Wnt/β-catenin signaling promotes expansion of Isl-1–positive cardiac progenitor cells through regulation of FGF signaling
Ethan David Cohen, … , Douglas J. Epstein, Edward E. Morrisey
Ethan David Cohen, … , Douglas J. Epstein, Edward E. Morrisey
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1794-1804. https://doi.org/10.1172/JCI31731.
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Research Article Cardiology

Wnt/β-catenin signaling promotes expansion of Isl-1–positive cardiac progenitor cells through regulation of FGF signaling

Abstract

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/β-catenin signaling, and these responsive cells contributed to the outflow tract and right ventricle of the heart. Loss of Wnt/β-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.

Authors

Ethan David Cohen, Zhishan Wang, John J. Lepore, Min Min Lu, Makoto M. Taketo, Douglas J. Epstein, Edward E. Morrisey

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Figure 6

FGF signaling is activated by Wnt signaling in the AHF.

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FGF signaling is activated by Wnt signaling in the AHF. (A and B) ERK1/2...
(A and B) ERK1/2 phosphorylation was used to assess the activity of FGF signaling in the AHF. SM22cre/Catnbflox/flox mutants expressed less phosphorylated ERK1/2 in the AHF and outflow tract than did wild-type littermates at E9.5 (arrowheads). PO4, phosphorylation. (C and D) ERK1/2 phosphorylation increased in the outflow tract and right ventricular myocardium in SM22cre/Catnbflox(ex3)/+ embryos at E10.5 (arrowheads). (E) FGF10 and FGF8 expression was assessed by Q-PCR in AHF explants treated with Wnt3a. Surprisingly, FGF10 expression was significantly upregulated, while expression of FGF8, which is also expressed in the AHF, was unchanged. Expression of both Isl-1 and Hand2 was upregulated as expected. (F) Expression of additional FGF ligands was determined by Q-PCR, and FGF3, FGF10, FGF16, and FGF20 were all significantly upregulated by Wnt3a treatment, whereas FGF4 was downregulated. (G and H) Activation of AHF gene expression (G) and Isl-1–positive AHF progenitor number (H) by Wnt3a was attenuated by the FGF receptor inhibitor SU5402, indicating that these pathways act cooperatively in regulating AHF development. (I) Conversely, Wnt3a and FGF10 cooperatively increased Isl-1 expression in AHF explants, further supporting interaction between Wnt and FGF signaling in AHF development. **P < 0.005. Scale bars: 100 μm.