Umbilical Mesenchymal Stem Cell-Derived Exosome-Encapsulated Hydrogels Accelerate Bone Repair by Enhancing Angiogenesis

Abstract

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 (^uMSCEXOs) 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 ^uMSCEXOs/Gel/nHP composites markedly enhanced bone regeneration <i>in vivo</i>, and the ^uMSCEXOs might play a key role in this process. Moreover, the <i>in vitro</i> results demonstrated that ^uMSCEXOs 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.