Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects

Nature. 2019 Aug;572(7767):120-124. doi: 10.1038/s41586-019-1414-x. Epub 2019 Jul 24.


Organogenesis involves integration of diverse cell types; dysregulation of cell-type-specific gene networks results in birth defects, which affect 5% of live births. Congenital heart defects are the most common malformations, and result from disruption of discrete subsets of cardiac progenitor cells1, but the transcriptional changes in individual progenitors that lead to organ-level defects remain unknown. Here we used single-cell RNA sequencing to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis, revealing how dysregulation of specific cellular subpopulations has catastrophic consequences. A network-based computational method for single-cell RNA-sequencing analysis that predicts lineage-specifying transcription factors2,3 identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite the failure of right ventricular formation in Hand2-null mice4. Temporal single-cell-transcriptome analysis of Hand2-null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was specified but failed to properly differentiate and migrate. Loss of Hand2 also led to dysregulation of retinoic acid signalling and disruption of anterior-posterior patterning of cardiac progenitors. This work reveals transcriptional determinants that specify fate and differentiation in individual cardiac progenitor cells, and exposes mechanisms of disrupted cardiac development at single-cell resolution, providing a framework for investigating congenital heart defects.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Cell Differentiation
  • Cell Movement
  • Cluster Analysis
  • Female
  • Heart / embryology*
  • Heart Defects, Congenital / embryology*
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology*
  • Male
  • Mice
  • Sequence Analysis, RNA
  • Single-Cell Analysis*
  • Tretinoin / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Hand2 protein, mouse
  • Tretinoin