Abstract
Transforming growth factor β (TGFβ) is a secreted growth factor that is sequestered to the ECM as a latent complex and released in response to cardiac stress. Once released, TGFβ is required for conversion of quiescent fibroblasts to myofibroblasts that support cardiac repair and fibrosis through production of ECM components. While these functional features of TGFβ are well known, the fibroblast-independent effector functions of TGFβ in the heart are unknown. We hypothesized that TGFβ is a critical ECM-cell cross talk mediator in the heart whereby cardiomyocyte -generated TGFβ communicates with fibroblasts to program the composition and stability of the ECM in a reinforcing feedback network. We found that deletion of TGFβ ligands ( Tgfb1 , Tgfb2 , and Tgfb3 ) from cardiomyocytes with an α-MHC-Cre transgene ( Tgfb123 fl/fl -αMHC-Cre ), but not a fibroblast-specific targeted allele ( Tgfb123 fl/fl -Tcf21-MCM ), results in cardiac dysfunction. These results suggest that cardiomyocytes (CMs) are the predominant source of TGFβ in the heart at baseline and that perhaps celltypes beyond the fibroblast were also involved. Interestingly, fibroblast numbers and ECM deposition are increased in Tgfb123 fl/fl -αMHC-Cre hearts and with acute injury hearts from these mice produce shorter, disorganized collagen fibers. Gene expression profiling of Tgfb123 fl/fl -αMHC-Cre hearts at 6 weeks of age demonstrates defective cardiomyocyte maturation. Indeed, Tgfb123 fl/fl -αMHC-Cre hearts are dysmorphic at neonatal day 1 and cardiomyocytes from these hearts remain in cell cycle for a longer duration with greater levels of mononucleation. However, deleting TGFβ receptors I/II or Smad2/3 from CMs does not recapitulate this phenotype suggesting that TGFβ is not driving CM maturation in an autocrine manner. Instead, these findings indicate that TGFβ functions as a critical cross-talk mediator to fibroblasts to establish proper ECM organization and content that drives CM maturation.
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