GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

Summary A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.
Graphical Abstract
Highlights • Gfra2 is specific for cardiac progenitors (CPs) among mesodermal cells • GFRA2 enables isolation of multipotent or unipotent CPs in mouse and human • Gfra2 and the related molecule Gfra1 play a vital role in heart development • The GFRA1/2 signal in heart development is independent of established ligands
Ishida et al. show that GPI-anchored neurotrophic factor receptor Gfra2 specifically marks cardiac progenitor cells (CPs) in mouse and human, providing a method for isolating CPs. Unexpectedly, Gfra2 plays a significant role in heart development via a non-canonical signaling pathway that is independent of known ligands and the co-receptor RET tyrosine kinase.