Mimicking developmental biology to regenerate the intervertebral disc

Abstract

Nearly three-quarters of the human population will be affected by low back pain at some stage in their lives. While this condition is multifactorial, intervertebral disc (IVD) degeneration is one of its major causes, involved in at least 40% of chronic (low) back pain cases. Like humans, also dogs suffer from spontaneous IVD degeneration with similar characteristics. As such, within the concept of One Health, regenerative medicine can benefit both patient populations. In this respect, the dog is considered to be a suitable model for its own species and for human IVD degeneration. As no effective therapies to retard or reverse IVD degeneration have yet been devised, there is huge interest in potential regenerative treatments for both human and veterinary patients. For this reason, new cell- and growth factor-based regenerative strategies for the treatment of human and canine IVD degeneration were investigated in this thesis. In this respect, the value of studying developmental biology was demonstrated, as interesting targets were identified, e.g. caveolin-1, parathyroid hormone related peptide (PTHrP) and indian hedgehog (IHH). Not all proposed agents appeared to exert a positive effect in vitro (mesenchymal stromal cells, Link-N), and promising in vitro results did not always translate to beneficial effects in vivo (bone morphogenetic protein 7; BMP7). However, notochordal cell-based therapies induced regenerative effects across both species susceptible for IVD disease. While identifying the bioactive factors secreted by notochordal cells (e.g. extracellular vesicles) is challenging, it is valuable from a fundamental perspective and will provide innovative insights for the improvement of regenerative treatment strategies. Nonetheless, a more straightforward and promising alternative for bench to (veterinary) bedside translation is the application of notochordal cell-derived matrix (NCM), which exerted regenerative effects on IVD cells and in dogs with IVD degeneration.