IL4Rα signaling promotes neonatal cardiac regeneration and cardiomyocyte cell cycle activity. J Mol Cell Cardiol 2021 Dec;161:62-74
Date
08/04/2021Pubmed ID
34343540Pubmed Central ID
PMC8629844DOI
10.1016/j.yjmcc.2021.07.012Scopus ID
2-s2.0-85112431618 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
Neonatal heart regeneration depends on proliferation of pre-existing cardiomyocytes, yet the mechanisms driving regeneration and cardiomyocyte proliferation are not comprehensively understood. We recently reported that the anti-inflammatory cytokine, interleukin 13 (IL13), promotes neonatal cardiac regeneration; however, the signaling pathway and cell types mediating this regenerative response remain unknown. Here, we hypothesized that expression of the type II heterodimer receptor for IL13, comprised of IL4Rα and IL13Rα1, expressed directly on cardiomyocytes mediates cardiomyocyte cell cycle and heart regeneration in neonatal mice. Our data demonstrate that indeed global deletion of one critical subunit of the type II receptor, IL4Rα (IL4Rα-/-), decreases cardiomyocyte proliferation during early postnatal development and significantly impairs cardiac regeneration following injury in neonatal mice. While multiple myocardial cell types express IL4Rα, we demonstrate that IL4Rα deletion specifically in cardiomyocytes mediates cell cycle activity and neonatal cardiac regeneration. This demonstrates for the first time a functional role for IL4Rα signaling directly on cardiomyocytes in vivo. Reciprocally, we examined the therapeutic benefit of activating the IL4Rα receptor in non-regenerative hearts via IL13 administration. Following myocardial infarction, administration of IL13 reduced scar size and promoted cardiomyocyte DNA synthesis and karyokinesis, but not complete cytokinesis, in 6-day old non-regenerative mice. Our data demonstrate a novel role for IL4Rα signaling directly on cardiomyocytes during heart regeneration and suggest the potential for type II receptor activation as one potential therapeutic target for promoting myocardial repair.
Author List
Paddock SJ, Swift SK, Alencar-Almeida V, Kenarsary A, Alvarez-Argote S, Flinn MA, Patterson M, O'Meara CCAuthors
Michael Andrew Flinn Postdoctoral Fellow in the Physiology department at Medical College of WisconsinCaitlin C. O'Meara PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Michaela Patterson PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Cell Cycle
Cells, Cultured
Female
Heart
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Myocardium
Myocytes, Cardiac
Rats
Receptors, Cell Surface
Regeneration
STAT3 Transcription Factor
Signal Transduction
