IL-13 promotes in vivo neonatal cardiomyocyte cell cycle activity and heart regeneration

There is great interest in identifying signaling mechanisms by which cardiomyocytes (CMs) can enter the cell cycle and promote endogenous cardiac repair. We previously demonstrated that IL13 stimulated cell cycle activity of neonatal CMs in vitro. However, the signaling events that occur downstream of IL13 in CMs, and the role of IL13 in CM proliferation and regeneration in vivo have not been explored. Here, we tested the role of IL13 in promoting neonatal CM cell cycle activity and heart regeneration in vivo, and investigated the signaling pathway(s) downstream of IL13 specifically in CMs. Compared to control, CMs from neonatal IL13 knockout (IL13-/-) mice showed decreased proliferative markers and coincident upregulation of the hypertrophic marker Brain Natriuretic Peptide (Nppb) and increased CM nuclear size. Following apical resection in anesthetized newborn mice, heart regeneration was significantly impaired in IL13-/- mice compared to wildtype. Administration of recombinant IL13 reversed these phenotypes by increasing CM proliferation markers and decreasing Nppb expression. RNAseq on primary neonatal CMs treated with IL13 revealed activation of gene networks regulated by ERK1/2 and AKT. Western blot confirmed strong phosphorylation of ERK1/2 and AKT in both neonatal and adult cultured CMs in response to IL13. Our data demonstrate a role for endogenous IL13 in neonatal CM cell cycle and heart regeneration. ERK1/2 and AKT signaling are important pathways known to promote CM proliferation and protect against apoptosis, respectively, thus, targeting IL13 transmembrane receptor signaling or administering rIL13 may be therapeutic approaches for activating pro-regenerative and survival pathways in the heart.