The developmental origin of postnatal cardiac regeneration

Abstract

Recent studies have shown that postnatal mammalian hearts undergo cardiomyocyte refreshment. However, evidence is lacking for the cell origin of these postnatal cardiomyogenesis. We first confirmed that myocardial injury triggered the expression of embryonic cardiogenesis genes at the external part of the heart. To determine whether cardiac lineage-specific progenitor cells exist in the postnatal mammalian heart and have cardiomyogenic potential, we created coronary artery ligation on the Nkx2.5 enhancer-eGFP transgenic mice. The number of Nkx2.5 enhancer-eGFP cells was increasing after myocardial injury and peaked at 2 weeks post injury. The activated eGFP+ cells expressed cardiac precursor markers. The eGFP signaling was not expressed in mature cardiomyocytes, hematopoietic cells or fibroblasts. These activated Nkx2.5 enhancer-eGFP cells would differentiate into striated cardiomyocytes in vitro. We further confirmed that cardiac progenitor cells contributed directly to postnatal cardiomyogenesis by lineage tracing using inducible Cre system. To trace the developmental origin of the activated Nkx2.5 enhancer-eGFP cells, we created different lineage-Cre/Nkx2.5 enhancer-eGFP/ ROSA26 reporter triple transgenic mice. The post-injury Nkx2.5 enhancer-eGFP+ cells originated from the embryonic epicardial cells, but did not originate from the pre-existing cardiomyocytes, endothelial cells, cardiac neural crest cells, and perinatal/ postnatal epicardial cells. Taken together, our data confirmed that cardiac-lineage progenitor cells, which originated from embryonic epicardium-derived cells, contributed to postnatal mammamian cardiomyogenesis. The discovery of cardiomyogenic cell population in the postnatal heart enables the future cell therapy for cardiac regeneration.