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Guerrero J, Maevskaia E, Pfister P, Dominguez AP, Ghayor C, Bhattacharya I, Scherberich A, Weber FE. Mineralized Osteoblast-Derived Exosomes and 3D-printed Ceramic-based Scaffolds for Enhanced Bone Healing: A Preclinical Exploration. Acta Biomater 2025:S1742-7061(25)00376-9. [PMID: 40409510 DOI: 10.1016/j.actbio.2025.05.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 04/25/2025] [Accepted: 05/21/2025] [Indexed: 05/25/2025]
Abstract
In regenerative medicine, addressing the complex challenge of bone tissue regeneration demands innovative strategies. Exosomes, nanoscale vesicles rich in bioactive molecules, have shown great promise in tissue repair. This study focuses on exosomes derived from mineralized osteoblasts (MOBs), which play a pivotal role in bone formation. We investigated the therapeutic potential of exosomes isolated from osteoblasts cultured in osteogenic medium for 21 days, delivered via 3D-printed gyroid scaffolds composed of hydroxyapatite (HA) and tricalcium phosphate (TCP). The exosomes were characterized through nanoparticle tracking analysis to determine size, morphology, and concentration, while proteomics revealed their cargo contents. In vitro, rabbit bone marrow mesenchymal stromal cells (rBMSCs) were cultured as monolayers and within ceramic scaffolds, where MOB-derived exosomes were shown to promote osteogenic differentiation. In vivo, their osteoconductive and bone augmentation capabilities were evaluated in two rabbit calvarial models, while the osteoinductive potential was further tested in a heterotopic mouse model. Neo-bone formation was assessed using µCT and histological analysis. Our findings demonstrated that MOB-derived exosomes upregulated bone-related gene expression and promoted mineralization in rBMSCs, even in the absence of osteogenic medium. Proteomics confirmed the presence of bone-associated proteins in these exosomes. In rabbit models, however, exosomes did not significantly enhance bone formation. In contrast, in the heterotopic mouse model, exosomes functionalized onto ceramic scaffolds exhibited strong osteoinductive activity. This study highlights the potential of MOB-derived exosomes to enhance 3D-printed ceramic scaffolds for bone regeneration, offering a promising avenue for bone healing without the need for additional growth factors or stem cells. STATEMENT OF SIGNIFICANCE: The here presented report of our project not only advances our understanding of the role of exosome-functionalized scaffolds in bone regeneration but also proposes a promising alternative to traditional growth factor- or cell-based approaches. We are confident that this study represents a novel and impactful contribution to the field.
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Affiliation(s)
- Julien Guerrero
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Zürich, Switzerland
| | - Ekaterina Maevskaia
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Zürich, Switzerland
| | - Pablo Pfister
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel, University of Basel, Basel, 4031, Switzerland
| | - Ana Pérez Dominguez
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Zürich, Switzerland
| | - Chafik Ghayor
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Zürich, Switzerland
| | - Indranil Bhattacharya
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Zürich, Switzerland
| | - Arnaud Scherberich
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University Hospital Basel, University of Basel, Basel, 4031, Switzerland
| | - Franz E Weber
- University of Zurich, Center of Dental Medicine, Oral Biotechnology & Bioengineering, Zürich, Switzerland; CABMM, Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland.
