Department of Emergency and Trauma, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
Department of Orthopaedics, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
ACS Appl Mater Interfaces. 2021 Apr 28;13(16):18472-18487. doi: 10.1021/acsami.0c22671. Epub 2021 Apr 15.
Repair of large bone defects represents a major challenge for orthopedic surgeons. The newly formed microvessels inside grafts play a crucial role in successful bone tissue engineering. Previously, an active role for mesenchymal stem cell (MSC)-derived exosomes in blood vessel development and progression was suggested in the repair of multiple tissues. However, the reports on the application of MSC-derived exosomes in the repair of large bone defects are sparse. In this study, we encapsulated umbilical MSC-derived exosomes (EXOs) in hyaluronic acid hydrogel (HA-Gel) and combined them with customized nanohydroxyapatite/poly-ε-caprolactone (nHP) scaffolds to repair cranial defects in rats. Imaging and histological evaluation indicated that the EXOs/Gel/nHP composites markedly enhanced bone regeneration , and the EXOs might play a key role in this process. Moreover, the results demonstrated that EXOs promoted the proliferation, migration, and angiogenic differentiation of endothelial progenitor cells (EPCs) but did not significantly affect the osteogenic differentiation of BMSCs. Importantly, mechanistic studies revealed that exosomal miR-21 was the potential intercellular messenger that promoted angiogenesis by upregulating the NOTCH1/DLL4 pathway. In conclusion, our findings exhibit a promising exosome-based strategy in repairing large bone defects through enhanced angiogenesis, which potentially regulated by the miR-21/NOTCH1/DLL4 signaling axis.
修复大骨缺损是骨科医生面临的主要挑战。移植物内新形成的微血管在骨组织工程的成功中起着至关重要的作用。先前有研究表明，间充质干细胞（MSC）衍生的外泌体在多种组织的修复中，在血管生成和进展中发挥积极作用。然而，关于 MSC 衍生的外泌体在大骨缺损修复中的应用的报道很少。在本研究中，我们将脐带 MSC 衍生的外泌体（EXOs）包裹在透明质酸水凝胶（HA-Gel）中，并将其与定制的纳米羟基磷灰石/聚己内酯（nHP）支架结合，用于修复大鼠颅骨缺损。成像和组织学评估表明，EXOs/Gel/nHP 复合材料显著增强了骨再生，EXOs 可能在这个过程中发挥关键作用。此外，结果表明 EXOs 促进了内皮祖细胞（EPCs）的增殖、迁移和血管生成分化，但对 BMSCs 的成骨分化没有显著影响。重要的是，机制研究表明，外泌体 miR-21 是通过上调 NOTCH1/DLL4 通路促进血管生成的潜在细胞间信使。总之，我们的研究结果表明，通过增强血管生成来修复大骨缺损的外泌体策略具有广阔的应用前景，该策略可能受 miR-21/NOTCH1/DLL4 信号通路的调节。
