Description du projet
Une thérapie de régénération osseuse plus simple et plus efficace
Les cellules souches mésenchymateuses (CSM) sont des cellules souches multipotentes capables de se différencier en plusieurs types de cellules, dont les ostéoblastes et les ostéocytes. Au cours de ces vingt dernières années, la thérapie cellulaire par CSM a été utilisée en contexte clinique pour favoriser la guérison et la régénération osseuses. Son efficacité dépend toutefois de nombreux facteurs. De plus, les CSM de la moelle osseuse sont prélevées sur la moelle osseuse de donneurs, ce qui rajoute de l’inconfort et de la complexité au processus. Le projet EVEREST, financé par l’UE, recherche à éliminer le besoin en cellules en allant directement à la source de leur activité. Les CSM sécrètent des vésicules extracellulaires (VE) à charge bioactive. Les scientifiques concentrent leurs efforts sur l’élucidation du composant des VE qui s’avère fondamental à la régénération osseuse et sur son exploitation pour une thérapie ciblée par VE sans cellules.
Objectif
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.
Champ scientifique
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesmedical biotechnologycells technologiesstem cells
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
H91 Galway
Irlande