Cohen Ethan David, Wang Zhishan, Lepore John J, Lu Min Min, Taketo Makoto M, Epstein Douglas J, Morrisey Edward E
Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
J Clin Invest. 2007 Jul;117(7):1794-804. doi: 10.1172/JCI31731.
The anterior heart field (AHF), which contributes to the outflow tract and right ventricle of the heart, is defined in part by expression of the LIM homeobox transcription factor Isl-1. The importance of Isl-1-positive cells in cardiac development and homeostasis is underscored by the finding that these cells are required for cardiac development and act as cardiac stem/progenitor cells within the postnatal heart. However, the molecular pathways regulating these cells' expansion and differentiation are poorly understood. We show that Isl-1-positive AHF progenitor cells in mice were responsive to Wnt/beta-catenin signaling, and these responsive cells contributed to the outflow tract and right ventricle of the heart. Loss of Wnt/beta-catenin signaling in the AHF caused defective outflow tract and right ventricular development with a decrease in Isl-1-positive progenitors and loss of FGF signaling. Conversely, Wnt gain of function in these cells led to expansion of Isl-1-positive progenitors with a concomitant increase in FGF signaling through activation of a specific set of FGF ligands including FGF3, FGF10, FGF16, and FGF20. These data reveal what we believe to be a novel Wnt-FGF signaling axis required for expansion of Isl-1-positive AHF progenitors and suggest future therapies to increase the number and function of these cells for cardiac regeneration.
前心脏区域（AHF）对心脏的流出道和右心室发育有贡献，其部分是由LIM同源框转录因子Isl-1的表达所定义。这些Isl-1阳性细胞在心脏发育和内环境稳定中的重要性体现在以下发现中：心脏发育需要这些细胞，并且它们在出生后的心脏中充当心脏干细胞/祖细胞。然而，调节这些细胞增殖和分化的分子途径却知之甚少。我们发现，小鼠中Isl-1阳性的AHF祖细胞对Wnt/β-连环蛋白信号有反应，并且这些反应性细胞对心脏的流出道和右心室发育有贡献。AHF中Wnt/β-连环蛋白信号的缺失导致流出道和右心室发育缺陷，Isl-1阳性祖细胞减少以及FGF信号丧失。相反，这些细胞中Wnt功能的获得导致Isl-1阳性祖细胞的扩增，同时通过激活一组特定的FGF配体（包括FGF3、FGF10、FGF16和FGF20）使FGF信号增加。这些数据揭示了我们认为的一种新的Wnt-FGF信号轴，它是Isl-1阳性AHF祖细胞扩增所必需的，并为未来增加这些细胞数量和功能以促进心脏再生的治疗方法提供了思路。
