title: Age-related changes in tissue macrophages precede cardiac functional impairment.
abstract: Cardiac tissue macrophages (cTMs) are abundant in the murine heart but the extent to which the cTM phenotype changes with age is unknown. This study characterizes aging-dependent phenotypic changes in cTM subsets. Using theCx3cr1(GFP/+) mouse reporter line where GFP marks cTMs, and the tissue macrophage marker Mrc1, we show that two major cardiac tissue macrophage subsets, Mrc1-GFP(hi) and Mrc1+GFP(hi) cTMs, are present in the young (<10 week old) mouse heart, and a third subset, Mrc1+GFP(lo), comprises ~50% of total Mrc1+ cTMs from 30 weeks of age. Immunostaining and functional assays show that Mrc1+ cTMs are the principal myeloid sentinels in the mouse heart and that they retain proliferative capacity throughout life. Gene expression profiles of the two Mrc1+ subsets also reveal that Mrc1+GFP(lo) cTMs have a decreased number of immune response genes (Cx3cr1, Lpar6, CD9, Cxcr4, Itga6 and Tgfβr1), and an increased number of fibrogenic genes (Ltc4s, Retnla, Fgfr1, Mmp9 and Ccl24), consistent with a potential role for cTMs in cardiac fibrosis. These findings identify early age-dependent gene expression changes in cTMs, with significant implications for cardiac tissue injury responses and aging-associated cardiac fibrosis.
authors.affiliation: Australian Regenerative Medicine Institute (ARMI), Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Pinto
authors.forename: James W
authors.initials: JW
authors.lastname: Godwin
authors.forename: Anjana
authors.initials: A
authors.lastname: Chandran
authors.forename: Lucy
authors.initials: L
authors.lastname: Hersey
authors.forename: Alexei
authors.initials: A
authors.lastname: Ilinykh
authors.forename: Ryan
authors.initials: R
authors.lastname: Debuque
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Rosenthal
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D005355:Fibrosis / Q000473:pathology; D005434:Flow Cytometry; D006331:Heart Diseases / Q000473:pathology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome