Lymphatic Vessels Orchestrate Immune And Lipid Homeostasis During Bone Regeneration

Lymphatic vessels play a pivotal role in fluid drainage and immune modulation; however, their precise function in alveolar bone regeneration remains unclear. Here, we investigate how lymphatic remodeling governs inflammation resolution, macrophage reprogramming, and mesenchymal stem cells (MSCs) fate during bone regeneration. By employing genetically engineered Lyve1-creERT2; tdTomato and Lyve1-creERT2; DTA mice, we established an alveolar bone injury model to track lymphatic vessel dynamics and functional consequences of lymphatic ablation. To investigate the mechanisms underlying lymphangiogenesis and its role in bone regeneration, we utilized LysM-creERT2; tdTomato, LepR-cre; tdTomato and Lyve1-creERT2; Sirt6f/f mice. Tissue clearing combined with high-resolution 3D imaging, single-cell RNA sequencing, and metabolic profiling were used to delineate cellular and molecular mechanisms. This research reveal that lymphatic vessels infiltrate the injury site early, interacting with macrophages to facilitate immune clearance. Furthermore, Lyve1+ macrophages undergo undergo metabolic and epigenetic reprogramming, transdifferentiating into endothelial cells to support lymphatic remodeling. Disruption of lymphatic function perturbs lipid metabolism and skews LepR+ MSCs differentiation towards adipogenesis, impairing bone regeneration, whereas promoting lymphatic remodeling in aged alveolar bone enhances lymphatic drainage and accelerates bone regeneration. Our findings identify lymphatic vessels as critical mediators of alveolar bone repair by integrating immune regulation and metabolic homeostasis. Lymphatic dysfunction accelerates lipid accumulation and delays bone healing, suggesting a mechanistic link between impaired lymphatic remodeling and age-related bone repair deficits. Targeting lymphangiogenesis may offer a promising therapeutic avenue to enhance alveolar bone regeneration in compromised conditions.