Sfrp5 identifies murine cardiac progenitors for all myocardial structures except for the right ventricle

Masayuki Fujii,Yutaka Kikuchi,Masataka Nagao,Hiroki Kokubo,Yumiko Saga,Akihiko Shimono,Ryo Kamata,Masao Yoshizumi,Akane Sakaguchi,Silvia M Evans

doi:10.1038/ncomms14664

Abstract

Upon acquirement of pulmonary circulation, the ancestral heart may have been remodelled coincidently with, or accompanied by, the production and rearrangement of progenitor cells. However, the progenitor populations that give rise to the left ventricle (LV) and sinus venosus (SV) are still ambiguous. Here we show that the expression of Secreted frizzled-related protein Sfrp5 in the mouse identifies common progenitors for the outflow tract (OFT), LV, atrium and SV but not the right ventricle (RV). Sfrp5 expression begins at the lateral sides of the cardiac crescent, excluding early differentiating regions, and continues in the venous pole, which gives rise to the SV. Lineage-tracing analysis revealed that descendants of Sfrp5-expressing cells at E7.5 contribute not only to the SV but also to the LV, atria and OFT and are found also in the dorsal splanchnic mesoderm accompanied by the expression of the secondary heart field marker, Islet1. These findings provide insight into the arrangement of cardiac progenitors for systemic circulation.

Highlights

Upon acquirement of pulmonary circulation, the ancestral heart may have been remodelled coincidently with, or accompanied by, the production and rearrangement of progenitor cells
During the heart tube looping stage (E8.0–E8.5), the expression of Secreted frizzled-related protein (Sfrp)[5] was observed continuously in the venous pole of the heart (Fig. 1c–e), the pattern of which was distinct from Myosin light chain 2a (Mlc2a) and Nkx[2,3,4,5], indicating that the Sfrp5-expressing area excludes differentiating cardiomyocytes
We propose a model for the contribution of Sfrp5-expressing cardiac precursors to heart development, except for the right ventricle (RV) (Supplementary Fig. 9)

Summary

Introduction

Upon acquirement of pulmonary circulation, the ancestral heart may have been remodelled coincidently with, or accompanied by, the production and rearrangement of progenitor cells. Lineage-tracing analysis revealed that descendants of Sfrp5-expressing cells at E7.5 contribute to the SV and to the LV, atria and OFT and are found in the dorsal splanchnic mesoderm accompanied by the expression of the secondary heart field marker, Islet[1]. These findings provide insight into the arrangement of cardiac progenitors for systemic circulation. The progenitor population that forms the first heart field (FHF), which gives rise to the left ventricle (LV) and the rest of the atria, and the sinus venosus (SV) are still ambiguous. Secreted frizzled-related protein (Sfrp) 1 and Sfrp[2], which are Wnt inhibitors, are expressed in the heart and are involved in cardiac tissue repair[26,27], while the expression pattern and function of another subfamily member, Sfrp[5], during cardiac development are unknown

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Conclusion