0130 : Is the stem cell antigen 1 involved in the brain natriuretic peptide effect on cardiac precursor cells?

Abstract

Cardiac cellular therapy can be intended by stimulation of “endogenous” cardiac precusor cells (CPCs), identified by several markers such as the Stem Cell Antigen 1 (Sca-1) or the stem cell factor c-kit. CPCs are able to proliferate and differentiate into beating cardiomyocytes in vivo and in vitro after brain natriuretic peptide (BNP) treatment. BNP is a cardiac hormone, whose role in the heart remains to be clarified. Interestingly, BNP treatments, in vivo and in vitro , induced an upregulation of mRNA coding for Sca-1 and a 2 fold increase of the number of CPCs. In previous work, we showed that Sca-1 KO mice had two times less CPCs, and two times less BNP mRNA expression compared to Wild Type mice. The aim of this project is to determine whether the effect of BNP on CPCs is linked to Sca-1 expression. Sca-1 KO mice developed a dilated cardiomyopathy with ageing. To determine whether reduced amount of BNP is responsible for the development of this cardiac disease, neonatal Sca-1 KO mice were treated with BNP for 2 weeks. Mice were sacrificed 13 weeks later, and cardiac parameters were measured by echocardiography. The thickness of the left ventricular posterior wall and the ejection fraction were increased in BNP-treated Sca-1 deficient mice (+15% and + 28%, respectively) compared to untreated Sca-1 KO mice. To explore the cellular mechanisms, in vitro experiments were performed. Non Myocytes cells (NMCs), containing CPCs, have been isolated from the heart of Sca-1 KO mice and cultured with or without BNP in media favouring either cell proliferation or differentiation into cardiomyocytes. BNP is not able to induce Sca-1KO cell proliferation, whereas CPC differentiation into cardiomyocytes is maintained even in absence of Sca-1 expression. In conclusion, BNP modulates the cardiomyopathy developed by Sca-1 KO mice. BNP effect on CPC proliferation is linked to Sca-1 expression, but its effect on differentiation is Sca-1 independent.