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Eshraghi N, Javidan A, Al-Saeidi NN, Makuku R, Mortezaei A, Mirghaderi P. Mesenchymal Stem Cell–Derived Exosome Efficacy and Safety in Musculoskeletal Tissues: State of The Art and Future Directions. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2025. [DOI: 10.1007/s40883-025-00414-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 03/25/2025] [Accepted: 04/05/2025] [Indexed: 06/04/2025]
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Le G, Wen R, Fang H, Huang Z, Wang Y, Luo H. Exosomal miR-122 derived from M2 macrophages induces osteogenic differentiation of bone marrow mesenchymal stem cells in the treatment of alcoholic osteonecrosis of the femoral head. J Orthop Surg Res 2025; 20:107. [PMID: 39881350 PMCID: PMC11776149 DOI: 10.1186/s13018-025-05515-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/17/2025] [Indexed: 01/31/2025] Open
Abstract
Alcoholic osteonecrosis of the femoral head (AIONFH) is caused by long-term heavy drinking, which leads to abnormal alcohol and lipid metabolism, resulting in femoral head tissue damage, and then pathological necrosis of femoral head tissue. If not treated in time in clinical practice, it will seriously affect the quality of life of patients and even require hip replacement to treat alcoholic femoral head necrosis. This study will confirm whether M2 macrophage exosome (M2-Exo) miR-122 mediates alcohol-induced BMSCs osteogenic differentiation, ultimately leading to the inhibition of femoral head necrosis. M2 macrophages were identified by flow cytometry, and the isolated exosomes were characterized by transmission electron microscopy (TEM) and Nanoparticle Tracking Analysis (NTA). Next, miR-122 was overexpressed by transfecting miR-122 mimic, and the expression of miR-122 in M2 macrophages and their exosomes was evaluated. Subsequently, the effect of exosomal miR-122 on the osteogenic differentiation ability of BMSCs was detected, including cell proliferation, expression of osteogenic-related genes (RUNX2, BMP2, OPN, ALP), and calcium nodule formation. Finally, the therapeutic effect of M2-Exo was analyzed in a rat model of AIONFH, and bone repair and pathological damage were evaluated by Micro-CT, RT-qPCR, HE, Masson staining, and immunohistochemistry (COL I). The results showed that M2 macrophages were successfully polarized, with an average M2-Exo particle size of 156.4 nm and a concentration of 3.2E + 12 particles/mL. The expression of miR-122 in M2 macrophages is significantly higher than that in M0 macrophages, and miR-122 mimic can increase the content of miR-122 in M2-Exo. miR-122 in M2-Exo can promote osteogenic differentiation of rat bone marrow BMSCs, enhance cell viability, and increase the expression of osteogenesis-related genes. After being applied to the AIONFH rat model, the injection of M2-exo and miR-122 mimics significantly improved the repair effect of articular cartilage, alleviated pathological changes, and promoted the regeneration of bone tissue. M2-macrophage-derived exosomal miR-122 induces osteogenic differentiation of bone mesenchymal stem cells in treating AIONFH.
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Affiliation(s)
- Guoping Le
- Department of Joint Osteopathy, Liuzhou Worker's Hospital, Liuzhou, Guangxi Province, 545000, China
| | - Riyou Wen
- Department of Joint Osteopathy, Liuzhou Worker's Hospital, Liuzhou, Guangxi Province, 545000, China
| | - Huaixi Fang
- Department of Joint Osteopathy, Liuzhou Worker's Hospital, Liuzhou, Guangxi Province, 545000, China
| | - Zhifa Huang
- Department of Joint Osteopathy, Liuzhou Worker's Hospital, Liuzhou, Guangxi Province, 545000, China
| | - Yong Wang
- Department of Joint Osteopathy, Liuzhou Worker's Hospital, Liuzhou, Guangxi Province, 545000, China
| | - Hanwen Luo
- Department of Joint Osteopathy, Liuzhou Worker's Hospital, Liuzhou, Guangxi Province, 545000, China.
