PT  - JOURNAL ARTICLE
AU  - Naisana S. Asli
AU  - Munira Xaymardan
AU  - Ralph Patrick
AU  - Nona Farbehi
AU  - James Cornwell
AU  - Elvira Forte
AU  - Ashley J. Waardenberg
AU  - Vaibhao Janbandhu
AU  - Scott Kesteven
AU  - Vashe Chandrakanthan
AU  - Helena Malinowska
AU  - Henrik Reinhard
AU  - Peter Schofield
AU  - Daniel Christ
AU  - Ishtiaq Ahmed
AU  - Romaric Bouveret
AU  - Surabhi Srivastava
AU  - Rakesh K. Mishra
AU  - Jyotsna Dhawan
AU  - James J.H. Chong
AU  - Robert Nordon
AU  - Peter Macdonald
AU  - Robert M. Graham
AU  - Michael Feneley
AU  - Richard P. Harvey
TI  - PDGFRα signaling in cardiac fibroblasts modulates quiescence, metabolism and self-renewal, and promotes anatomical and functional repair
AID  - 10.1101/225979
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 225979
4099  - http://biorxiv.org/content/early/2019/06/13/225979.short
4100  - http://biorxiv.org/content/early/2019/06/13/225979.full
AB  - 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, playing 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 (PDGFs) are secreted by several cell types involved in cardiac injury and repair, and are recognized mitogens for cardiac fibroblasts and mesenchymal stem cells. However, their roles are complex and investigations of their impact on heart repair have produced contrasting outcomes, leaving therapeutic potential uncertain. Here, we use new approaches and tools, including single cell RNA sequencing, to explore cardiac fibroblast heterogeneity and how PDGF receptor α (PDGFRα) signaling impacts fibroblasts during heart repair. Short-term systemic delivery of PDGF-AB to mice from the time of myocardial infarction (MI) led to enhanced anatomical and functional recovery. Underpinning these benefits was a priming effect, in which PDGF-AB accelerated exit of fibroblasts from quiescence and induced a higher translational biosynthetic capacity in both fibroblasts and macrophages without triggering fibrosis. Our study highlights the significant biosynthetic heterogeneity and plasticity in cardiac fibroblast populations, and suggests a rationale for a novel therapeutic approach to cardiac injury involving controlled stimulation of fibroblast activation.