Macrophages and fibroblasts: key regulators in wound healing, fibrosis and the foreign body reaction

Macrophages and fibroblasts are key regulators in wound healing, fibrosis and foreign body reaction (FBR). After injury macrophages migrate through the extracellular matrix (ECM) towards the wounded area, and adopt a M1 or M2 phenotype. M1 macrophages are associated with tissue injury and inflammation whereas M2 macrophages are associated with tissue repair and regeneration. In all processes, fibroblasts become activated and start to produce ECM, which is required for wound closure and the formation of a fibrous capsule in the FBR. In this thesis, we showed that macrophages, via secreted factors, affect the activation of fibroblasts. M2 macrophages stimulated fibroblast proliferation while M1 macrophages induced pro-inflammatory fibroblasts. In addition, we showed that macrophages and fibroblasts are able to change their phenotype within hours. We concluded that both macrophages and fibroblasts are highly dynamic cells and that their activation status is affected by the microenvironment. This implies that macrophages and fibroblasts are highly responsive to the microenvironment and that this can direct them towards healing or fibrosis. During fibrosis and the formation of a fibrotic capsule, the ECM becomes cross-linked, leading to stiffening of the tissue. This has a direct influence on the activation of fibroblasts; however, the effect of stiffness on macrophages is unknown. We showed that macrophage fusion, one of the characteristics of the FBR, depends on different stiffness. This indicates that the rigidity of a biomaterial and/or the fibrotic capsule can induce macrophage fusion, which is important for the course of the FBR.