Mononuclear diploid cardiomyocytes support neonatal mouse heart regeneration in response to paracrine IGF2 signaling

Elife. 2020 Mar 13:9:e53071. doi: 10.7554/eLife.53071.

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.

Keywords: IGF2; developmental biology; heart regeneration; insulin receptor; insulin-like growth factor 2; mononuclear diploid cardiomyocyte; mouse; neonatal heart.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Diploidy
  • Gene Expression Regulation
  • Genotype
  • Heart / physiology*
  • Heart Injuries / etiology
  • Heart Injuries / therapy*
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism*
  • Mice
  • Mice, Knockout
  • Myocytes, Cardiac / physiology*
  • Regeneration / physiology*
  • Signal Transduction

Substances

  • IGF2 protein, mouse
  • Insulin-Like Growth Factor II