The tendon interfascicular matrix: a mechanically unique tendon progenitor cell niche

Musculoskeletal injuries affect 1 million people and cost the economy £7 billion/year. One of the structures commonly affected is tendon, with tendinopathy affecting 6% of the population.

Healing is often insufficient, with the formation of functionally inferior fibrotic scar tissue leading to pain and chronic disability.

Treatments are ineffective as the cell populations responsible for maintaining tendon homeostasis and repairing injury remain ill-defined.

During my fellowship, I have identified the presence of a CD146+ resident tendon progenitor population, localised to the interfascicular matrix (IFM).

While it has been established that the IFM provides a unique, high shear environment, the factors maintaining the IFM progenitor niche remain undefined.

I have also demonstrated that IFM progenitors migrate to sites of injury, but their role in healing, and contribution to fibrosis, are yet to be established.

This proposal will therefore test the central hypothesis: tendon homeostasis and repair is coordinated by progenitors maintained by the mechanical environment provided by the interfascicular matrix niche, and that pharmacological interventions can modify tendon progenitor recruitment to diminish the fibrotic response to tendon injury and improve healing.

This hypothesis will be tested by addressing three aims: Aim 1: To fully establish the identity of the putative CD146+ tendon progenitor cell population. Aim 2: To examine whether mechanical cues function to maintain IFM cell phenotype.

Aim 3: To establish the effect of the anti-fibrotic, rapamycin on tendon progenitor recruitment and fibrotic response to injury.

Defining how endogenous progenitors behave in tendon injury and how their response is modified by rapamycin will provide a new appreciation of how their behaviour can be controlled to limit tendon pathology and aid regeneration.

Establishing the optimum mechanical conditions to stimulate repair will enable manipulation of tendon progenitors to improve healing, increasing our understanding of how tendinopathy develops and how to treat it.