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Price check on A(i)s(l)e 13: investigation of interleukin-13 activity in cardiac regeneration.

Progressive cardiac disease can lead to heart failure in adults due to permanent loss of cardiomyocytes. In contrast, the early aged mammalian neonatal heart in rodents and, most recently, porcine models exhibits significant tissue renewal of beating cells after injury (2, 8, 11). Despite the insufficient regenerative response of the adult heart to disease and damage, an emerging consensus supports the proliferative capacity of a subpopulation(s) of cardiomyocytes during development into mammalian adulthood (2, 6). The nature of cardiomyocyte proliferation has been informed by study of prenatal cardiac development, interspecies comparisons with lower vertebrates, surgical injury, and the neonatal cardiac regenerative mouse model. Neonatal mice restore damaged ventricular tissue by a variety of insults (apical resection or vessel ligation) over several weeks by transient proliferation of cardiomyocytes, similar to phenomena in zebrafish. This robust regenerative response in early aged neonates is suppressed just a few days after birth, and injured hearts follow an adult phenotype of permanent fibrosis and loss of cardiac physiology (2, 8, 11). Deep genome sequencing has identified modulators of the tissue regeneration and cardiomyocyte proliferation activity, including gene programming downstream of environmental factors, such as oxygen tension and paracrine signaling from the epicardium and immune cell activity. For example, expression patterns of microRNAs (miR-590, miR-199a, and miR15) and immune cell secretome (M2 and regulatory T cells) indicate developmental remodeling of the epigenetic and transcriptome landscape is correlated with postnatal silencing of fetal pathways associated with cardiac regeneration (3, 5, 10). A report by Wodsedalek and colleagues (7) recently published in the American Journal of Physiology-Heart and Circulatory Physiology builds on a previous study that identified interleukin (IL)-13 as a novel pathway for inducing cell cycle activity in cultured neonatal and adult cardiomyocytes through IL-13 receptor and IL-14 in the STAT3/6 signaling axis (Fig. 1) (3, 7). IL-13 is an anti-inflammatory cytokine secreted primarily from T helper (Th)2 cells and is known to play a significant role in regenerative wound healing in other tissue types. In the previous study, a comparative RNA-seq screen was conducted to identify critical signaling nodes for proliferative plasticity by profiling stages of maturation in the mouse heart and correlated synthetic induced pluripotent stem cardiomyocytes to compare with stages of putative dedifferentiation in the actively healing neonatal heart with surrogate cultured primary cardiomyocytes. To validate the screen, cultured neonatal and adult rat cardiomyocytes were treated with recombinant (r)IL-13 and exhibited increased cell cycle activity, as assessed by bromodeoxyuridine incorporation, Ki-67 staining, phosphorylated histone H3 (pH3) staining, and cell count in the dish (3). Wodsedalek et al. (7) provided a followup study that used next-generation transcriptome sequencing and a IL-13 transgenic knockout (KO) mouse model to investigate the role of IL-13 signaling in cardiac regeneration. In the IL-13 KO model, unoperated hearts, as characterized, have fewer cell cycling cardiomyocytes at postnatal day 8 accompanied by increases in expression of the hypertrophic marker Nppb and increases in the nuclear size of cardiomyocyte nuclei (Mef2 nuclei), which are indicative of hypertrophy compared with wild-type controls. Hypertrophy was also supported by increased distance between nuclei in the tissue. To test the role of IL-13 in the cardiac proliferative response to injury, as previously observed in the neonatal heart, the authors used the apical resection model in neonatal mice as a tool. At 3 wk postinjury, IL-13 KO mice exhibited impaired regeneration. Specifically, tissue repair was grossly limited in IL-13 KO neonatal mice compared with agematched day 1 wild-type control mice when characterized for regional deposition of fibrotic tissue. In addition, left ventricular diameters at systole and diastole were increased in KO mice compared with wild-type mice at 21 days after resection. IL-13 KO resected hearts also exhibited a larger cross-sectional area of cardiomyocytes. In rescue experiments, administration of rIL-13 increased cardiomyocyte cell cycle activity [pH3 /cardiac-type troponin T2 (cTnnt ) cells] in IL-13 KO mice after 1 wk. RNA-seq confirmed that exogenous delivery of IL-13 stimulated progrowth ERK1/2 and Akt activation, likely downstream of the IL-13 STAT3/6 signaling axis. Interestingly, wild-type animals injected with rIL-13 showed a trend toward decreased cycling cardiomyocytes (pH3 /cTnnt cells), although this did not reach statistical significance. These findings begin to suggest an intriguing switch between hypertrophic signaling and hyperplasia via extracellular cytokine signaling of IL-13 (7). Further investigation will need to determine whether the timing of administration, pleiotropic IL-13 activity, and altered cell interactions can provide a better understanding of these findings. A growing body of work revisits the role of immune cells in the process of wound healing and regeneration (10). IL-13 is an Address for reprint requests and other correspondence: S. E. Senyo, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106 (e-mail: ssenyo@case.edu). Am J Physiol Heart Circ Physiol 316: H262–H264, 2019; First published November 21, 2018; doi:10.1152/ajpheart.00718.2018.