Abstract 302: IL4Ra is Required for Cardiomyocyte Cell Cycle Activity and Cardiac Regeneration

Abstract

Introduction: During the first week of life, neonatal mice are able to regenerate their hearts after injury with minimal scarring. Work from our lab demonstrates that IL13 signaling is required for neonatal heart regeneration, however multiple IL13 receptors exist. Here, we aim to identify the specific receptor ligand interaction that promotes regenerative healing in the heart. In vitro data suggests the IL4Ra/IL3Ra1 receptor heterodimer may mediate cardiomyocyte (CM) proliferation and heart regeneration. Thus, we aim to test the functional role of this receptor in cardiac regeneration in vivo . We hypothesize that IL13 signals through IL4Ra/IL13Ra1 directly on CMs to promote CM cell cycle activity and cardiac regeneration. Methods: To delineate IL13 signaling mechanisms in murine hearts, we utilized two knockouts of IL4Ra—global IL4Ra knockout (KO) and CM-specific IL4Ra knockout (IL4Ra fl/fl Myh6 CRE ) mice. To assess regeneration, mice received cardiac apical resection surgery at postnatal day 1 (P1). Regeneration was assessed by echocardiography and histological analysis of residual scars and CM proliferation indices. We next tested if IL13 administration could extend the regenerative window. We performed myocardial infarction (MI) on P7 mice and administered IL13 for two weeks. We assessed scar size through trichrome staining and CM cell cycle activity through immunostaining. Results: We observed impaired cardiac regeneration, determined by scar formation and decreased cardiac function in IL4Ra KO mice compared to littermate controls. Similar to global KOs, we observed decreased function in IL4Ra fl/fl Myh6 CRE mice. IL13 administration to wildtype mice after P7 MI decreased MI severity and increased CM cell cycle activity, suggesting improved reparative capacity. Interestingly, IL13 administration in IL4Ra fl/fl Myh6 CRE mice did not improve cardiac recovery phenotypes indicating that IL13 functions through IL4Ra directly on CMs to promote cardiac healing. Conclusion: These results demonstrate that the IL4Ra receptor subunit is required for cardiac regeneration, and activation of this receptor can extend the regenerative window. These findings lay the groundwork for potential therapeutic targets for promoting cardiac healing.