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 1

Expression of Wnt/β-catenin signaling components during cardiac development.

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Expression of Wnt/β-catenin signaling components during cardiac developm...
Expression of TCF3 was observed in the aortic sac (as) and atria (a) at E9.5 (A) and in the developing outflow tract (OFT) at E12.5 (B) and E14.5 (C). v, ventricle. TCF4 expression was also observed in the aortic sac and atria at E9.5 (D) and at much lower levels in the developing outflow tract at E12.5 (E) and E14.5 (F). Arrowheads indicate compact zone of the myocardium. (G) BATGAL lacZ expression was not observed in the heart proper at E10.5 or any other time tested. (H and I) However, extensive lacZ expression was observed in the outflow tract and pharyngeal mesoderm (PM) at E10.5 (arrowheads). (J) Wnt signaling was fate-mapped using the TOP–cre-ERT2 transgenic line, which consists of 3 reiterated LEF/TCF DNA binding sites upstream of a minimal c-fos promoter driving the tamoxifen-inducible cre-ERT2 cDNA (14). (K) Strong lacZ expression was observed in the outflow tract and right ventricle of the heart but little contribution was observed in the left ventricle. (L–N) LacZ expression driven from the BATGAL transgene colocalized with Isl-1 expression in the outflow tract of the developing heart (brackets) using immunostaining with anti–β-galactosidase and anti–Isl-1 antibodies. Scale bars: 125 μm (A, D, H, I, and L–N); 500 μm (B, C, E, and F).