From single-cell transcriptomics to organ development

Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects. De Sousa et al., Nature, 572:120-124 (2019)

Single-cell sequencing (SCS) has rapidly become a state-of-the art technology that is widely used to analyse the transcriptional diversity and complexity of cell populations. Although extremely powerful and sophisticated, SCS primarily provides results that have a clear descriptive character and that do not, per se, allow for the identification of the key molecular mechanisms involved in normal biological processes like tissue histogenesis or organ morphogenesis. In the commented paper of the month, Dr. D. Srivastava’s laboratory provides remarkable data on the use of SCS to interrogate cardiac progenitors during both normal and abnormal cardiac morphogenesis. The authors hypothesize that SCS may be a suitable method to dissect and characterize the small pool of cells whose anomalous behaviour underlies organ defects at birth. Taking advantage of murine transgenic tools combined with SCS, this study identifies Hand2 as a transcriptional specifier of the embryonic cardiac outflow tract (arterial pole of the heart), a cardiac domain that is frequently affected in in patients with congenital heart defects. Moreover, this work demonstrates that Hand-2 is not required for right cardiac ventricular cell specification, but rather for the proper maturation and migration right ventricular cardiomyocytes. Indeed, the authors provide data strongly suggesting that it is demonstrates that it is the Hand-2-dependent dysregulation of retinoic acid signalling and the disruption of the antero-posterior patterning of cardiac progenitors (resulting in posteriorization of anterior second heart field cells) what really causes morphogenetic defects in Hand-2 mutants, including right ventricular cardiomyocytes . In summary, this paper proves that SCS approaches can be used to identify disrupted molecular mechanisms involved in the onset of congenital heart defects, therefore opening new avenues for the investigation on the causes of cardiac anomalies in the newborn.