Wnt/β-catenin signaling promotes expansion of Isl-1 -: positive cardiac progenitor cells through regulation of FGF signaling
Wnt/β-catenin signaling promotes expansion of Isl-1 -: positive cardiac progenitor cells through regulation of FGF signaling
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DOI：
10.1172/jci31731
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Morrisey, Edward E.
中科院分区：
文献类型：
--
作者：
Cohen, Ethan David;Wang, Zhishan;Morrisey, Edward E.
心前区(AHF)是心脏流出道和右室的组成部分，部分由LIM同源框转录因子ISL-1的表达决定。ISL-1阳性细胞是心脏发育所必需的，在出生后的心脏中充当心脏干/祖细胞，这一发现突显了ISL-1阳性细胞在心脏发育和内环境稳定中的重要性。然而，调控这些细胞扩张和分化的分子途径却知之甚少。我们发现，ISL-1阳性的小鼠AHF前体细胞对Wnt/β-catenin信号有反应，这些反应细胞参与心脏的流出道和右心室。AHF中Wnt/β-catenin信号的丢失导致流出道缺陷和右室发育，ISL-1阳性祖细胞减少，成纤维细胞生长因子信号丢失。相反，Wnt在这些细胞中的功能增强导致ISL-L阳性祖细胞的扩张，同时通过激活一组特定的成纤维细胞生长因子配体，包括成纤维细胞生长因子3、成纤维细胞生长因子10、成纤维细胞生长因子16和成纤维细胞生长因子20，伴随着成纤维细胞生长因子信号的增加。这些数据揭示了我们认为扩增ISL-1阳性的AHF前体细胞所需的新的WNT-FGF信号轴，并建议未来增加这些细胞的数量和功能以促进心脏再生。
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-l-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.