Abstract
Injury to the newborn mouse heart is efficiently regenerated, but this capacity is lost by one week after birth. We found that IGF2, an important mitogen in heart development, is required for neonatal heart regeneration. IGF2 originates from the endocardium/endothelium and is transduced in cardiomyocytes by the insulin receptor. Following injury on postnatal day 1, absence of IGF2 abolished injury-induced cell cycle entry during the early part of the first postnatal week. Consequently, regeneration failed despite the later presence of additional cell cycle-inducing activities 7 days following injury. Most cardiomyocytes transition from mononuclear diploid to polyploid during the first postnatal week. Regeneration was rescued in Igf2-deficient neonates in three different contexts that elevate the percentage of mononuclear diploid cardiomyocytes beyond postnatal day 7. Thus, IGF2 is a 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.
Highlights
In heart development, an initial pool of cardiomyocytes is derived by differentiation from early mesodermal progenitors
We showed that the epicardium is the source of secreted mitogenic factors that promote cardiomyocyte proliferation (Chen et al, 2002), and identified IGF2 as the major epicardial mitogen responsible for this activity (Li et al, 2011; Shen et al, 2015)
We find that IGF2 is a required factor for neonatal heart regeneration, with mechanistic features that are distinct compared to its role in embryonic heart development
Summary
An initial pool of cardiomyocytes is derived by differentiation from early mesodermal progenitors. Once this early process has completed, in every later context in the embryo and throughout postnatal life, essentially all new cardiomyocytes are generated by proliferation of preexisting cardiomyocytes rather than by differentiation from a non-cardiomyocyte progenitor source (Sereti et al, 2018; Li et al, 2019). The rate of embryonic cardiomyocyte proliferation is high as growth of the heart keeps pace with overall embryo growth, but tapers down by the end of gestation (Soonpaa et al, 1996).
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