Wnt/β-catenin signaling promotes expansion of Isl-1–positive cardiac progenitor cells through regulation of FGF signaling
Ethan David Cohen, Zhishan Wang, John J. Lepore, Min Min Lu, Makoto M. Taketo, Douglas J. Epstein, Edward E. Morrisey
Ethan David Cohen, Zhishan Wang, John J. Lepore, Min Min Lu, Makoto M. Taketo, Douglas J. Epstein, Edward E. Morrisey
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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 3

Regulation of AHF marker genes and progenitor number by Wnt signaling.

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Regulation of AHF marker genes and progenitor number by Wnt signaling. (...
(A and B) FGF10 and Hand2 expression was reduced specifically in the hearts of SM22cre/Catnbflox/flox mutants (arrowheads). (C) Q-PCR was used to quantitate expression changes in the hearts of E9.5 SM22cre/Catnbflox/flox mutants. Expression of FGF10 and Hand2 was significantly downregulated, while expression of cTnI and Nkx2.5 was not appreciably affected by loss of β-catenin. (D–F) To activate canonical Wnt signaling in vivo, developing embryos were treated with LiCl as described in Methods. LiCl treatment of embryos increased outflow tract (brackets) length. (G and H) This increased outflow tract length was associated with an increase in the number of Isl-1–positive AHF progenitors migrating into the outflow tract (brackets) and increased Isl-1 staining in the pharyngeal mesoderm harboring the Isl-1–positive AHF progenitor pool (arrows). (I) The number of Isl-1–positive cells in the outflow tract/right ventricle increased approximately 50% in Isl-1–positive AHF progenitors after LiCl treatment. (J and K) FGF10 and Hand2 expression was upregulated in the outflow tract and right ventricle after LiCl treatment (arrows). ***P < 0.001. Scale bars: 250 μm (D and E); 125 μm (G and H).