Ishida Hidekazu, Saba Rie, Kokkinopoulos Ioannis, Hashimoto Masakazu, Yamaguchi Osamu, Nowotschin Sonja, Shiraishi Manabu, Ruchaya Prashant, Miller Duncan, Harmer Stephen, Poliandri Ariel, Kogaki Shigetoyo, Sakata Yasushi, Dunkel Leo, Tinker Andrew, Hadjantonakis Anna-Katerina, Sawa Yoshiki, Sasaki Hiroshi, Ozono Keiichi, Suzuki Ken, Yashiro Kenta
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; 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; Department of Paediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
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; 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.
Cell Rep. 2016 Jul 26;16(4):1026-1038. doi: 10.1016/j.celrep.2016.06.050. Epub 2016 Jul 7.
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.
一种能够清晰识别心脏祖细胞（CPs）的表面标志物对于这些细胞的高效分离至关重要，从而避免了基因改造的必要性。在此，我们证明了一种含糖基磷脂酰肌醇锚的神经营养因子受体，即胶质细胞系衍生的神经营养因子受体α2（Gfra2），可特异性标记CPs。GFRA2的表达有助于通过荧光激活细胞分选从分化的小鼠和人类多能干细胞中分离出CPs。Gfra2突变体揭示了GFRA2在体外和体内心肌细胞分化与发育中的重要作用。从机制上讲，心脏GFRA2信号通路不同于依赖RET酪氨酸激酶及其既定配体的经典通路。总体而言，我们的研究结果建立了一个平台，用于研究CPs的生物学特性，为未来开发用于治疗心力衰竭的CP移植奠定基础。