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Xu Y, Ye Z, Wang Y, Ma Y, Chen X, Wang S, Zhang B, Xia C. Alleviating osteoarthritis-induced damage through extracellular vesicles derived from inflammatory chondrocytes. Int Immunopharmacol 2025; 146:113829. [PMID: 39675196 DOI: 10.1016/j.intimp.2024.113829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 11/19/2024] [Accepted: 12/08/2024] [Indexed: 12/17/2024]
Abstract
The role of extracellular vesicles (EVs) derived from inflammatory chondrocytes in EV-based therapy for osteoarthritis (OA) has received little attention. We examined the effects of EVs derived from both normal rat chondrocytes (nEVs) and IL-1β-treated rat chondrocytes (iEVs) on IL-1β-treated rat chondrocytes, macrophages, and osteoblasts, alongside mRNA-seq and miRNA-seq analyses of both them. Additionally, nEVs and iEVs were administered intra-articularly in the joints of rat models subjected to anterior cruciate ligament transection (ACLT), and the morphological alterations across the joints were assessed. These findings indicated that iEVs, compared with nEVs, significantly enhanced collagen II synthesis in IL-1β-treated chondrocytes, accompanied by marked increases in ER stress and autophagy. In comparison to nEVs, iEVs exhibited a greater effect on facilitating M2-type macrophage polarization while simultaneously diminishing M1-type polarization, a process likely mediated by the downregulation of chemotactic cytokines such as Cxcl10, Ccl5, Cxcl9, Cxcl1, and Cxcl11. iEVs exerted a more pronounced influence on the phenotypic characteristics of IL-1β-treated osteoblasts than nEVs. In the ACLT-rat model, iEVs, akin to nEVs, effectively mitigated articular cartilage degradation. However, there was no significant difference in OARSI Scores between the two groups, despite iEVs exerting a greater effect on increasing hyaline cartilage thickness and proteoglycan content. iEVs were superior to nEVs in attenuating synovium inflammation and promoting trabecula formation in the femur subchondral bone. Consequently, iEVs, akin to nEVs, significantly alleviated OA-induced damage. Moreover, iEVs outperformed nEVs in certain aspects, notably in augmenting hyaline cartilage, reducing synovium inflammation, and promoting trabecular formation in the subchondral bone during the early stage of OA.
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Affiliation(s)
- Yang Xu
- Department of Joint Surgery & Sports Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China
| | - Zesen Ye
- Department of Joint Surgery & Sports Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China
| | - Yue Wang
- Department of Joint Surgery & Sports Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China
| | - Yongkang Ma
- Department of Joint Surgery & Sports Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China
| | - Xiaolei Chen
- Department of Joint Surgery & Sports Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China
| | - Shaojie Wang
- Department of Joint Surgery & Sports Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China.
| | - Bing Zhang
- School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
| | - Chun Xia
- Department of Joint Surgery & Sports Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China.
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Torkashvand M, Rezakhani L, Habibi Z, Mikaeili A, Rahmati S. Innovative approaches in lung tissue engineering: the role of exosome-loaded bioscaffolds in regenerative medicine. Front Bioeng Biotechnol 2024; 12:1502155. [PMID: 39758953 PMCID: PMC11695380 DOI: 10.3389/fbioe.2024.1502155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/04/2024] [Indexed: 01/07/2025] Open
Abstract
Lung diseases account for over four million premature deaths every year, and experts predict that this number will increase in the future. The top cause of death globally is diseases which include conditions like lung cancer asthma and COPD. Treating severe acute lung injury is a complex task because lungs struggle to heal themselves in the presence of swelling inflammation and scarring caused by damage, to the lung tissues. Though achieving lung regeneration, in controlled environments is still an ambition; ongoing studies are concentrating on notable progress, in the field of lung tissue engineering and methods for repairing lung damage. This review delves into methods, for regenerating lungs with a focus on exosome carry bioscaffolds and mesenchymal stem cells among others. It talks about how these new techniques can help repair lung tissue and improve lung function in cases of damage. Also noted is the significance of ex vivo lung perfusion (EVLP), for rejuvenating donor lungs and the healing properties of exosomes in supporting lung regeneration.
