Cardiac progenitors instruct second heart field fate through Wnts

Area of Science:

• Developmental biology
• Molecular biology
• Genetics

Background:

• Heart development involves coordinated proliferation and differentiation of cardiac progenitor cells (CPCs) from distinct pools: the first heart field (FHF) and second heart field (SHF).
• Congenital heart defects often stem from dysregulated CPC development, particularly within SHF derivatives.
• The Wnt signaling pathway is critical for SHF development, but its source has been unknown, with ectodermal or endodermal origins previously hypothesized.

Purpose of the Study:

• To identify the source of Wnt ligands essential for second heart field (SHF) development.
• To elucidate the role of cardiac progenitor cells (CPCs) in regulating SHF development through Wnt signaling.
• To investigate the molecular mechanisms underlying SHF cell fate decisions and their link to congenital heart defects.

Main Methods:

• Genetic manipulation of the Wnt export protein Wntless (Wls) in CPCs.
• Single-cell RNA sequencing (scRNA-seq) analysis of CPCs.
• Utilizing a novel precardiac organoid system for studying heart development in vitro.

Main Results:

• CPCs autoregulate SHF development via Wnt signaling, challenging previous hypotheses about external Wnt sources.
• Genetic disruption of Wls led to dysregulated anterior SHF cell fate trajectories and a single ventricle phenotype in knockout embryos.
• Wnt2 was identified as sufficient to restore SHF cell fate in a precardiac organoid model with disrupted endogenous Wnt signaling.

Conclusions:

• Cardiac progenitor cells (CPCs) autoregulate second heart field (SHF) development through autocrine Wnt signaling.
• This autocrine Wnt signaling pathway is crucial for balancing proliferation versus differentiation in SHF progenitor cells.
• Understanding this mechanism provides insights into congenital heart defects and potential therapeutic strategies targeting Wnt signaling in CPCs.