title: Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-β1.
abstract: Following myocardial infarction (MI), cardiac myofibroblasts remodel the extracellular matrix (ECM), preventing mechanical complications. However, prolonged myofibroblast activity leads to dysregulation of the ECM, maladaptive remodeling, fibrosis, and heart failure (HF). Chronic inflammation is believed to drive persistent myofibroblast activity; however, the mechanisms are unclear. We assessed the influence of peripheral blood monocytes on human cardiac myofibroblast activity in a three-dimensional (3D) ECM microenvironment. Human cardiac myofibroblasts isolated from surgical biopsies of the right atrium and left ventricle were seeded into 3D collagen matrices. Peripheral blood monocytes were isolated from healthy human donors and cocultured with myofibroblasts. Monocytes increased myofibroblast activity measured by collagen gel contraction (baseline: 57.6 ± 5.9% vs. coculture: 65.2 ± 7.1% contraction; P < 0.01) and increased local ECM remodeling quantified by confocal microscopy. Under coculture conditions that allow indirect cellular interaction via paracrine factors but prevent direct cell-cell contact, monocytes had minimal effects on myofibroblast activity (17.9 ± 11.1% vs. 6.4 ± 7.0% increase, respectively; P < 0.01). When cells were cultured under direct contact conditions, multiplex analysis of the coculture media revealed an increase in the paracrine factors TGF-β1 and matrix metalloproteinase 9 compared with baseline (122.9 ± 10.1 pg/ml and 3,496.0 ± 190.4 pg/ml, respectively, vs. 21.5 ± 16.3 pg/ml and 183.3 ± 43.9 pg/ml; P < 0.001). TGF-β blockade abolished the monocyte-induced increase in cardiac myofibroblast activity. These data suggest that direct cell-cell interaction between monocytes and cardiac myofibroblasts stimulates TGF-β-mediated myofibroblast activity and increases remodeling of local matrix. Peripheral blood monocyte interaction with human cardiac myofibroblasts stimulates myofibroblast activity through release of TGF-β1. These data implicate inflammation as a potential driver of cardiac fibrosis.
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada; and.
authors.forename: Holly E M
authors.initials: HE
authors.lastname: Mewhort
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada; and.
authors.forename: Brodie D
authors.initials: BD
authors.lastname: Lipon
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada; and.
authors.forename: Daniyil A
authors.initials: DA
authors.lastname: Svystonyuk
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada; and.
authors.forename: Guoqi
authors.initials: G
authors.lastname: Teng
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada; and.
authors.forename: David G
authors.initials: DG
authors.lastname: Guzzardi
authors.affiliation: Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.affiliation: Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
authors.affiliation: Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Canada; and paul.fedak@gmail.com.
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
mesh_terms: D064752:Atrial Remodeling; D018920:Coculture Techniques; D003094:Collagen; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D005782:Gels; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018613:Microscopy, Confocal; D009000:Monocytes / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D058628:Myofibroblasts / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D005782:Gels; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D003094:Collagen; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: cardiac fibrosis; cardiac myofibroblasts; extracellular matrix; inflammation; remodeling