PDGFRα signaling in cardiac fibroblasts modulates quiescence, metabolism and self-renewal, and promotes anatomical and functional repair

The interstitial and perivascular spaces of the mammalian heart contain a highly interactive tissue community essential for cardiac homeostasis, repair and regeneration. Mesenchymal cells (fibroblasts) are one of the most abundant cell types and make up the organ superstructure. They play key roles as sentinels, tissue architects, paracrine signaling hubs and lineage precursors, and are linked to heart disease through their roles in inflammation and fibrosis. Platelet-derived growth factors (PFGFs) are secreted by several cell types involved in cardiac injury and repair. Here we explore in detail how PDGF receptor α (PDGFRα) signaling in cardiac fibroblasts affects their activation, differentiation and self-renewal. Short-term systemic delivery of PDGF-AB to mice from the time of myocardial infarction (MI) led to activation, proliferation and increased self-renewal of fibroblasts, and subsequent expansion of myofibroblasts. Underpinning this, as evidenced in uninjured mice, was a cell cycle priming effect, in which PDGF-AB induced exit of fibroblasts from quiescence without stimulating proliferation. Despite fibrogenesis, however, treated MI hearts showed enhanced anatomical and functional repair that was associated with pro-regenerative effects on endothelial cells, immune cells and cardiomyocytes. Our study provides a rationale for a novel therapeutic approach to cardiac injury involving stimulating fibroblast activation and endogenous repair mechanisms.