P524Cardiac fibroblasts as a stimulator for cardiac inflammation

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Abstract

Background

The transdifferentiation of fibroblasts to pathological myofibroblasts is known to contribute to cardiac extracellular matrix remodelling favouring increased LV stiffness. This transdifferentiation is triggered by inflammatory cells, which transmigrated into the cardiac tissue. Nevertheless, why these inflammatory cells invade into the tissue is still unkown. Here, we investigate the chemotactic properties of fibroblasts as a stimulator for cardiac inflammation.

Methods

Endomyocardial biopsies were used to obtain cardiac fibroblasts from patients. This human cardiac fibroblast cell culture system was used to investigate the transdifferentiation of cardiac fibroblasts to myofibrobalsts after TGF-beta treatment in regard to different matrix regulation and chemokine production. Moreover, cardiac fibroblasts from mice were used to investigate the chemokine secretion after mechanical stretch using the flexercell system.

Results

Cardiac fibroblasts, which transdifferentiate into myofibroblasts after TGF-beta treatment, produce increased amount of extracellular matrix proteins in in vitro studies. Moreover, chemokines (CCL2, CCL7 and CCL8) were produced by myofibroblasts. Using cell culture supernatant from cardiac fibroblasts in trans-well migration assays for inflammatory cells, we could document the chemotactic properties of fibroblasts. Furthermore, we treated inflammatory cells with the cell culture supernatant of cardiac fibroblasts and showed an increase in degradatory activity (increased MMP-2 and MMP-9 expression), allowing easier transendothelial migration through the basal membrane. The treatment of inflammatory cells with fibroblast cell culture supernatant resulted in the activation of these cells documented by a highly increased expression of chemokines which leads to a further recruitment of inflammatory cells into the cardiac tissue. Furthermore, we here demonstrate that mechanical stretch using the flexercell system resulted in increased chemokine secretion of cardiac fibroblasts.

Conclusions

Tissue inflammation modulates matrix remodelling by inducing transdifferentiation of fibroblasts to myofibroblasts, leading to collagen accumulation. Fibroblasts, known as the main contributor for extracellular matrix proteins were highly chemotactic active and therefore increase the number of inflammatory cells in cardiac tissue. This makes the fibroblast to an inflammatory supporter cell and may be one explanation for cardiac inflammation in heart failure in general.

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