Natriuretic Peptide Receptor B modulates the proliferation of the cardiac cells expressing the Stem Cell Antigen-1

Stéphanie Rignault-Clerc,Lucas Liaudet,Christelle Bielmann,François Feihl,Bernard Waeber,Nathalie Rosenblatt-Velin

doi:10.1038/srep41936

Stéphanie Rignault-Clerc, Lucas Liaudet + Show 4 more

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https://doi.org/10.1038/srep41936

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Abstract

Brain Natriuretic Peptide (BNP) injections in adult “healthy” or infarcted mice led to increased number of non-myocyte cells (NMCs) expressing the nuclear transcription factor Nkx2.5. The aim of this study was to identify the nature of the cells able to respond to BNP as well as the signaling pathway involved. BNP treatment of neonatal mouse NMCs stimulated Sca-1+ cell proliferation. The Sca-1+ cells were characterized as being a mixed cell population involving fibroblasts and multipotent precursor cells. Thus, BNP treatment led also to increased number of Sca-1+ cells expressing Nkx2.5, in Sca-1+ cell cultures in vitro and in vivo, in the hearts of neonatal and adult infarcted mice. Whereas BNP induced Sca-1+ cell proliferation via NPR-B receptor and protein kinase G activation, CNP stimulated Sca-1+ cell proliferation via NPR-B and a PKG-independent mechanism. We highlighted here a new role for the natriuretic peptide receptor B which was identified as a target able to modulate the proliferation of the Sca-1+ cells. The involvement of NPR-B signaling in heart regeneration has, however, to be further investigated.

Highlights

As the endogenous cardiac precursor cells (CPCs) have been shown to contribute to heart regeneration in physiological as well as in pathophysiological conditions[1,2,3,4], the challenge in the coming years is to increase their potential to proliferate and differentiate into mature functional cardiomyocytes
We recently demonstrated that Brain Natriuretic Peptide (BNP) injections into neonatal and adult healthy or infarcted mice led to reduced heart dilation associated at the cellular level to increased number of Nkx2.5+ αactinin− cells and newly formed cardiomyocytes[16]
To determine whether BNP treatment modified the number of c-kit+ or/and Sca-1+ cells, flow cytometry analysis using antibodies against c-kit or Sca-1 proteins were performed on non-myocyte cells (NMCs) isolated from neonatal mouse hearts and cultured with or without BNP for up to 11 days

Summary

Introduction

As the endogenous cardiac precursor cells (CPCs) have been shown to contribute to heart regeneration in physiological as well as in pathophysiological conditions[1,2,3,4], the challenge in the coming years is to increase their potential to proliferate and differentiate into mature functional cardiomyocytes. One of the major problems which limited the development of strategies aimed to improve heart regeneration, is the identification of the CPCs which remains a difficult task, due to the lack of a defined, highly specific marker. These last years, the use of different markers (most notably the c-kit and the Stem Cell antigen-1 (Sca-1) proteins and the islet-1 nuclear transcription factor) as well as different isolation methods (colony forming assays, dye-efflux methods, flow cytometry cell sorting) generated confusing results[3,4,5,6,7,8,9]. Identifying the factors able to stimulate CPC proliferation and differentiation will be essential for further development of therapeutically strategies aimed to stimulate heart regeneration even in elderly patients suffering from cardiac vascular diseases

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