Analyzing the effects of fibroblast programming on early heart maturation

These, in turn, impact cardiomyocyte maturation through cell-cell interactions, ECM-cellular interactions, and paracrine factors. We observed that deletion of Tgfb1, Tgfb2, Tgfb3 genes (TGFβ ligands), together, from cardiomyocytes in the early developing heart results in cardiac dysfunction by 6 weeks of age with altered fibroblast activity and perturbed ECM content.

Early postnatal hearts from Tgfb1/2/3 cardiomyocyte deleted mice are dysmorphic and cardiac fibroblasts have incorrect activity and produce inappropriate ECM with reduced stiffness, indicating effects during embryonic development itself. In order to tease out the effects of altered fibroblast programming on cardiomyocyte maturation even before birth, we generated transcriptional profiles of embryonic hearts from two models of dysregulated fibroblast programming; the first model was E17.5 embryonic hearts from our Tgfb1/2/3 cardiomyocyte deleted line and the second model was E17.5 embryonic hearts from the previously reported Tcf21-null line [PMID: 22573622], which lack cardiac fibroblasts.