Mesenchymal stem cell priming to improve the therapeutic potential of extracellular vesicles for intervertebral disc regeneration

• Applicant: Dr. Graciosa Quelhas Teixeira
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 534998372

Back pain is a leading cause of disability worldwide and it is primarily considered to be triggered by intervertebral disc (IVD) degeneration (IVDD). Current treatments may improve pain and mobility, but carry high costs and fail to address IVD repair or regeneration. As no effective therapeutic approach has been proposed to restore inflamed and degenerated IVDs, there is the urgent need to clarify the key pathomechanism of IVDD, the involvement of inflammation, particularly complement activation in matrix catabolism, and how to target them towards tissue repair/regeneration. Mesenchymal stem cell (MSC)-based therapies have become the focus of several regenerative IVD studies. Although patients in clinical trials reported less pain after cell therapy, the long-term success of cell engraftment is unclear due to the hostile IVD environment. In the preliminary work of this proposal, we showed that MSC’s mechanism-of-action is mostly dependent on the secreted soluble factors. Moreover, priming of MSC with interleukin (IL)-1β modulates the secretome content, improving its anti-inflammatory and regenerative effect on IVDD organ culture models. Our further results indicate that the extracellular vesicles (EV)-rich fraction of the primed MSC secretome modulates human IVD cells towards a healthy IVD phenotype in vitro. However, the mechanisms mediating the beneficial effects of EV in tissue homeostasis and regeneration are not yet fully understood. Therefore, the main aim of the proposed project is to identify signaling pathways involved in the mechanism of action of EV, particularly with regard to immunomodulation and matrix metabolism. For IVDD therapeutics, we hypothesize that EV secreted by IL-1β-primed MSC present beneficial effects that impair IVD matrix degradation and/or improve matrix formation and the mechanical properties of the degenerated IVD. By targeting the complement activation and inflammatory processes in IVDD, the remaining viable cells in the disc will be able to re-establish the balance between anabolism and catabolism via reduced inflammatory response and production of tissue inhibitors of metalloproteinases 1 and 2. The proposed project combines expertise in protein characterization, MSCs and IVD biology. The results are clinically relevant especially because they will provide scientific basis for cell-free, off-the-shelf therapeutic approaches for minimally invasive administration. For this purpose, EV will be used to modulate the pro-regenerative response of native cells.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Dr. Makarand Risbud