophysiological analysis of hESC-derived cardiomyocytes (~160 days of differentiation) also found that T21-derived cells differed greatly from euploid-derived cells, with T21-cardiomyocytes displaying increased spontaneous beating, a faster diastolic depolarization rate (DDR), and a shorter duration of repolarization. The authors correlated these differences to alterations in the expression of the NCX sodium-calcium exchanger gene and the KCNE2 ion channel gene which are both found on chromosome 21 and are likely to affect electrophysiological properties.

Finally, next generation sequencing (NGS) of day 60 beating cardiomyocytes found 280 upregulated genes in the trisomic group and 221 downregulated genes in the T21 cells as compared to the euploid cells. The 221 genes downregulated in the trisomic samples represented genes associated with developmental and cellular adhesion processes, while the 280 upregulated genes represented genes related to muscle and heart contraction or development processes, and contained genes involved in important heart function related signaling pathways.

While this detailed study has identified genes potentially involved in the CHD observed in DS, and identified functional differences between T21 and euploid cardiomyocytes, it also represents a wealth of data from which to base further studies. This data, and the cell lines themselves, may aid in the identification of drug targets and the testing of identified compounds towards treating the defects observed in DS patients, allowing for an increased quality of life, and perhaps even lifespan for those affected.


  1. Patterson D and Costa AC Down syndrome and genetics - a case of linked histories. Nat Rev Genet 2005;6:137-147.
  2. Sailani MR, Makrythanasis P, Valsesia A, et al. The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome. Genome Res 2013;23:1410-1421.
  3. Williams AD, Mjaatvedt CH, and Moore CS Characterization of the cardiac phenotype in neonatal Ts65Dn mice. Developmental dynamics : an official publication of the American Association of Anatomists 2008;237:426-435.
  4. Letourneau A, Santoni FA, Bonilla X, et al. Domains of genome-wide gene expression dysregulation in Down's syndrome. Nature 2014;508:345-350.
  5. Bosman A, Letourneau A, Sartiani L, et al. Perturbations of heart development and function in cardiomyocytes from human embryonic stem cells with trisomy 21. Stem Cells 2015;33:1434-1446.