Abstract
Background: The adult mammalian heart is unable to regenerate after an injury. However, newborn mice are able to fully regenerate the heart after myocardial infarction (MI). The neonatal MI model therefore is a potential blueprint for regenerating the adult heart that could offer novel therapies for patients suffering from heart disease. To investigate the mechanism by which neonatal heart regeneration occurs, we screened for secreted proteins that are upregulated after neonatal MI but not after adult MI. We hypothesized that such a protein could be a cardiomyocyte mitogen that underlies the cardiomyocyte proliferation that occurs after neonatal MI. Methods: We performed microarrays on neonatal and adult MI (and sham) heart tissue samples: we identified IGFBP3 (Insulin Growth Factor Binding Protein 3), which canonically transports IGF ligands in circulation, as a secreted protein that is uniquely upregulated after neonatal MI. We used in situ hybridization, reporter mice, and immunostaining to validate the findings from the microarray. Single cell RNA-seq data revealed that IGFBP3 is expressed in vascular cells. Results: We first tested whether IGFBP3 is necessary during neonatal heart regeneration: we performed neonatal (P1) MI in global Igfbp3 knockout mice and wild-type mice, and found that knockout mice have more fibrosis and worse ejection fraction (EF) one month after P1 MI. To determine if IGFBP3 is sufficient to promote cardiomyocyte proliferation, we injected recombinant IGFBP3 protein into the heart of one week-old mice (P7) and saw more cycling myocytes. We generated novel transgenic vascular-Igfbp3-overexpression mice, which exhibit less fibrosis as well as improved EF after P7 MI compared to controls. Conclusions: IGFBP3 is a secreted protein that is necessary for complete regeneration after a neonatal MI. Its ectopic expression can cause cardiomyocyte proliferation and can improve systolic function, and it prolongs the window of neonatal heart regeneration. Therefore, IGFBP3 may represent a cardiomyocyte mitogen with potential therapeutic value for adult heart disease.
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