Identification of growth factors and cytokines regulating the postnatal cell cycle arrest of cardiomyocytes

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During intrauterine mammalian development the embryonic and fetal heart grows by proliferation of cardiomyocytes resulting in a progressive increase in cell number. Cardiomyocyte cell cycle activity ceases after birth, however, such that the postnatal heart primarily grows by increasing the size of existing cells without substantial generation of new cardiomyocytes. This postnatal cardiomyocyte cell cycle arrest is considered a main reason for the inability of the adult mammalian heart to regenerate after injury. It furthermore has major consequences for children born preterm, as a potential cardiomyocyte deficit due to the early interruption of intrauterine growth could not be normalized postnatally.The molecular mechanisms regulating postnatal cardiomyocyte cell cycle arrest are complex and incompletely understood. During the first postnatal week a switch from a glycolytic towards an oxidative metabolism in mitochondria accompanied by progressive maturation and differentiation of cardiomyocytes to meet the increasing workload of the post- compared to the prenatal heart are involved. The regulation of cardiomyocyte cell cycle activity in the immediate perinatal period, however, is less well understood. Our preliminary work in mice shows that proliferation rates in the heart drop within hours after birth. This is paralleled by inactivation of a variety of signaling pathways which regulate cardiac growth and cardiomyocyte cell cycle activity and are responsive to extracellular growth factors and cytokines. We therefore hypothesize that an early phase of postnatal cardiomyocyte cell cycle arrest is induced immediately after birth by the exposure to an extrauterine environment. This could be caused by rapid changes in the expression and availability of growth factors and cytokines in the myocardium.This project aims at precisely timing and characterizing cardiomyocyte proliferation in the perinatal mouse heart over a period of five days before and after birth. At the same time using an unbiased proteomics screen, growth factors and cytokines will be quantified in the myocardium and the circulating blood on the day before compared to the day after birth. Extracellular factors identified by this screen showing the most significant changes will subsequently be analyzed in vitro and in vivo for their ability to stimulate proliferation of neonatal mouse and rat cardiomyocytes as well as their potential to maintain cell cycle activity in fetal cardiomyocytes and delay cell cycle arrest in the latter. The data anticipated from this project will foster the understanding of postnatal cardiac growth and long-term function after preterm birth and might have major implications for regeneration of the neonatal and potentially the adult heart.