Cell-cell interaction between cardiomyocytes and cardiac fibroblasts regulates ferroptosis and fibrosis after myocardial injury

The heart suffers from a severe loss of cardiomyocyte after myocardial infarction (MI). However, it is not known which type of cell death is the major contributor of the loss of cardiomyocytes. By studying a mouse heart MI model at a regenerative and a non-regenerative stage, we demonstrate that ferroptosis, not apoptosis or necroptosis, is the major contributor to cardiomyocyte death starting at 1 day-post-MI. Intrinsic Pitx2 signaling in cardiomyocyte prevents ferroptosis. Meanwhile, cardiac fibroblasts expressing high level of Fth1 interact with cardiomyocytes to share the iron burden, therefore inhibit cardiomyocyte ferroptosis. Cardiomyocyte Pitx2 also inhibits Tsp1 expression, therefore negatively regulate fibroblast-to-myofibroblast activation to limit fibrosis. Overall design: Comparative gene expression profiling analysis of RNA-seq data from induced cardiomyocyte (iCMs) treated with siRNA targeting Pitx2 or a scramble control at various doses. Some cultures were exposed to oxidative stress via H2O2 treatment.