Lymphatic-stem cell crosstalk promotes tendon regeneration via Notch1-Srebp2-mediated cholesterol metabolism

Tendons, as bradytrophic tissues, exhibit limited healing capacity. The role of lymphatic vessels in tendon regeneration is largely overlooked. By comparing gene expression of the control and injured tendon cells from both neonatal and adult mice, we identify lymphatic vessels as key regenerative niche elements. Using the Transparent Embedding Solvent System for clearing in Prox1-Cre^ERT2; tdTomato mice, we find that lymphatic signaling was activated following tendon injury, directing the fate of distinct tendon stem/progenitor cell (TSPC) subsets. Mechanistically, the glycoprotein Reelin secreted from lymphatic endothelial cells (LECs) triggers VLDLR-dependent phosphorylation of DAB1 in TSPCs. Activated DAB1 binds to NOTCH1 at the tyrosine Y-200 residue, initiating Srebp2-mediated cholesterol metabolism. Functionally, Reln^-/- mice and Prox1-Cre^ERT2; Reln^fl/fl mice exhibit impaired tendon regeneration, underscoring the critical role of Reelin signaling. Furthermore, a slow-release Reelin delivery system established using mesoporous silica nanoparticles enhance tendon regeneration in mice and rabbits. These findings highlight the key role of lymphoangiocrine signaling in determining TSPC fate during tendon regeneration. Overall, this study provides a foundation for promoting tissue regeneration by targeting lymphatic signals.