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Affiliation(s)
| | - Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zahra Habibi
- Clinical Research Development Unit, Hajar Hospital, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Abdolhamid Mikaeili
- Medical Biology Research Center, Health Technology Institute, University of Medical Sciences, Kermanshah, Iran
| | - Shima Rahmati
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Tang A, Shu Q, Jia S, Lai Z, Tian J. Adipose Mesenchymal Stem Cell-Derived Exosomes as Nanocarriers for Treating Musculoskeletal Disorders. Int J Nanomedicine 2024; 19:13547-13562. [PMID: 39720215 PMCID: PMC11668248 DOI: 10.2147/ijn.s486622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/22/2024] [Indexed: 12/26/2024] Open
Abstract
Musculoskeletal disorders are a series of diseases involving bone, muscle, cartilage, and tendon, mainly caused by chronic strain, degenerative changes, and structural damage due to trauma. The disorders limit the function of patients due to pain and significantly reduce their quality of life. In recent years, adipose-derived mesenchymal stem cells have been extensively applied in regeneration medicine research due to their particular abilities of self-renewal, differentiation, and targeted homing and are more easily accessed compared with other sources. The paracrine effect of ADSCs plays a crucial role in intercellular communication by releasing mass mediators, including cytokines and growth factors, particularly the exosomes they secrete. Not only do these exosomes possess low immunogenicity, low toxicity, and an enhanced ability to penetrate a bio-barrier, but they also inherit their parent cells' characteristics and carry various bioactive molecules to release to targeted cells, modulating their biological process. Meanwhile, these characteristics also make exosomes a natural nanocarrier capable of targeted drug delivery to specific sites, enhancing the bioavailability of drugs within the body and achieving precision therapy with fewer toxic side effects. Furthermore, the integration of exosomes with tissue engineering and chemical modification strategies can also significantly enhance their efficacy in facilitating tissue repair. However, the current research on ADSC-Exos for improving MSDs remains at an early stage and needs further exploration. Therefore, this review summarized the ADSC-Exo as a nanodrug carrier characteristics and mechanism in the treatment of fracture, osteoporosis, osteoarthritis, intervertebral disc degeneration, and tendon injury, which push forward the research progress of ADSC-Exo therapy for MSDs.
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Affiliation(s)
- Ao Tang
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China
- College of Sports Medicine, Wuhan Sports University, Wuhan, People’s Republic of China
| | - Qing Shu
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China
- College of Sports Medicine, Wuhan Sports University, Wuhan, People’s Republic of China
| | - Shaohui Jia
- College of Sports Medicine, Wuhan Sports University, Wuhan, People’s Republic of China
| | - Zhihao Lai
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Jun Tian
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China
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He Y, Wang Y, Yu S, Wang L, Dou Y, Ma R, Cao S, Song W, Ma P. BMP2 enhance the osteogenic effect of BMSCs-derived exosomes in skull defect of diabetic rats. MATERIALS & DESIGN 2024; 248:113517. [DOI: 10.1016/j.matdes.2024.113517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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8
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Deng L, Liu Y, Wu Q, Lai S, Yang Q, Mu Y, Dong M. Exosomes to exosome-functionalized scaffolds: a novel approach to stimulate bone regeneration. Stem Cell Res Ther 2024; 15:407. [PMID: 39521993 PMCID: PMC11550564 DOI: 10.1186/s13287-024-04024-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
Bone regeneration is a complex biological process that relies on the orchestrated interplay of various cellular and molecular events. Bone tissue engineering is currently the most promising method for treating bone regeneration. However, the immunogenicity, stable and cell quantity of seed cells limited their application. Recently, exosomes, which are small extracellular vesicles released by cells, have been found to effectively address these problems and better induce bone regeneration. Meanwhile, a growing line of research has shown the cargos of exosomes may provide effective therapeutic and biomarker tools for bone repair, including miRNA, lncRNA, and proteins. Moreover, engineered scaffolds loaded with exosomes can offer a cell-free bone repair strategy, addressing immunogenicity concerns and providing a more stable functional performance. Herein, we provide a comprehensive summary of the role played by scaffolds loaded with exosomes in bone regeneration, drawing on a systematic analysis of relevant literature available on PubMed, Scopus, and Google Scholar database.
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Affiliation(s)
- Li Deng
- Center for Medicine Research and Translation, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611135, Sichuan, China
| | - Yang Liu
- Center for Medicine Research and Translation, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611135, Sichuan, China
| | - Qian Wu
- Center for Medicine Research and Translation, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611135, Sichuan, China
| | - Shuang Lai
- Stomatology Department, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China
| | - Qiu Yang
- Center for Medicine Research and Translation, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611135, Sichuan, China
| | - Yandong Mu
- Stomatology Department, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China.
| | - Mingqing Dong
- Center for Medicine Research and Translation, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611135, Sichuan, China.
