Regulatory T cell-exosomal miR-142-3p promotes angiogenesis and osteogenesis via TGFBR1/SMAD2 inhibition to accelerate fracture repair

Although the immune system is well recognized as a key player in fracture repair, the exact mechanisms, particularly the role of regulatory T-cells (Tregs), have not yet been established. Our increased understanding of the Tregs and exosomes involved in organ repair creates opportunity of application of Tregs derived Exosomes (TregD-Exos) in the modulation of fracture repair. In the present study, we report that TregD-Exos containing miR-142-3p can be shuttled into bone mesenchymal stem cells (BMSCs) and Human umbilical vein endothelial cells (HUVECs) promoting osteogenesis and angiogenesis. Overexpression of miR-142-3p remarkedly promoted BMSC osteoblastic differentiation, and enhanced HUVEC function, including proliferation, migration and angiogenesis. Furthermore, TGFBR1/SMAD2 was shown to be involved in the TregD-Exos' promotive effect on bone healing. Moreover, both TregD-Exos and miR-142-3p administration restored bone repair in vivo. Taken together, our results indicate that TregD-Exos containing miR-142-3p can be transferred to BMSCs and HUVECs with robust effects on osteogenesis and angiogenesis. These findings shed a new light for the use of Tregs in facilitating bone repair, suggesting that both TregD-Exos and miR-142-3p are promising effective therapeutic agents for bone remodeling.