Descripción del proyecto
Una terapia de regeneración ósea más simple y eficaz
Las células madre mesenquimales (CMM) son células madre multipotentes capaces de diferenciarse en múltiples tipos de células, incluidos los osteoblastos y los osteocitos. A lo largo de las dos últimas décadas, la terapia con CMM se ha utilizado clínicamente para potenciar la curación y la regeneración ósea. Sin embargo, su eficacia depende de muchos factores. Además, las CMM de la médula ósea se extraen de la médula ósea de un donante, lo cual suma incomodidad y complejidad al proceso. El proyecto financiado con fondos europeos EVEREST intenta eliminar la necesidad de emplear estas células recurriendo directamente a la fuente de su actividad: las CMM secretan vesículas extracelulares (VE) repletas de carga bioactiva. Los científicos se centran en dilucidar qué componente de las VE es fundamental para la regeneración ósea y en aprovecharlo para la terapia dirigida de VE sin células.
Objetivo
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.
Ámbito científico
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesmedical biotechnologycells technologiesstem cells
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
H91 Galway
Irlanda