Regenerative messages from young disc cells: Exploring the cues hidden in notochordal cell-derived extracellular vesicles

Abstract

Low back pain is a common health problem in both people and dogs. While the pain is often brief, it can lead to chronic pain that impacts the daily life of patients. A common cause of chronic back pain is intervertebral disc degeneration. A young, healthy disc is resilient, allowing it to withstand spinal forces easily. However, as the disc ages, it becomes less resilient, and its composition changes, which can lead to disc degeneration. In a degenerating disc, a pro-inflammatory environment and disc bulging can irritate nearby nerves and lead to back pain. Despite its prevalence, current standard-of-care treatments often do not fully resolve the pain long-term as they do not address the underlying degeneration process. Therefore, recent research focuses on regenerative therapies that repair the degenerated disc. A promising approach involves extracellular vesicles (EVs). EVs are secreted by all types of cells and carry biological messages between cells. The EVs secreted by juvenile disc cells (notochordal cells, NCs) are particularly interesting as they may carry key regenerative messages. This thesis presents an explorative investigation into the potential of NC-EVs as a future therapy. We developed and validated a methodology for characterizing EVs with broader applicability in other regenerative medicine fields. Furthermore, we discovered that EVs from NCs carry many proteins linked to inflammation. By using deteriorated disc cells and tissues from two species that suffer from disc-related back pain, dogs and humans, we explored the therapeutic potential of NC-EVs. We demonstrated that they subtly reduce inflammatory mediators. Overall, these findings improve our understanding of how NC-EVs function and offer a stepping stone for a better translation of such therapies to the clinic.