Role of Telocytes in the Synovial Lymphatic System

About This Grant

Abstract Rheumatoid Arthritis (RA) is a prevalent autoimmune inflammatory disorder that arises through dysregulation of multiple mucosal endotypes via an array of pathways. Thus, effective treatment requires tailored therapies that target inflammation and adjuvants to ameliorate common physiologic maladies. To this end and based on our discoveries, we generated a transgenic mouse (Efhd1-CreERT2) and identified peri-popliteal lymphatic vessel (PLV) telocyte networks elaborated with mast cells, and synoviocytes phenotypic of telocytes. Of particular relevance is that telocytes regulate smooth muscle contractions through mast cell interactions, telocytes are greatly diminished in RA synovium, and their numbers increase following exercise. Based on the findings, we hypothesize that: 1) contiguous telocyte networks elaborated with mast cells extend from the synovium to their joint-draining collecting lymphatic vessels (cLV); 2) these telocyte networks fragment during chronic inflammatory arthritis; and 3) exercise preserves the telocyte network within the synovial lymphatic system (SLS). We also hypothesize that exercise maintains a stable synovial telocyte network, which results in improved lymphatic function and decreased arthritis-associated inflammation. To test these hypotheses, we propose two Specific Aims. In Aim 1 we will perform whole-mount immunofluorescent microscopy (WMIFM) and light-sheet microscopy (LSM) to formally examine the existence of contiguous mast cell elaborated telocyte networks adjacent to lymphatic capillaries in the synovium that extend to joint-draining cLV. We will also use these methods to examine telocyte network fragmentation in mice with lymphatic defects and advanced inflammatory arthritis. In Aim 2 we will investigate the effects of exercise on telocytes within the SLS in WT mice and its efficacy in preventing telocyte loss and lymphatic dysfunction in mice with inflammatory- erosive arthritis. Currently the mechanisms responsible for lymphatic dysfunction in RA are unknown, and there are no FDA-approved drugs that alter lymphatic function. Thus, it has been argued that addressing this therapeutic approach requires a deep characterization of lymphatic biology that is now a high priority area of research for the NIH. Thus, we developed a novel transgenic mouse for SLS telocyte genetic gain and loss of function studies, and a unifying hypothesis of SLS telocyte function, which begs testing in a R01 research program. To this end, we propose high risk-high-reward critical proof of concept studies that will provide sufficient scientific rigor of prior research to support an R01 application and provide a quantum leap in the field both in terms of understanding RA progression and the benefits of exercise.