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Zhou JP, Peng SS, Xu J, Cheng XW, Wang XH, Tao JL, Dai HW, Cao X. Exploring the therapeutic potential of urine-derived stem cell exosomes in temporomandibular joint osteoarthritis. FASEB J 2024; 38:e23852. [PMID: 39101942 DOI: 10.1096/fj.202400448rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/15/2024] [Accepted: 07/21/2024] [Indexed: 08/06/2024]
Abstract
Temporomandibular joint osteoarthritis (TMJOA) is a degenerative ailment that causes slow cartilage degeneration, aberrant bone remodeling, and persistent discomfort, leading to a considerable reduction in the patient's life quality. Current treatment options for TMJOA have limited efficacy. This investigation aimed to explore a potential strategy for halting or reversing the progression of TMJOA through the utilization of exosomes (EXOs) derived from urine-derived stem cells (USCs). The USC-EXOs were obtained through microfiltration and ultrafiltration techniques, followed by their characterization using particle size analysis, electron microscopy, and immunoblotting. Subsequently, an in vivo model of TMJOA induced by mechanical force was established. To assess the changes in the cartilage of TMJOA treated with USC-EXOs, we performed histology analysis using hematoxylin-eosin staining, immunohistochemistry, and histological scoring. Our findings indicate that the utilization of USC-EXOs yields substantial reductions in TMJOA, while concurrently enhancing the structural integrity and smoothness of the compromised condylar cartilage surface. Additionally, USC-EXOs exhibit inhibitory effects on osteoclastogenic activity within the subchondral bone layer of the condylar cartilage, as well as attenuated apoptosis in the rat TMJ in response to mechanical injury. In conclusion, USC-EXOs hold considerable promise as a potential therapeutic intervention for TMJOA.
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Affiliation(s)
- Jian-Ping Zhou
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Si-Si Peng
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jie Xu
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Xing-Wang Cheng
- Department of Orthopedic Surgery, Center for Joint Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Hui Wang
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Jun-Li Tao
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Hong-Wei Dai
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
| | - Xin Cao
- College of Stomatology, Chongqing Medical University, Chongqing, China
- Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing, China
- Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China
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Arbade G, Jose JV, Gulbake A, Kadam S, Kashte SB. From stem cells to extracellular vesicles: a new horizon in tissue engineering and regenerative medicine. Cytotechnology 2024; 76:363-401. [PMID: 38933869 PMCID: PMC11196501 DOI: 10.1007/s10616-024-00631-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 04/07/2024] [Indexed: 06/28/2024] Open
Abstract
In the fields of tissue engineering and regenerative medicine, extracellular vesicles (EVs) have become viable therapeutic tools. EVs produced from stem cells promote tissue healing by regulating the immune system, enhancing cell proliferation and aiding remodeling processes. Recently, EV has gained significant attention from researchers due to its ability to treat various diseases. Unlike stem cells, stem cell-derived EVs show lower immunogenicity, are less able to overcome biological barriers, and have a higher safety profile. This makes the use of EVs derived from cell-free stem cells a promising alternative to whole-cell therapy. This review focuses on the biogenesis, isolation, and characterization of EVs and highlights their therapeutic potential for bone fracture healing, wound healing, and neuronal tissue repair and treatment of kidney and intestinal diseases. Additionally, this review discusses the potential of EVs for the treatment of cancer, COVID-19, and HIV. In summary, the use of EVs derived from stem cells offers a new horizon for applications in tissue engineering and regenerative medicine.
