Cardiomyocyte-expressed TGFβ programs early heart maturation and adult myocyte identity

Transforming growth factor β (TGFβ) is a secreted factor sequestered in the extracellular matrix (ECM), but its role in developing mouse heart maturation is unknown. Here we show that cardiomyocyte-specific deletion of Tgfb1, Tgfb2 and Tgfb3 genes (TGFβ ligands) in the developing heart results in cardiac dysfunction by 6 weeks of age, altered fibroblast activity, abnormal ECM properties and endothelial and immune changes. Gene profiling reveals defective cardiomyocyte/fibroblast maturation with cardiomyocyte ectopic skeletal muscle gene expression beginning at embryonic day 17.5 (E17.5). Cardiomyocyte deletion of Tgfbr1/Tgfbr2 or Smad2/Smad3 does not phenocopy Tgfb1/2/3 deletion, suggesting that cardiomyocyte TGFβ acts through non-myocytes to regulate heart maturation. Similarly, Col1a2^-/-;Col6a2^-/- mice with reduced ECM stiffness, cardiomyocyte-specific Itgb1 deletion reducing ECM mechanosensing and Tcf21^-/- embryos lacking cardiac fibroblasts fail to reproduce ectopic skeletal muscle gene expression. Thus, embryonic cardiomyocyte-derived TGFβ signals to non-myocytes to establish an environment that directs cardiomyocyte maturation and identity.