Abstract Body: Background: Macrophages play a pivotal role in cardiac development, homeostasis and disease. After myocardial infarction (MI), macrophages expand and regulate inflammation, repair, angiogenesis and fibrosis. Colony-Stimulating Factor -1 (CSF-1), a critical regulator of macrophage function, is significantly upregulated following MI and acts through its receptor CSF-1R. However, the role and the molecular mechanisms of CSF-1/CSF-1R signaling in repair and remodeling after MI are unknown. We hypothesize that the CSF1-CSF1R axis may play a central role in repair and remodeling after MI, modulating infarct macrophage phenotype.
Methods and Results: ScRNA-Seq identified a large cluster of reparative macrophages (RMp) 7 days after MI. Ingenuity Pathway Analysis (IPA) identified CSF-1 as the top-ranked upstream regulator mediating the RMp molecular signature. ScRNA-seq showed that Csf1 is predominantly expressed by infarct fibroblasts, while Csf1r is mainly expressed by infarct macrophages. To investigate the role of fibroblast-derived CSF-1, inducible fibroblast-specific CSF-1 knockout mice (FCSF1KO) were generated using the Col1a2-CreER driver. FCSF1 KO mice had no short-term baseline defects. In a model of non-reperfused MI, FCSF1KO mice exhibited higher mortality, impaired left ventricular (LV) systolic function, and exacerbated LV dilative remodeling at 7 and 28 days post-MI compared to Col1a2-CreER controls. To investigate the role of macrophage CSF-1R signaling, macrophage-specific CSF-1R knockout mice (MaCSF1RKO) were generated using the CX3CR1-CreER driver. Tamoxifen was administrated before and after MI to continuously target Cx3cr1-expressing macrophages. MaCSF1RKO mice displayed worse LV dysfunction and accentuated LV dilation 7 days after MI. To examine whether CSF1 supplementation had beneficial effects on the infarcted heart, a single intravenous dose of recombinant human CSF-1 (rhCSF-1, 2.5mg/kg) was administrated upon reperfusion in a model of reperfused MI. CSF-1 administration significantly improved systolic function 14 days after MI.
Conclusions: Fibroblast-derived CSF-1 protects the infarcted heart from adverse post-MI remodeling by promoting reparative macrophage function. Macrophage CSF-1R signaling plays a critical role in cardiac repair and remodeling. Early administration of CSF-1 improves cardiac function in reperfused MI. Targeting CSF-1/CSF-1R axis in macrophage may represent a therapeutic strategy to improve outcome after MI.