Abstract Body: Background: Cardiomyocyte (CM) loss is a critical consequence of myocardial infarction (MI), a condition further exacerbated by the low turnover rate of adult CMs. However, current therapies only target preserving existing CM rather than replenishing lost ones. We previously demonstrated that cycling CMs exhibit upregulation of Wilms’ Tumor 1 (WT1) and genes associated with retinoic acid (RA) production, mirroring the expression patterns of epicardial cells. Epicardial-derived CMs make up 7% of murine cardiomyocytes, though their role in cardiac repair post-MI remains unclear. While WT1 and RA have been independently implicated in cardiac regeneration, their interactions in CM cycling are not well defined. To address this, we developed a WT1 computational model to identify key regulators of cardiomyocyte cycling and explore their therapeutic potential for cardiac repair.
Hypothesis: We hypothesize that WT1+ epicardial-derived CMs retain their ability to re-enter the cell cycle and facilitate cardiac repair after injury by modulating the cardiac microenvironment through paracrine signaling.
Methods: We developed a logic-based differential equations model using Netflux to investigate WT1 contribution to cardiac regeneration. Simulations of knockdown and overexpression were performed on the injury model to predict key regulators of DNA replication and epithelial-mesenchymal transition (EMT). Validation using primary literature articles as performed to compare our model simulations (n) to experiments in various cell types.
Results: Our model’s predictions aligned with 94.4% of experimental results in cancer cell lines (n = 18) and 100% in non-cancer cell lines (n = 10). The simulation of WT1 knockout after injury predicted decreased EMT and DNA replication.
Conclusions: Our model exhibited strong predictive accuracy across different cellular contexts, providing insights into WT1 driven CM cycling. To provide a comprehensive view of signaling in cardiac repair, we will integrate this model with our RA signaling model. These findings will further guide in vitro and in vivo studies to validate our simulations in CMs, potentially informing novel regenerative therapies for cardiac regeneration.