Mononuclear diploid cardiomyocytes support neonatal mouse heart regeneration in response to paracrine IGF2 signaling
Hua Shen,
Peiheng Gan,
Kristy Wang,
Ali Darehzereshki,
Kai Wang,
S Ram Kumar,
Ching-Ling Lien,
Michaela Patterson,
Ge Tao,
Henry M Sucov
Affiliations
Hua Shen
Department of Stem Cell Biology and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, United States
Peiheng Gan
Department of Stem Cell Biology and Regenerative Medicine, University of Southern California Keck School of Medicine, Los Angeles, United States; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States; Department of Medicine Division of Cardiology, Medical University of South Carolina, Charleston, United States
Kristy Wang
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States
Ali Darehzereshki
Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, United States
Kai Wang
Department of Cardiovascular Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
S Ram Kumar
Department of Surgery, University of Southern California Keck School of Medicine, Los Angeles, United States
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, United States; Department of Medicine Division of Cardiology, Medical University of South Carolina, Charleston, United States
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.
