Mammalian heart renewal by pre-existing cardiomyocytes

Abstract

During normal ageing a low rate of division of pre-existing cardiomyocytes, rather than progenitor cells, is responsible for cardiomyocyte genesis; this process is increased fourfold during myocardial infarction. There is controversy in the cardiovascular field regarding the extent of existing cardiomyocyte turnover versus progenitor cell contributions during mammalian cardiac homeostasis throughout adult life. This study takes a novel approach to settling the debate by using a combination of prospective labelling with the nitrogen-15 isotope and genetic pulse–chase to measure DNA synthesis in the adult mammalian heart. The authors conclude that during normal ageing, preexisting cardiomyocytes are the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis, a process that is increased fivefold during recovery from myocardial infarction. Although recent studies have revealed that heart cells are generated in adult mammals, the frequency of generation and the source of new heart cells are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes1. Other studies suggest that new cardiomyocytes are born at a very low rate2,3,4, and that they may be derived from the division of pre-existing cardiomyocytes. Here we show, by combining two different pulse–chase approaches—genetic fate-mapping with stable isotope labelling, and multi-isotope imaging mass spectrometry—that the genesis of cardiomyocytes occurs at a low rate by the division of pre-existing cardiomyocytes during normal ageing, a process that increases adjacent to areas of myocardial injury. We found that cell cycle activity during normal ageing and after injury led to polyploidy and multinucleation, but also to new diploid, mononucleate cardiomyocytes. These data reveal pre-existing cardiomyocytes as the dominant source of cardiomyocyte replacement in normal mammalian myocardial homeostasis as well as after myocardial injury.