Key result
Direct coculture of human cardiac myofibroblasts with peripheral blood monocytes increased myofibroblast activity (65.2% vs. 57.6% contraction; P<0.01) through the release of TGF-β1.
Absolute Event Rate: 65.2% vs 57.6%
p-value: p=<0.01
Direct cell-cell interaction between peripheral blood monocytes and human cardiac myofibroblasts stimulates TGF-β1-mediated myofibroblast activity, implicating inflammation as a driver of cardiac fibrosis.
Targeting monocytes may curb post-MI fibrosis; extends mechanistic insight into inflammation-driven HF remodeling.
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.
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Mewhort et al. (2016) studied Cardiac fibrosis. Coculture with peripheral blood monocytes vs. Baseline (myofibroblasts alone) was evaluated on Myofibroblast activity measured by collagen gel contraction (p=<0.01). Direct coculture of human cardiac myofibroblasts with peripheral blood monocytes increased myofibroblast activity (65.2% vs. 57.6% contraction; P<0.01) through the release of TGF-β1.
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