GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway
Hidekazu Ishida,
Rie Saba,
Ioannis Kokkinopoulos,
Masakazu Hashimoto,
Osamu Yamaguchi,
Sonja Nowotschin,
Manabu Shiraishi,
Prashant Ruchaya,
Duncan Miller,
Stephen Harmer,
Ariel Poliandri,
Shigetoyo Kogaki,
Yasushi Sakata,
Leo Dunkel,
Andrew Tinker,
Anna-Katerina Hadjantonakis,
Yoshiki Sawa,
Hiroshi Sasaki,
Keiichi Ozono,
Ken Suzuki,
Kenta Yashiro
Affiliations
Hidekazu Ishida
Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Rie Saba
Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Ioannis Kokkinopoulos
Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Masakazu Hashimoto
Laboratory for Embryogenesis, Osaka University Graduate School of Frontier Biosciences, Osaka 565-0871, Japan
Osamu Yamaguchi
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Sonja Nowotschin
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Manabu Shiraishi
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Prashant Ruchaya
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Duncan Miller
Cardiac Electrophysiology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Stephen Harmer
Cardiac Electrophysiology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Ariel Poliandri
Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Shigetoyo Kogaki
Department of Paediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Yasushi Sakata
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Leo Dunkel
Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Andrew Tinker
Cardiac Electrophysiology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Anna-Katerina Hadjantonakis
Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Yoshiki Sawa
Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Hiroshi Sasaki
Laboratory for Embryogenesis, Osaka University Graduate School of Frontier Biosciences, Osaka 565-0871, Japan
Keiichi Ozono
Department of Paediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Ken Suzuki
Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Kenta Yashiro
Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
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.
