Project description
Simpler and more effective bone regeneration therapy
Mesenchymal stem cells (MSCs) are multipotent stem cells capable of differentiating into multiple cell types including osteoblasts and osteocytes. Over the past couple of decades, MSC therapy has been used clinically to promote bone healing and regeneration. However, its efficacy depends on numerous factors. Moreover, BMSCs are harvested from donors' bone marrow, adding discomfort and complexity to the process. The EU-funded EVEREST project is seeking to eliminate the need for the cells themselves by getting straight to the source of their activity. MSCs secrete extracellular vesicles (EVs) loaded with bioactive cargo. Scientists are focusing on elucidating which EV component is critical to bone regeneration and harnessing it for cell-free targeted EV therapy.
Objective
The therapeutic benefits of mesenchymal stem cells (MSCs), the state-of-the-art treatment for healing bone defects following trauma, resection of cancerous bone tumors, or metabolic bone diseases, has been attributed to their secreted factors. The regenerative potential of MSC-secreted extracellular vesicles (EVs), nanoparticles which deliver bioactive cargo (nucleic acids, proteins, and lipids) between cells, has recently been reported. The applicant will embark upon frontier research with the objective of progressing beyond the state-of-the-art, by harnessing the therapeutic effects of MSCs, but in a cutting-edge, cell-free manner, by developing high potency EV-based bone replacements. This objective will be addressed by firstly testing novel hypotheses to delineate how culture environments, specifically mechanical cues (substrate elasticity and 3D dynamic), hypoxia, and cell stress can modulate the cargo of EVs secreted by MSC. Size exclusion chromatography, which separates EVs from soluble proteins will be employed. Heterogeneity of EV cargo and functionality between human MSC donors will also be evaluated. Answering these hypotheses will permit the intelligent design of targeted EV therapies. The hypothesis that EV-functionalized constructs, fabricated by 3D-printing, will lead to controlled and sustained release of EVs and induce bone formation in vivo will best tested. Together, this will answer critical questions, namely the most favorable environment for collection of potent EVs for regenerative medicine, which secretome component (EV, soluble factors) is responsible for bone regeneration, and whether MSC cell therapy can be replaced by cell-free EVs. EVEREST will develop a platform for targeted EV delivery in ground-breaking, easy to transport and handle, ‘off-the-shelf’ anatomically correct constructs, which have the potential to reduce pain by elimination of bone or bone marrow harvest, and revolutionize the treatment of bone defects.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesmedical biotechnologycells technologiesstem cells
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
H91 Galway
Ireland