Tenocyte-mediated extracellular matrix remodeling mechanisms important to intrinsic tendon matrix repair
Embargo Date
2027-05-28
OA Version
Citation
Abstract
Tendon is susceptible to mechanical damage, as a single overloading event stretching the tendon past its yield point can induce microdamage to the extracellular matrix (ECM). While it is generally accepted that tendon healing following widespread extracellular matrix trauma is limited, tenocytes are thought to have the capacity to repair small amounts of microdamage generated through activities of daily living to maintain the mechanobiological function of the tendon. A compromised ability of tenocytes to maintain and repair the extracellular matrix, either through aging, overuse, or other disease, results in the gradual accumulation of matrix microdamage and eventually to chronic degeneration. Despite this, few studies have directly studied the mechanisms governing the process of microdamage repair. Therefore, the overall goal of this thesis was to develop a novel system to study the microdamage repair process in real-time and to identify the key cellular mechanisms of matrix remodeling important to this process. To achieve this, I took advantage of the regenerative MRL/MpJ mouse model, which is known to be able to fully regenerate the tendon tissue following acute injury through a response innate to the tendon. I used this understanding to explore if the regenerative capacity translates to an enhanced capacity for matrix remodeling in MRL/MpJ mouse tendons, with hopes to identify cellular mechanisms that may be important to more robust matrix repair (Aim 1). To understand the local repair capacity, I built a custom laser ablation bioreactor system to induce localized microdamage to a tendon explant and study the repair response in real time ex vivo (Aim 2). Finally, by using the laser ablation bioreactor system to induce localized microdamage to MRL/MpJ tendon explants, I demonstrated that MRL/MpJ regenerative tendon repair is likely dependent on improved cell-mediated extracellular matrix repair mechanisms (Aim 3). Specifically, tissue clearance following injury is critically dependent on proteolytic activity, including roles for both serine proteases and matrix metalloproteinases and is modulated by the number and activity of resident tendon cells. Importantly, a faster rate of clearance leads to more effective closure of the injury site, and proteoglycan turnover plays a distinct role in supporting superior matrix deposition during tissue repair. Altogether, the studies in this thesis provide a comprehensive framework for understanding how intrinsic tenocyte-mediated mechanisms regulate extracellular matrix remodeling and repair. These insights not only deepen our knowledge of tendon biology but also establish a foundation for future work targeting cell-specific pathways to enhance tissue regeneration and functional recovery following injury, disease, or age-related degeneration.
Description
2026
License
Attribution-NonCommercial-NoDerivatives 4.0 International