Cellular and molecular landscapes of human tendons across the lifespan revealed by spatial and single-cell...

Tendon injuries are common and heal poorly, whereas developing tendons repair with minimal scarring; how this capacity declines with age remains poorly understood. Here, we combine histology, single-nucleus, single-cell, and spatial transcriptomic profiling of human Achilles and quadriceps tendons across embryonic, fetal, and adult stages, including ruptured adult tendons. We identify seven embryonic progenitor states that are predicted to contribute to three tendon-associated lineages-fibrillar, connective tissue, and chondrogenic-which diversify over development, occupy discrete spatial niches, and appear to acquire specialized roles in matrix synthesis, remodeling, and mechanical adaptation. While non-fibroblast populations remain transcriptionally stable with age, fibroblasts undergo marked reprogramming, shifting to homeostatic or injury-responsive states. In ruptured adult tendons, a subset of fibroblasts partially reactivates developmental programs yet remains transcriptionally distinct from developmental states that exhibit scarless healing. These findings define the cellular architecture of human tendon development and aging and reveal lineage-specific targets for therapeutic repair.