Abstract
BackgroundThe regeneration of bone loss that occurs after periodontal diseases is a significant challenge in clinical dentistry. Extracellular vesicles (EVs)-based cell-free regenerative therapies represent a promising alternative for traditional treatments. Developmental biology suggests matrix vesicles (MVs), a subtype of EVs, contain mineralizing-related biomolecules and play an important role in osteogenesis. Thus, we explore the therapeutic benefits and expect to find an optimized strategy for MV application.MethodsHealthy human dental follicle cells (DFCs) were cultured with the osteogenic medium to generate MVs. Media MVs (MMVs) were isolated from culture supernatant, and collagenase-released MVs (CRMVs) were acquired from collagenase-digested cell suspension. We compared the biological features of the two MVs and investigated their induction of cell proliferation, migration, mineralization, and the modulation of osteogenic genes expression. Furthermore, we investigated the long-term regenerative capacity of MMVs and CRMVs in an alveolar bone defect rat model.ResultsWe found that both DFC-derived MMVs and CRMVs effectively improved the proliferation, migration, and osteogenic differentiation of DFCs. Notably, CRMVs showed better bone regeneration capabilities. Compared to MMVs, CRMVs-induced DFCs exhibited increased synthesis of osteogenic marker proteins including ALP, OCN, OPN, and MMP-2. In the treatment of murine alveolar bone defects, CRMV-loaded collagen scaffold brought more significant therapeutic outcomes with less unhealing areas and more mature bone tissues in comparison with MMVs and acquired the effects resembling DFCs-based treatment. Furthermore, the western blotting results demonstrated the activation of the PLC/PKC/MAPK pathway in CRMVs-induced DFCs, while this cascade was inhibited by MMVs.ConclusionsIn summary, our findings revealed a novel cell-free regenerative therapy for repairing alveolar bone defects by specific MV subtypes and suggest that PLC/PKC/MAPK pathways contribute to MVs-mediated alveolar bone regeneration.
Highlights
The regeneration of bone loss that occurs after periodontal diseases is a significant challenge in clinical dentistry
We evaluated the ability of the different subtypes of matrix vesicles (MVs) to induce cell osteogenic differentiation, modulate the expression of genes involved in bone formation processes in vitro and promote bone regeneration in vivo in rats subjected to alveolar bone defects
The transmembrane protein CD63 and the cytosolic protein TSG101 were enriched in collagenase-released MVs (CRMVs), while cytosolic protein HSP70 was abundant in Media MVs (MMVs)
Summary
The regeneration of bone loss that occurs after periodontal diseases is a significant challenge in clinical dentistry. Mesenchymal stem cells (MSCs)-based therapies exhibited curative effects [10], while the associated inflammatory responses and safety issues seem inevitable [11,12,13,14]. It is indicated the efficacy of MSCs relies on the paracrine course and the induction of extracellular vesicles (EVs) [15, 16]. The EVs-based treatment has been proposed as a feasible cell-free therapy to manage these clinical scenarios, with the goal of regenerating lost or damaged tissues to restore normal function and structure [14, 15, 17]. Utilizing cell-type-specific or tissue-specific EVs to restore damaged tissue might have intrinsic advantages and bring more therapeutic benefits
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