Affiliation:
1. Department of Orthodontics Shanghai Stomatological Hospital and School of Stomatology Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai 200001 P. R. China
2. State Key Laboratory of Molecular Engineering of Polymers Department of Macromolecular Science Fudan University Shanghai 200438 P. R. China
3. Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan University Shanghai 200001 P. R. China
Abstract
AbstractExtracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have emerged as an appealing alternative to cell therapy in regenerative medicine. Unlike bone marrow MSCs (BMSCs) cultured in vitro with normoxia, bone marrow in vivo is exposed to a hypoxic environment. To date, it remains unclear whether hypoxia preconditioning can improve the function of BMSC‐derived EVs and be more conducive to bone repair. Herein, it is found that hypoxia preconditioned BMSCs secrete more biglycan (Bgn)‐rich EVs via proteomics analysis, and these hypoxic EVs (Hypo‐EVs) significantly promote osteoblast proliferation, migration, differentiation, and mineralization by activating the phosphatidylinositide 3‐kinase/protein kinase B pathway. Subsequently, an injectable bioactive hydrogel composed of poly(ethylene glycol)/polypeptide copolymers is developed to improve the stability and retention of Hypo‐EVs in vivo. The Hypo‐EVs‐laden hydrogel shows continuous liberation of Hypo‐EVs for 3 weeks and substantially accelerates bone regeneration in 5‐mm rat cranial defects. Finally, it is confirmed that Bgn in EVs is a pivotal protein regulating osteoblast differentiation and mineralization and exerts its effects through paracrine mechanisms. Therefore, this study shows that hypoxia stimulation is an effective approach to optimize the therapeutic effects of BMSC‐derived EVs and that injectable hydrogel‐based EVs delivery is a promising strategy for tissue regeneration.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Shanghai
Subject
Electrochemistry,Condensed Matter Physics,Biomaterials,Electronic, Optical and Magnetic Materials
Cited by
4 articles.
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