PDGF-AB Reduces Myofibroblast Differentiation Without Increasing Proliferation After Myocardial Infarction

[Display omitted] •PDGFs can induce fibroblast proliferation, myofibroblast differentiation, and subsequent fibrosis, but their therapeutic addition after MI improves heart function without inducing additional fibrosis.•We show PDGF-AB does not induce fibroblast proliferation but rather reduces myofibroblast differentiation and induces cells with a transcriptome distinct from myofibroblasts.•Using de novo library assembly of pig RNA sequencing data, this study improves on the current pig reference genome, reveals that PDGF-AB reduces proinflammatory cytokines, and elucidates PDGF-AB effects on transcript variants and long noncoding RNA expression post-MI.•This study shows the underlying unique effects by which PDGF-AB therapy improves post-MI heart function and contrasts with previous research, highlighting PDGF-AB’s pleiotropic effects. After myocardial infarction (MI), fibroblasts progress from proliferative to myofibroblast states, resulting in fibrosis. Platelet-derived growth factors (PDGFs) are reported to induce fibroblast proliferation, myofibroblast differentiation, and fibrosis. However, we have previously shown that PDGFs improve heart function post-MI without increasing fibrosis. We treated human cardiac fibroblasts with PDGF isoforms then performed RNA sequencing to show that PDGFs reduced cardiac fibroblasts myofibroblast differentiation and downregulated cell cycle pathways. Using mouse/pig MI models, we reveal that PDGF-AB infusion increases cell-cell interactions, reduces myofibroblast differentiation, does not affect proliferation, and accelerates scar formation. RNA sequencing of pig hearts after MI showed that PDGF-AB reduces inflammatory cytokines and alters both transcript variants and long noncoding RNA expression in cell cycle pathways. We propose that PDGF-AB could be used therapeutically to manipulate post-MI scar maturation with subsequent beneficial effects on cardiac function.