Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant
A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-a...
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KeAi Communications Co., Ltd.
2022-07-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X21005065 |
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| author | Ze Lin Yuan Xiong Weilin Meng Yiqiang Hu Lili Chen Lang Chen Hang Xue Adriana C. Panayi Wu Zhou Yun Sun Faqi Cao Guodong Liu Liangcong Hu Chenchen Yan Xudong Xie Chuanchuan Lin Kaiyong Cai Qian Feng Bobin Mi Guohui Liu |
| author_facet | Ze Lin Yuan Xiong Weilin Meng Yiqiang Hu Lili Chen Lang Chen Hang Xue Adriana C. Panayi Wu Zhou Yun Sun Faqi Cao Guodong Liu Liangcong Hu Chenchen Yan Xudong Xie Chuanchuan Lin Kaiyong Cai Qian Feng Bobin Mi Guohui Liu |
| author_sort | Ze Lin |
| collection | DOAJ |
| description | A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site. In the present study, we achieved an enriched concentration of PD-L1 from exosomes (Exos) of a genetically engineered Human Umbilical Vein Endothelial Cell (HUVECs), and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface, suppressing the activation of T cells. Furthermore, exosomal PD-L1 induced Mesenchymal Stem Cells (MSCs) towards osteogenic differentiation when pre-cultured with T cells. Moreover, embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner. Additionally, exosomal PD-L1, embedded in a hydrogel, markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase. Importantly, our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites, while T cells in distant immune organs such as the spleen were not affected. In summary, this study provides the first example of using PD-L1-enriched Exos for bone fracture repair, and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects. |
| first_indexed | 2024-04-24T08:43:37Z |
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| language | English |
| last_indexed | 2024-04-24T08:43:37Z |
| publishDate | 2022-07-01 |
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| series | Bioactive Materials |
| spelling | doaj.art-c8f730caba8a4a5abbd86e75f40674062024-04-16T14:37:44ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2022-07-0113300311Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressantZe Lin0Yuan Xiong1Weilin Meng2Yiqiang Hu3Lili Chen4Lang Chen5Hang Xue6Adriana C. Panayi7Wu Zhou8Yun Sun9Faqi Cao10Guodong Liu11Liangcong Hu12Chenchen Yan13Xudong Xie14Chuanchuan Lin15Kaiyong Cai16Qian Feng17Bobin Mi18Guohui Liu19Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China; Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaDivision of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02152, USADepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaDepartment of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaMedical Center of Trauma and War Injuries, Daping Hospital, Army Medical University, Chongqing, 400042, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaDepartment of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, ChinaKey Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China; Corresponding author. College of Bioengineering Chongqing University, Chongqing, 400044, China.Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China; Corresponding author. Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China; Corresponding author. Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.A moderate inflammatory response at the early stages of fracture healing is necessary for callus formation. Over-active and continuous inflammation, however, impairs fracture healing and leads to excessive tissue damage. Adequate fracture healing could be promoted through suppression of local over-active immune cells in the fracture site. In the present study, we achieved an enriched concentration of PD-L1 from exosomes (Exos) of a genetically engineered Human Umbilical Vein Endothelial Cell (HUVECs), and demonstrated that exosomes overexpressing PD-L1 specifically bind to PD-1 on the T cell surface, suppressing the activation of T cells. Furthermore, exosomal PD-L1 induced Mesenchymal Stem Cells (MSCs) towards osteogenic differentiation when pre-cultured with T cells. Moreover, embedding of Exos into an injectable hydrogel allowed Exos delivery to the surrounding microenvironment in a time-released manner. Additionally, exosomal PD-L1, embedded in a hydrogel, markedly promoted callus formation and fracture healing in a murine model at the early over-active inflammation phase. Importantly, our results suggested that activation of T cells in the peripheral lymphatic tissues was inhibited after local administration of PD-L1-enriched Exos to the fracture sites, while T cells in distant immune organs such as the spleen were not affected. In summary, this study provides the first example of using PD-L1-enriched Exos for bone fracture repair, and highlights the potential of Hydrogel@Exos systems for bone fracture therapy through immune inhibitory effects.http://www.sciencedirect.com/science/article/pii/S2452199X21005065PD-L1ExosomeFracture healingHydrogelImmunotherapy |
| spellingShingle | Ze Lin Yuan Xiong Weilin Meng Yiqiang Hu Lili Chen Lang Chen Hang Xue Adriana C. Panayi Wu Zhou Yun Sun Faqi Cao Guodong Liu Liangcong Hu Chenchen Yan Xudong Xie Chuanchuan Lin Kaiyong Cai Qian Feng Bobin Mi Guohui Liu Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant Bioactive Materials PD-L1 Exosome Fracture healing Hydrogel Immunotherapy |
| title | Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant |
| title_full | Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant |
| title_fullStr | Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant |
| title_full_unstemmed | Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant |
| title_short | Exosomal PD-L1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant |
| title_sort | exosomal pd l1 induces osteogenic differentiation and promotes fracture healing by acting as an immunosuppressant |
| topic | PD-L1 Exosome Fracture healing Hydrogel Immunotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X21005065 |
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