Cardiac Fibroblasts in Postnatal Development and Adult Injury Response

Abstract The cardiac fibroblast and its ability to convert into a myofibroblast for extracellular matrix (ECM) production, ventricular remodeling and the fibrotic response has been an area of recent investigation with important medical relevance. Here, a dual-PI renewal resubmission application is proposed by a developmental cardiac biologist and adult disease-based cardiac biologist to address how the postnatal heart matures in adulthood and then transitions back to a fetal-like program with disease stimulation through direct paracrine crosstalk and ECM feedback. During the past funding cycle of this award, we identified key regulatory relationships that exist between myocytes and fibroblasts in both the developing and diseased adult heart, whereby the ECM and transforming growth factor-β (TGFβ) served as an integrating platform between these 2 cell-types. We have also observed that fibroblast-expressed GDF10 and the epidermal growth factor (EGF) family member pleiotrophin (Ptn) mediate critical crosstalk between fibroblasts and myocytes. Here, we will investigate the hypothesis that TGFβ is a myocyte selective maturation factor that controls fibroblast activity in generating an effective ECM within the postnatal heart that also underlies adult disease, and that parallel Ptn and GDF10 signaling crosstalk further regulates fibroblast proliferation and promotes cardiomyocyte hypertrophy in development and disease. The dual-PI renewal application has 3 specific aims: 1) To examine how cardiomyocyte generated TGFβ1/2/3 and its subsequent signaling to cardiac fibroblasts underlie ECM neonatal maturation and adult ventricular remodeling, 2) To examine how cardiac fibroblast generated ECM regulates developmental cardiomyocyte maturation and adult heart remodeling, in part through TGFβ1/2/3 sequestration/release, and 3) To examine the function of the cardiac fibroblast-secreted growth factors Ptn and GDF10 in postnatal heart development and adult injury. Collectively, these specific aims will uncover novel signaling mechanisms that underlie heart maturation just after birth and determine how these mechanisms are redeployed in disease. Thus, the impact of this program will be the identification of novel signaling mechanisms and effectors that can be therapeutically targeted in human heart disease to positively effect cardiac remodeling and longstanding fibrosis, with added implications for treating congenital malformations and developmental growth abnormalities.