Macrophages modulate the function of msc-and ipsc-derived fibroblasts in the presence of polyethylene particles

Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (Mϕs). On the other hand, the response of Mϕs to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)-and induced pluripotent stem cell (iPSC)-derived fibrob-lasts. These were co-cultured with either M1 or M2 Mϕs, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 Mϕs: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 Mϕs. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 Mϕs may be a critical target for the clinical treatment of cPE induced fibrosis.