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

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

Author information

1
Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA.
2
Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA.
3
Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA.
4
Computational Biology Group, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, Luxembourg.
5
Integrated BioBank of Luxembourg, Dudelange, Luxembourg.
6
CIC bioGUNE, Derio, Spain.
7
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
8
Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA. casey.gifford@gladstone.ucsf.edu.
9
Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA. casey.gifford@gladstone.ucsf.edu.
10
Gladstone Institute of Cardiovascular Disease, San Francisco, CA, USA. dsrivastava@gladstone.ucsf.edu.
11
Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA, USA. dsrivastava@gladstone.ucsf.edu.
12
Department of Pediatrics, University of California, San Francisco, CA, USA. dsrivastava@gladstone.ucsf.edu.
13
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA. dsrivastava@gladstone.ucsf.edu.

Abstract

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.

PMID:
31341279
DOI:
10.1038/s41586-019-1414-x

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