Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion
Abstract Background As important players in cell-to-cell communication, exosomes (exo) are believed to play a similar role in promoting fracture healing. This study investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exos) could improve fracture healing of nonunion....
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| Format: | Article |
| Language: | English |
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BMC
2020-01-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-020-1562-9 |
| _version_ | 1818934345692348416 |
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| author | Lu Zhang Guangjun Jiao Shanwu Ren Xiaoqian Zhang Ci Li Wenliang Wu Hongliang Wang Haichun Liu Hongming Zhou Yunzhen Chen |
| author_facet | Lu Zhang Guangjun Jiao Shanwu Ren Xiaoqian Zhang Ci Li Wenliang Wu Hongliang Wang Haichun Liu Hongming Zhou Yunzhen Chen |
| author_sort | Lu Zhang |
| collection | DOAJ |
| description | Abstract Background As important players in cell-to-cell communication, exosomes (exo) are believed to play a similar role in promoting fracture healing. This study investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exos) could improve fracture healing of nonunion. Methods BMMSC-Exos were isolated and transplanted into the fracture site in a rat model of femoral nonunion (Exo group) every week. Moreover, equal volumes of phosphate-buffered saline (PBS) and exosome-depleted conditioned medium (CM-Exo) were injected into the femoral fracture sites of the rats in the control and CM-Exo groups. Bone healing processes were recorded and evaluated by radiographic methods on weeks 8, 14 and 20 after surgery. Osteogenesis and angiogenesis at the fracture sites were evaluated by radiographic and histological methods on postoperative week 20. The expression levels of osteogenesis- or angiogenesis-related genes were evaluated in vitro by western blotting and immunohistochemistry. The ability to internalize exosomes was assessed using the PKH26 assay. Altered proliferation and migration of human umbilical vein endothelial cells (HUVECs) and mouse embryo osteoblast precursor cells (MC3TE-E1s) treated with BMMSC-Exos were determined by utilizing EdU incorporation, immunofluorescence staining, and scratch wound assay. The angiogenesis ability of HUVECs was evaluated through tube formation assays. Finally, to explore the effect of exosomes in osteogenesis via the BMP-2/Smad1/RUNX2 signalling pathway, the BMP-2 inhibitors noggin and LDN193189 were utilized, and their subsequent effects were observed. Results BMMSC-Exos were observed to be spherical with a diameter of approximately 122 nm. CD9, CD63 and CD81 were expressed. Transplantation of BMMSC-Exos obviously enhanced osteogenesis, angiogenesis and bone healing processes in a rat model of femoral nonunion. BMMSC-Exos were taken up by HUVECs and MC3T3-E1 in vitro, and their proliferation and migration were also improved. Finally, experiments with BMP2 inhibitors confirmed that the BMP-2/Smad1/RUNX2 signalling pathway played an important role in the pro-osteogenesis induced by BMMSC-Exos and enhanced fracture healing of nonunion. Conclusions Our findings suggest that transplantation of BMMSC-Exos exerts a critical effect on the treatment of nonunion by promoting osteogenesis and angiogenesis. This promoting effect might be ascribed to the activation of the BMP-2/Smad1/RUNX2 and the HIF-1α/VEGF signalling pathways. |
| first_indexed | 2024-12-20T05:02:48Z |
| format | Article |
| id | doaj.art-22f145b804084e539415122ccf9665c0 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-20T05:02:48Z |
| publishDate | 2020-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-22f145b804084e539415122ccf9665c02022-12-21T19:52:29ZengBMCStem Cell Research & Therapy1757-65122020-01-0111111510.1186/s13287-020-1562-9Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunionLu Zhang0Guangjun Jiao1Shanwu Ren2Xiaoqian Zhang3Ci Li4Wenliang Wu5Hongliang Wang6Haichun Liu7Hongming Zhou8Yunzhen Chen9Department of Spine Surgery, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalDepartment of Radiology, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalDepartment of Spine Surgery, Shandong University Qilu HospitalAbstract Background As important players in cell-to-cell communication, exosomes (exo) are believed to play a similar role in promoting fracture healing. This study investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSC-Exos) could improve fracture healing of nonunion. Methods BMMSC-Exos were isolated and transplanted into the fracture site in a rat model of femoral nonunion (Exo group) every week. Moreover, equal volumes of phosphate-buffered saline (PBS) and exosome-depleted conditioned medium (CM-Exo) were injected into the femoral fracture sites of the rats in the control and CM-Exo groups. Bone healing processes were recorded and evaluated by radiographic methods on weeks 8, 14 and 20 after surgery. Osteogenesis and angiogenesis at the fracture sites were evaluated by radiographic and histological methods on postoperative week 20. The expression levels of osteogenesis- or angiogenesis-related genes were evaluated in vitro by western blotting and immunohistochemistry. The ability to internalize exosomes was assessed using the PKH26 assay. Altered proliferation and migration of human umbilical vein endothelial cells (HUVECs) and mouse embryo osteoblast precursor cells (MC3TE-E1s) treated with BMMSC-Exos were determined by utilizing EdU incorporation, immunofluorescence staining, and scratch wound assay. The angiogenesis ability of HUVECs was evaluated through tube formation assays. Finally, to explore the effect of exosomes in osteogenesis via the BMP-2/Smad1/RUNX2 signalling pathway, the BMP-2 inhibitors noggin and LDN193189 were utilized, and their subsequent effects were observed. Results BMMSC-Exos were observed to be spherical with a diameter of approximately 122 nm. CD9, CD63 and CD81 were expressed. Transplantation of BMMSC-Exos obviously enhanced osteogenesis, angiogenesis and bone healing processes in a rat model of femoral nonunion. BMMSC-Exos were taken up by HUVECs and MC3T3-E1 in vitro, and their proliferation and migration were also improved. Finally, experiments with BMP2 inhibitors confirmed that the BMP-2/Smad1/RUNX2 signalling pathway played an important role in the pro-osteogenesis induced by BMMSC-Exos and enhanced fracture healing of nonunion. Conclusions Our findings suggest that transplantation of BMMSC-Exos exerts a critical effect on the treatment of nonunion by promoting osteogenesis and angiogenesis. This promoting effect might be ascribed to the activation of the BMP-2/Smad1/RUNX2 and the HIF-1α/VEGF signalling pathways.https://doi.org/10.1186/s13287-020-1562-9ExosomesNonunionOsteogenesisAngiogenesis |
| spellingShingle | Lu Zhang Guangjun Jiao Shanwu Ren Xiaoqian Zhang Ci Li Wenliang Wu Hongliang Wang Haichun Liu Hongming Zhou Yunzhen Chen Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion Stem Cell Research & Therapy Exosomes Nonunion Osteogenesis Angiogenesis |
| title | Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion |
| title_full | Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion |
| title_fullStr | Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion |
| title_full_unstemmed | Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion |
| title_short | Exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion |
| title_sort | exosomes from bone marrow mesenchymal stem cells enhance fracture healing through the promotion of osteogenesis and angiogenesis in a rat model of nonunion |
| topic | Exosomes Nonunion Osteogenesis Angiogenesis |
| url | https://doi.org/10.1186/s13287-020-1562-9 |
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