Modeling the synovium on a chip for studying the interactions between lymphatic vasculature and synoviocytes in rheumatoid arthritis.
L’essentiel
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that afflicts the synovial lining of joints and manifests in reduced range of motion, pain, swelling, and numerous other complications with no effective cure. In recent years, attention has shifted toward eradicating the source of synovial autoimmunity and inflammation, with a key focus on the synovial-draining lymphatics. However, very few in vitro models of the synovial microenvironment have been developed to date, and none yet include the synovial lymphatics. We therefore create a microfluidic chip device that models the synovial-draining lymphatics within the subintimal synovium microenvironment. Functional assays on our synovium-on-chip demonstrate increased lymphatic permeability and decreased drainage under RA inflammation compared to healthy controls, accompanied by increased lymphatic endothelial cell (LEC) junctional disruption and altered LEC phenotype following interaction with fibroblast-like synoviocytes (FLS). We identify overexpression of chitinase-3 like-protein-1 (CHI3L1) from RA patient-derived synoviocytes as a key target in inducing junctional loosening and lymphatic dysfunction, which is reversed in our microfluidic chip and in vivo mouse models by neutralizing antibody inhibition. Our novel synovium-on-chip model can provide a physiologically accurate representation of lymphatic drainage and activity under disease conditions, informing tissue engineering, drug testing, and high-throughput screening for rheumatoid arthritis.
Synthèse détaillée
Résumé original
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that afflicts the synovial lining of joints and manifests in reduced range of motion, pain, swelling, and numerous other complications with no effective cure. In recent years, attention has shifted toward eradicating the source of synovial autoimmunity and inflammation, with a key focus on the synovial-draining lymphatics. However, very few in vitro models of the synovial microenvironment have been developed to date, and none yet include the synovial lymphatics. We therefore create a microfluidic chip device that models the synovial-draining lymphatics within the subintimal synovium microenvironment. Functional assays on our synovium-on-chip demonstrate increased lymphatic permeability and decreased drainage under RA inflammation compared to healthy controls, accompanied by increased lymphatic endothelial cell (LEC) junctional disruption and altered LEC phenotype following interaction with fibroblast-like synoviocytes (FLS). We identify overexpression of chitinase-3 like-protein-1 (CHI3L1) from RA patient-derived synoviocytes as a key target in inducing junctional loosening and lymphatic dysfunction, which is reversed in our microfluidic chip and in vivo mouse models by neutralizing antibody inhibition. Our novel synovium-on-chip model can provide a physiologically accurate representation of lymphatic drainage and activity under disease conditions, informing tissue engineering, drug testing, and high-throughput screening for rheumatoid arthritis.