Arthritis & rheumatology (Hoboken, N.J.) · 2026
Telocyte Deletion Associated With Loss of Lymphatic Drainage and Exacerbation of Inflammatory-Erosive Arthritis in Mice.
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Peng Yue, Kenney H Mark, Lydon Sean, de Mesy Bentley Karen L, Xing Lianping, Korman Benjamin D, Ritchlin Christopher T, Schwarz Edward M
Аннотация
OBJECTIVE: Patients with rheumatoid arthritis (RA) have lymphatic defects characterized by loss of collecting lymphatic vessel (cLV) contractions of unknown etiology. To elucidate underlying mechanisms, we generated transgenic mice with lymphatic-specific inducible genetics and studied joint-draining lymphatics in zymosan-induced arthritis (ZIA).
METHODS: We crossed novel Efhd1-CreERT2 and Myoc-CreERT2 mice to Ai9 tdTomato (tdT) reporter mice to assess tamoxifen-induced transgene expression via single-cell RNA sequencing, whole-mount immunofluorescent microscopy (WMIFM), and immunohistochemistry. We applied electron and confocal microscopy of popliteal lymphatic vessels (PLVs) to examine α smooth muscle actin positive lymphatic muscle cells, mast cell tryptase-positive mast cells, and CD31-/CD34+ cells. We crossed Efhd1-CreERT2 and Myoc-CreERT2 mice to diphtheria toxin-alphafloxed mice to examine: (1) tamoxifen-induced targeted cell deletion; (2) lymphatic function via near-infrared imaging of injected indocyanine green; and (3) effects on ZIA in the knee via longitudinal ultrasound, micro-computed tomography, and histology.
RESULTS: Multimodal microscopy discovered the presence of peri-PLV spindle-shaped cells with elongated cytoplasmic extensions physically integrated into mast cells. Gene expression studies confirmed these cells are consistent with telocytes, and WMIFM demonstrated peri-PLV tdT+ telocyte networks extending from capillaries in the ankle synovium to cLV near the knee. In vivo telocyte depletion decreased lymphatic drainage and exacerbated synovitis and focal erosions in ZIA.
CONCLUSION: Telocyte networks extend from the synovium into mast cells proximal to joint-draining cLVs, and telocyte loss is associated with synovial lymphatic system (SLS) defects and exacerbated joint pathology from inflammatory-erosive arthritis. Thus, SLS telocytes are a novel drug target for RA, and interventions that maintain telocytes (eg, exercise) may improve lymphatic function.
METHODS: We crossed novel Efhd1-CreERT2 and Myoc-CreERT2 mice to Ai9 tdTomato (tdT) reporter mice to assess tamoxifen-induced transgene expression via single-cell RNA sequencing, whole-mount immunofluorescent microscopy (WMIFM), and immunohistochemistry. We applied electron and confocal microscopy of popliteal lymphatic vessels (PLVs) to examine α smooth muscle actin positive lymphatic muscle cells, mast cell tryptase-positive mast cells, and CD31-/CD34+ cells. We crossed Efhd1-CreERT2 and Myoc-CreERT2 mice to diphtheria toxin-alphafloxed mice to examine: (1) tamoxifen-induced targeted cell deletion; (2) lymphatic function via near-infrared imaging of injected indocyanine green; and (3) effects on ZIA in the knee via longitudinal ultrasound, micro-computed tomography, and histology.
RESULTS: Multimodal microscopy discovered the presence of peri-PLV spindle-shaped cells with elongated cytoplasmic extensions physically integrated into mast cells. Gene expression studies confirmed these cells are consistent with telocytes, and WMIFM demonstrated peri-PLV tdT+ telocyte networks extending from capillaries in the ankle synovium to cLV near the knee. In vivo telocyte depletion decreased lymphatic drainage and exacerbated synovitis and focal erosions in ZIA.
CONCLUSION: Telocyte networks extend from the synovium into mast cells proximal to joint-draining cLVs, and telocyte loss is associated with synovial lymphatic system (SLS) defects and exacerbated joint pathology from inflammatory-erosive arthritis. Thus, SLS telocytes are a novel drug target for RA, and interventions that maintain telocytes (eg, exercise) may improve lymphatic function.