Neonatal Mouse Heart Regeneration is Dependent on Mononuclear Diploid Cardiomyocytes and Paracrine IGF2 Signaling
Circulation Research(2019)
摘要
In normal mice, injury to the newborn heart is efficiently regenerated, but this capacity is lost by one week after birth when most cardiomyocytes have become post-mitotic. Concurrently during the first week, most cardiomyocytes become polyploid. Despite this temporal association, the relation of polyploidization to neonatal heart regeneration has not been adequately examined. In this study, we find that IGF2, an important mitogenic factor in heart development, is required to support neonatal mouse heart regeneration. Following injury on postnatal day 1, absence of IGF2 abolished injury-induced cell cycle entry (as indicated by phospho-histone H3 staining) during the early part of the first postnatal week, when cardiomyocytes are still mononuclear and diploid. Consequently, regeneration failed despite the later presence of additional activities that support robust cell cycle entry 7 days following injury, a time when most cardiomyocytes are polyploid and no longer able to complete cytokinesis. IGF2 originates from the endocardium/endothelium lineage and is transduced by the insulin receptor; both features distinguish the action of IGF2 in neonatal heart regeneration from that in embryonic heart development. Regeneration in injured Igf2-deficient neonates was rescued by three different contexts that elevate the percentage of mononuclear diploid cardiomyocytes beyond postnatal day 7. Thus, IGF2 is the primary paracrine-acting mitogen for heart regeneration during the early postnatal period, and IGF2-deficiency unmasks the dependence of this process on proliferation-competent mononuclear diploid cardiomyocytes.
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关键词
neonatal mouse heart regeneration,mononuclear diploid cardiomyocytes
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