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. 2008 Oct 24;375(3):450-3.
doi: 10.1016/j.bbrc.2008.08.044. Epub 2008 Aug 21.

Nkx2-5- and Isl1-expressing cardiac progenitors contribute to proepicardium

Bin Zhou  1 , Alexander von Gise, Qing Ma, José Rivera-Feliciano, William T Pu
Affiliations

Nkx2-5- and Isl1-expressing cardiac progenitors contribute to proepicardium

Bin Zhou et al. Biochem Biophys Res Commun. .

Abstract

Correct delineation of the hierarchy of cardiac progenitors is a key step to understanding heart development, and will pave the way for future use of cardiac progenitors in the treatment of heart disease. Multipotent Nkx2-5 and Isl1 cardiac progenitors contribute to cardiomyocyte, smooth muscle, and endothelial lineages, which constitute the major lineages of the heart. Recently, progenitors located within the proepicardium and epicardium were reported to differentiate into cardiomyocytes, as well as smooth muscle and endothelial cells. However, the relationship of these proepicardial progenitors to the previously described Nkx2-5 and Isl1 cardiac progenitors is incompletely understood. To address this question, we performed in vivo Cre-loxP-based lineage tracing. Both Nkx2-5- and Isl1-expressing progenitors contributed to the proepicardium and expressed Wt1 and Tbx18, markers of proepicardial progenitor cells. Interestingly, Nkx2-5 knockout resulted in abnormal proepicardial development and decreased expression of Wt1, suggesting a functional role for Nkx2-5 in proepicardium formation. Taken together, these results suggest that Nkx2-5 and/or Isl1 cardiac progenitors contribute to proepicardium during heart development.

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Figures

Fig. 1
Fig. 1. Nkx2-5-derived cells contribute to proepicardium
(A) Nkx2-5IRESCre/+;Rosa26fsLz and littermate control Nkx2-5+/+;Rosa26fsLz embryos, stained in whole mount with X-gal and then sagitally sectioned. Arrowheads mark the X-gal positive cells in proepicardium. (B) Co-staining of Nkx2-5 (green), Wt1 (green), and β-gal (red) on the same slide. Nuclei were stained with DAPI (blue). Arrows indicate PE cells that are β-gal and Wt1 positive, and Nkx2-5 negative. Black bar = 500 µm. White bar=100 µm. A, atrium; RV, right ventricle; LV, left ventricle; OFT, outflow tract; PE, proepicardium.
Fig. 2
Fig. 2. Isl1-derived cells contribute to proepicardium
(A) Wholemount X-gal staining of Isl1Cre/+;Rosa26fsLz and littermate control Isl1+/+;Rosa26fsLz embryos. Sagittal sections of whole mount stained embryos are shown. Arrowheads mark the X-gal positive proepicardium. (B) Immunostaining of Wt1 and β-gal on sections from Isl1Cre/+;Rosa26fsLz embryos. Asterisk indicates proepicardium. Arrows indicate cells positive for both β-gal and Wt1. Bar = 100 µm. Other abbreviations as in Fig. 1.
Fig. 3
Fig. 3. Loss of Nkx2-5, but not Isl1, leads to malformation of proepicardium
(A) Wholemount figure of Nkx2-5Cre/Cre (Nkx2-5 KO) and littermate control Nkx2-5+/+. Black arrow indicates PE in control embryo, and corresponding region of the mutant embryo. (B) Immunostaining of Wt1 (red) and Nkx2-5 (green) shows decreased Wt1 expression and no Nkx2-5 expression in mutants. Arrow indicates Wt1+ cells in PE of control embryo, and corresponding area deficient in Wt1 expression in mutant embryo. Arrowhead indicates preserved Wt1 expression outside of the heart-forming regions of the mutant embryo. (C) Wholemount figure of Isl1Cre/Cre (Isl1 KO) and littermate control Isl1+/+. Black arrow indicates PE in control and mutant embryos. (D) Immunostaining of Wt1 (red) and cardiac marker Desmin (green) shows existence of proepicardium. White arrow indicates Wt1-expressing proepicardium. A,C bar = 500 µm; B,D bar = 50 µm.
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