Coupling Inflammatory Resolution to Osteogenesis: Lymphatic Vessels as Stage-specific Niche Regulators in Skeletal Healing

Skeletal healing requires the coordinated resolution of inflammation and precise lineage commitment of mesenchymal progenitors, yet the mechanisms coupling these processes remain incompletely elucidated. Here, we reveal that lymphatic vessels in bone serve as dynamic orchestrators bridging inflammatory clearance with stromal fate determination during regeneration. Using lineage tracing in Lyve1-creERT2; tdTomato mice combined with genetic ablation strategies, we demonstrate that injury-induced lymphangiogenesis is essential for timely osteogenesis. Pre-depletion of lymphatic endothelial cells (LECs) exacerbates post-injury inflammation and impairs bone regeneration. Notably, we identify Lyve1high macrophages as lymphatic endothelial -like cells capable of transdifferentiation following efferocytosis. Mechanistically, engulfment of apoptotic cells activates fatty acid b-oxidation, leading to increased acetyl-CoA level that drive histone acetylation at the Lyve1 and Vegfc promoters, thereby licensing the macrophage-to-LECs transition. During the remodeling phase, lymphatic vessels contribute to maintaining local lipid homeostasis. Impaired lymphatic function during bone repair results in the accumulation of polyunsaturated fatty acid-containing phosphatidylethanolamines (PE-PUFAs), which stabilize PPARr via ZDHHC4-mediated palmitoylation. This process blocks ubiquitin-proteasome degradation and skews LepR+ bone mesenchymal stromal cells (BMSCs) toward adipogenesis at the expense of osteogenesis. Age-related lymphatic insufficiency recapitulates this pathological cascade, characterized by impaired lymphatic drainage, systemic lipid dysregulation, and compromised bone quality. Collectively, our findings establish lymphatic vessels, reconstructed by macrophage-to-LECs transdifferentiation, as stage-specific niche that guides osteogenic-adipogenic fate decision of BMSCs through lymphatic drainage capacity during skeletal repair.