Runx1 in Postn-expressing fibroblasts exacerbates adverse cardiac remodeling post myocardial infarction

Runx1 is strongly induced in the heart after acute injury and in chronic disease settings. Its expression negatively correlates with outcomes, and past work has shown a protective effect when Runx1 is inhibited through a variety of experimental means. We sought to establish the cell type(s) responsible for Runx1-dependent adverse remodeling following infarction. Using immunostaining for RUNX1 along with existing single cell RNA sequencing data sets, we established which cell types express Runx1 and prioritized two from this list – cardiomyocytes and fibroblasts. Cre drivers for the respective cell populations were paired with a Runx1 floxed allele to generate inducible, cell-type specific knockout mice. Following myocardial infarction induced by permanent ligation, mice were assessed for functional recovery by echocardiography and histological measurements, including scar size, cardiomyocyte dimension, and cell proliferation. Detailed transcriptomic analysis was used to assess mechanism of action. In contrast to existing literature, we did not observe a measurable impact of cardiomyocyte-specific loss of Runx1 on heart function or histology following myocardial infarction when compared to Cre-positive controls. On the other hand, loss of Runx1 in the Postn-expressing activated fibroblast population resulted in a protective effect on heart function seen as early as 3 days post-infarction and maintained until the 56-day experimental endpoint. These functional benefits were accompanied by smaller scars, reduced cardiomyocyte hypertrophy, and a reduction of activated fibroblasts progressing to an SMA-positive myofibroblast. Overall, we demonstrate Runx1 expression in activated fibroblasts drives adverse remodeling phenotypes following myocardial infarction.