Projektbeschreibung
Einfachere und wirkungsvollere Knochenregenerationstherapie
Mesenchymale Stammzellen sind multipotente Stammzellen, die sich in mehrere Zelltypen, auch Osteoblasten und Osteozyten, ausdifferenzieren können. In den letzten Jahrzehnten wurde die mesenchymale Stammzelltherapie klinisch eingesetzt, um Knochenheilung und -regeneration zu fördern. Ihre Wirksamkeit hängt jedoch von zahlreichen Faktoren ab. Außerdem werden mesenchymale Stammzellen aus Spenderknochenmark gewonnen, was den Prozess unangenehm und kompliziert werden lässt. Das EU-finanzierte Projekt EVEREST versucht, die Zellen selbst überflüssig werden zu lassen, indem es direkt zur Quelle ihrer Aktivität vordringt. Mesenchymale Stammzellen sondern extrazelluläre Vesikel ab, die mit bioaktiver Fracht beladen sind. Das Forschungsteam konzentriert sich im Kern darauf, welche Komponente der extrazellulären Vesikel für die Knochenregeneration entscheidend ist, und möchte klären, wie sie für eine zellfreie, gezielte Therapie mit extrazellulären Vesikeln nutzbar ist.
Ziel
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.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acids
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencescell biology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesmedical biotechnologycells technologiesstem cells
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
H91 Galway
Irland