Defining the transcriptional landscapes of human developing and aged tendons: insights into the signalling pathways and cellular contributions to regenerative tendon formation

Thesis

Tendon diseases present a significant global health challenge, affecting individuals of all ages and leading to substantial socioeconomic impacts, often necessitating surgical interventions with high failure rates. While tendons can regenerate without scarring during development, this ability diminishes with age, increasing susceptibility to injuries and impairing healing. Understanding the mechanisms underlying tendon regeneration and its decline is essential for developing treatments that enhance tendon repair. This thesis advances this understanding by identifying and describing the transcriptomes at the single-cell level in both regenerative, developing tendons and non-regenerative, aged tendons. Using single-nucleus and spatial RNA-sequencing techniques, it identifies 14 distinct cell types within foetal Achilles and quadriceps tendons, including diverse fibroblast populations essential for extracellular matrix (ECM) synthesis and organisation, support of attachment sites, and tissue remodelling. Analysis of tendon development from embryonic to foetal stages reveals 7 states of embryonic progenitors contributing to the formation of tendon main body fibroblasts, loose connective tissue fibroblasts, and chondrocytes, with lineage trajectories mapped into foetal stages. Comparative histological and transcriptomic analyses between developing and adult tendons highlight structural and molecular differences, including variations in cellular densities and compositions, morphologies, and ECM organisation. Notably, adult tendons exhibit a complex immune cell repertoire and distinct fibroblast populations focused on maintaining homeostasis. Furthermore, fibroblasts in ruptured aged tendons display a limited reactivation of developmental programs associated with repair. These findings provide insights into the cellular mechanisms underpinning tendon development, ageing, and repair, identifying key cell types and their functions. This work lays a foundation for future research aimed at validating these findings and translating them into clinical applications to enhance tendon repair and improve patient outcomes.

Authors: Kurjan, A

• DOI: 10.5287/ora-mvnnva1zj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: adult tendon; musculoskeletal development; spatial RNA-sequencing; single-cell RNA-sequencing; tendon fibroblasts; embryonic tendon; single-nucleus RNA-sequencing; tendon atlas; tendon transcriptomics; human tendon; tendon; foetal tendon; tendon histology; tendon development
• Subjects: musculoskeletal development; musculoskeletal biology; spatial RNA-sequencing; tendon development; single-cell RNA-sequencing; transcriptomics; quadriceps tendon; Achilles tendon; single-nucleus RNA-sequencing