Exosomal Mir-21 Derived from Umbilical Cord Mesenchymal Stem Cells Promotes Angiogenesis by Activating SPRY1/PI3K/AKT Pathway and Contributes New Bone Formation in a Rat Model.

Abstract Background: Delayed atrophic healing and non-union remain the most difficult types of complications to treat and can lead to numerous re-operations and high socioeconomic cost. Exosome derived from MSCs is a promising strategy in the treatment of fracture. However, it’s still not fully clear in the underlying mechanisms. Methods: In this study, we first elucidated the underlying mechanism of umbilical cord MSC (uMSC)-Exo-induced angiogenesis in bone regeneration and fracture repair. RT-PCR, luciferase reporter, western blot and immunofluorescence in situ hybridization assay were performed to identify the expression of related genes and pathways in uMSC-Exo. Proliferation, tube formation and transwell migration assay were used to evaluated the effects of uMSC-Exo in vitro. A rat calvarial defect model was used to evaluated the effects of uMSC-Exo in vivo.Results: We found that, miR-21 was the most abundant miRNA in the uMSC-Exos. In vivo and in vitro experiments demonstrated that, the uMSC-Exo could promote the migration, angiogenic and capacity of HUVECs via miR-21, inhibition of miR-21 could attenuate the effects of uMSC-Exos. For mechanical study, we found that, exosomal miR-21 derived from uMSCs activates PI3K/AKT signalling by targeting SPRY1 in HUVECs, SPRY1 knockdown could promote the PI3K/AKT activation and HUVEC proliferation, migration and angiogenesis. In addition, exosomal miR-21 derived from uMSCs enhanced local microvascular network formation and bone regeneration in vivo. ConclusionIn: In conclusion, we firstly reported that uMSC-derived exosomes as a ready-made regenerative medicine therapy to bone healing.