Defining the transciptional and extracellular matrix landscapes of developing human tendons

Tendon diseases affect millions of people worldwide, leading to a significant socioeconomic burden and a healthcare challenge. The spectrum of aetiologies from injuries to age-related degeneration means that people of all ages can become vulnerable to tendinopathies. While non-surgical interventions are available, they are limited in scope and tend to mostly focus on symptomatic relief and restoration of functionality. Many patients do not benefit from conservative treatment and elect to undergo surgery with widely varying but generally high failure rates. In order to reduce surgery failure rates, novel biomaterials are being developed with the potential to provide structural support as well as a biologically active niche conducive to tendon regeneration. However, selection of candidate biomaterial strategies has been severely hampered by a paucity of research into the cellular biology defining healthy and diseased, or developing and aging tendons. To address this problem, a multi-disciplinary 'Tendon Seed Network' has recently been established within the Human Cell Atlas (HCA) initiative to undertake single-cell sequencing on healthy adult tendons. My project aims to complement this initiative with an open source, detailed and unbiased dataset of the cellular populations within diseased and developing tendons to ultimately provide critical metrics for informing the design of biomaterials capable of guiding diseased tissue repair towards a normal phenotype. Specifically, I will first extend the HCA of healthy tendons by characterising diseased tendons at single-cell and metabolomic resolutions to identify disease-specific transcriptomic signatures. Next, I will generate a spatial single-cell resolution map of gene expression in embryonic and adolescent healthy human tendons and compare it with the adult map to gain insight into the cellular mechanisms controlling the differentiation of tendon cells. Finally, once the diseased and developing tendon blueprints are established, I will develop and screen a biomaterial library for material candidates that induce diseased tendon cells to express gene modules representative of healthy or developing tendons and indicative of healing. This work will greatly enhance our understanding of tendon disease and contribute to the development of more effective therapies.