Cardiac progenitors instruct second heart field fate through Wnts

Matthew Miyamoto, Suraj Kannan, Matthew J. Anderson, Xihe Liu, David Suh, Myo Htet, Biyi Li, Tejasvi Kakani, Sean Murphy, Emmanouil Tampakakis, Mark Lewandoski, Peter Andersen, Hideki Uosaki, Chulan Kwon

Research output: Contribution to journalArticlepeer-review


The heart develops in a synchronized sequence of proliferation and differentiation of cardiac progenitor cells (CPCs) from two anatomically distinct pools of cells, the first heart field (FHF) and second heart field (SHF). Congenital heart defects arise upon dysregulation of these processes, many of which are restricted to derivatives of the FHF or SHF. Of the conserved set of signaling pathways that regulate development, the Wnt signaling pathway has long been known for its importance in SHF development. The source of such Wnts has remained elusive, though it has been postulated that these Wnts are secreted from ectodermal or endodermal sources. The central question remains unanswered: Where do these Wnts come from? Here, we show that CPCs autoregulate SHF development via Wnt through genetic manipulation of a key Wnt export protein (Wls), scRNA-seq analysis of CPCs, and use of our precardiac organoid system. Through this, we identify dysregulated developmental trajectories of anterior SHF cell fate, leading to a striking single ventricle phenotype in knockout embryos. We then applied our findings to our precardiac organoid model and found that Wnt2 is sufficient to restore SHF cell fate in our model of disrupted endogenous Wnt signaling. In this study, we provide a basis for SHF cell fate decision—proliferation vs. differentiation—autoregulated by CPCs through Wnt.

Original languageEnglish (US)
Article numbere2217687120
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
StatePublished - Jan 24 2023


  • Wls
  • Wnt
  • heart development
  • organoid
  • second heart field

ASJC Scopus subject areas

  • General


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