Identification of growth factors and cytokines regulating the postnatal cell cycle arrest of cardiomyocytes
Developmental Biology
Cell Biology
Final Report Abstract
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 might have consequences for children born preterm, as a potential cardiomyocyte deficit due to the early interruption of intrauterine growth could not be normalized postnatally. In mice cardiomyocyte proliferation ceases within 14 days after birth whereas the dynamics in the immediate perinatal period are less clear. The results derived from this project show that cardiomyocyte mitosis drops within hours after birth and cell cycle activity progressively decreases over the first two postnatal days. 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 is involved which according to our data does not play a major role in the immediate perinatal phase. In contrast, several intracellular signaling pathways regulating cell cycle activity and cardiac growth are altered in the mouse heart within hours after birth. Given that these pathways are responsive to growth factors and cytokines we performed a proteomics screen and identified 26 extracellular factors whose protein availability changes within hours after birth in the heart. 9 of these factors were tested for their ability to alter cell cycle activity in cultured neonatal mouse cardiomyocytes. Of these PDGFAA is able to increase cell cycle activity whereas Adiponectin, Osteopontin and IGFBP1 have inhibitory effects. The remaining factors either have no effect or the currently available data do not allow a final conclusion yet. In summary, the results show that an early phase of the postnatal cardiomyocyte cell cycle arrest is induced immediately after birth by the exposure to an extrauterine environment. This is paralleled by altered activity of growth promoting signaling pathways and could be caused by rapid changes in the expression and availability of growth factors and cytokines in the perinatal myocardium. These data provide new insights in perinatal cardiac growth regulation and might have implications for long-term consequences after preterm birth as well as regeneration of the neonatal and potentially the adult heart.
