TGF-b signaling in infarct fibroblasts prevents adipocyte conversion through Smad-independent mechanisms

The adult mammalian myocardium has very limited endogenous regenerative capacity; thus, repair of the heart after myocardial infarction is dependent on timely activation of matrix-secreting reparative fibroblasts and myofibroblasts that deposit a collagenous matrix network, thus replacing dead cardiomyocytes and protecting the heart from catastrophic rupture or excessive dilation. Infarct fibroblasts undergo dynamic phenotypic transitions critical for the reparative response. During the proliferative phase of cardiac repair, the abundant myocardial fibroblast-like cells undergo myofibroblast conversion, expressing contractile proteins such as alpha-smooth muscle actin, and secrete large amounts of extracellular matrix proteins. As the scar matures, myofibroblasts become de-activated and convert to matrifibrocytes, fibroblast-like cells that lack expression of myofibroblast markers, such as and periostin and express genes encoding specialized matricellular and tendon proteins. Cardiac repair is dependent on retention of fibroblast identity and cell specification throughout the healing response. Defects in the reparative cellular response, resulting in infiltration of the infarct with fatty or calcified tissue, have been reported in both experimental models of and in human patients with myocardial infarction. However, the cellular mechanisms responsible for these perturbations remain enigmatic. In the current study, we discovered that disruption of TGF-b signaling specifically in infarct fibroblasts triggers their conversion to adipocytes, resulting in extensive infiltration of the scar with adipose tissue. Overall design: To examine the effects of fibroblast-specific TbR2 loss on the transcriptional profile of infarct fibroblasts, we harvested PDGFRa+ fibroblasts from FTbR2 KO and TbR2 fl/fl infarcts 7 days after coronary occlusion and we performed RNA-seq. 4 samples in each group.