GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.
GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway.
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DOI：
10.1016/j.celrep.2016.06.050
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发表时间：
2016-07-26
期刊：
影响因子：
8.8
通讯作者：
Yashiro K
中科院分区：
文献类型：
--
作者：
Ishida H;Saba R;Kokkinopoulos I;Hashimoto M;Yamaguchi O;Nowotschin S;Shiraishi M;Ruchaya P;Miller D;Harmer S;Poliandri A;Kogaki S;Sakata Y;Dunkel L;Tinker A;Hadjantonakis AK;Sawa Y;Sasaki H;Ozono K;Suzuki K;Yashiro K
一个明确识别心脏祖细胞（CP）的表面标记物对于这些细胞的稳健分离是必不可少的，避免了遗传修饰的必要性。在这里，我们证明了一个糖基磷脂酰肌醇锚含有神经营养因子受体，胶质细胞系源性神经营养因子受体α 2（Gfra2），特异性标记CP。GFRA 2表达有助于通过荧光激活细胞分选从分化的小鼠和人多能干细胞中分离CP。GFRA 2突变体揭示了GFRA 2在体外和体内心肌细胞分化和发育中的重要作用。从机制上讲，心脏GFRA 2信号传导途径与依赖于RET酪氨酸激酶及其已建立配体的经典途径不同。总的来说，我们的研究结果建立了一个研究CP生物学的平台，作为未来开发CP移植治疗心力衰竭的基础。GFra2对中胚层细胞中的心脏祖细胞（CPs）具有特异性。GFra2能够在小鼠和人中分离多能或单能CPs。GFra2和相关分子GFra1在心脏发育中起重要作用。显示GPI锚定的神经营养因子受体Gfra2特异性标记小鼠和人的心脏祖细胞（CP），提供了分离CP的方法。出乎意料的是，Gfra2在心脏发育中起着重要的作用，通过一个非经典的信号通路，是独立的已知的配体和共受体RET酪氨酸激酶。
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. 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.