Abstract 348: Interleukin 13 is Required for Neonatal Heart Regeneration

Abstract

Shortly after birth neonatal mice can fully regenerate their hearts, but this potential is lost in the first week of life. Cell cycle entry of existing cardiomyocytes is thought to be an essential mechanism enabling neonatal mouse heart regeneration. In previous studies we found that the cytokine interleukin 13 (IL13) was a an upstream regulator of differentially expressed gene networks during neonatal heart regeneration and stimulated cell cycle activity of cultured rat cardiomyocytes, suggesting that this factor might be important in neonatal heart regeneration in vivo . In the present study, we subjected wildtype and IL13 knockout mice to ventricular apical resection at one day of age and assessed heart regeneration 21 days post resection (dpr). Compared to wildtype controls, IL13 knockout mice failed to regenerate their hearts as determined by extensive scar formation at the ventricular apex. To gain insight into the mechanism of impaired regeneration, we quantified cardiomyocyte proliferation and expression of macrophage markers at 7 dpr. We found no difference in gene expression of macrophage markers in IL13 knockout mice compared to wildtype. Interestingly, IL13 knockout mice demonstrate a significant increase cardiomyocyte cell cycle activity as determined by phosphorylated Histone H3 (pH3) staining. This seemingly contradictory result appears to be due to an underlying developmental defect in IL13 knockout hearts. Cardiomyocytes in IL13 knockout mice appeared large and disorganized. Cardiomyocytes from IL13 knockout unoperated mice showed decreased pH3 staining and had increased expression marker of hypertrophic growth such as Nppb and Nppa. Histologically, hearts from IL13 knockout mice appeared to have a dilated cardiomyopathy phenotype. Collectively our data suggests that during heart development IL13 influences proliferative versus hypertrophic growth. We surmise that following neonatal apical resection in IL13 knockout mice the significant increase in cardiomyocyte proliferation is a compensatory attempt to repair the injury, but the underlying cardiomyocyte phenotype inhibits complete regeneration. These data are the first to report a role for IL13 in normal heart development and neonatal heart regeneration.