| First Author | Paddock SJ | Year | 2021 |
| Journal | J Mol Cell Cardiol | Volume | 161 |
| Pages | 62-74 | PubMed ID | 34343540 |
| Mgi Jnum | J:320568 | Mgi Id | MGI:6740963 |
| Doi | 10.1016/j.yjmcc.2021.07.012 | Citation | Paddock SJ, et al. (2021) IL4Ralpha signaling promotes neonatal cardiac regeneration and cardiomyocyte cell cycle activity. J Mol Cell Cardiol 161:62-74 |
| abstractText | 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 IL4Ralpha and IL13Ralpha1, 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, IL4Ralpha (IL4Ralpha(-/-)), decreases cardiomyocyte proliferation during early postnatal development and significantly impairs cardiac regeneration following injury in neonatal mice. While multiple myocardial cell types express IL4Ralpha, we demonstrate that IL4Ralpha deletion specifically in cardiomyocytes mediates cell cycle activity and neonatal cardiac regeneration. This demonstrates for the first time a functional role for IL4Ralpha signaling directly on cardiomyocytes in vivo. Reciprocally, we examined the therapeutic benefit of activating the IL4Ralpha 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 IL4Ralpha 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. |