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Affiliation(s)
| | | | - Arvind Gulbake
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Guwahati, (NIPER G), Guwahati, Assam 781101 India
| | - Sachin Kadam
- Sophisticated Analytical and Technical Help Institute, Indian Institute of Technology, Delhi, New Delhi 110016 India
| | - Shivaji B. Kashte
- Department of Stem Cell and Regenerative Medicine, Centre for Interdisciplinary Research, D. Y. Patil Education Society (Institution Deemed to be University), Kolhapur, MS 416006 India
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Jin A, Shao Y, Wang F, Feng J, Lei L, Dai M. Designing polysaccharide materials for tissue repair and regeneration. APL MATERIALS 2024; 12. [DOI: 10.1063/5.0223937] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Tissue repair and regeneration are critical processes for maintaining the integrity and function of various organs and tissues. Recently, polysaccharide materials and protein materials have garnered interest for use in tissue repair strategies. However, polysaccharides are more stable and unaffected by temperature and pH changes compared to proteins, and some polysaccharides can provide stronger mechanical support, which is particularly important for constructing tissue-engineered scaffolds and wound dressings. This Review provides an in-depth overview of the origins of polysaccharides, the advantages of polysaccharide materials, and processing and design strategies. In addition, the potential of polysaccharide materials for the restoration of tissues such as skin, heart, and nerves is highlighted. Finally, we discuss in depth the challenges that polysaccharide materials still face in tissue repair, such as the stability of the material, regulating mechanical characteristics and deterioration rates under different conditions. To achieve more effective tissue repair and regeneration, future research must focus on further improving the characteristics and functionalities of polysaccharide materials.
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Affiliation(s)
- Anqi Jin
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University 1 , Hangzhou 310015, China
| | - Yunyuan Shao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University 1 , Hangzhou 310015, China
| | - Fangyan Wang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University 1 , Hangzhou 310015, China
| | - Jiayin Feng
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University 1 , Hangzhou 310015, China
| | - Lanjie Lei
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Institute of Translational Medicine, Zhejiang Shuren University 1 , Hangzhou 310015, China
| | - Minghai Dai
- The Third Affiliated Hospital of Wenzhou Medical University 2 , Wenzhou 325200, China
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Lv H, Feng Z, Chen X, Zhang Z, Zhou T, Wei J, Feng L, Tao Y, Chen F, Lu S. Global scientific trends on exosomes therapy for osteoporosis from 2004 to 2023: A bibliometric and visualized analysis. Medicine (Baltimore) 2024; 103:e38835. [PMID: 38996093 PMCID: PMC11245275 DOI: 10.1097/md.0000000000038835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 06/14/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Exosomes have emerged as pivotal mediators in modulating physiological and pathological processes implicated in osteoporosis (OP) through their distinctive mode of intracellular communication. The use of exosomes has evoked considerable interest, catalyzing a surge in research endeavors on a global scale. This study endeavors to scrutinize contemporary landscapes and burgeoning trends in this realm. METHODS The Web of Science Core Collection was used to retrieve publications on exosomes therapy for OP within the time frame of January 1, 2004 to December 31, 2023. The bibliometric methodology was applied to study and index the collected data. VOSviewer and citespace software were used to conduct visualization, co-authorship, co-occurrence, and publication trend analyses of exosome therapy in OP. RESULTS A total of 610 publications (443 articles and 167 reviews) from 51 countries and 911 institutions were included in this study. Shanghai Jiao Tong University, Central South University, Sichuan University, and Zhejiang University are leading research institutions in this field. Stem Cell Research Therapy published the highest number of articles and has emerged as the most cited journal. Of the 4077 scholars who participated in the study, Xie, Hui, Zhang, Yan, Tan, and Yi-Juan had the largest number of articles. Furthermore, according to the cluster analysis of external keywords, future research hotspots can be categorized into 3 directions: research status of exosomes for the treatment of OP, treatment of OP through exosome-regulated signaling pathways, and exosomes as targeted drug delivery systems. CONCLUSION This study suggests that the number of future publications on exosome therapy for OP will increase, with a focus on fundamental investigations into drug-loading capacities and molecular mechanisms. In summary, this study presents the first systematic bibliometric analysis of exosome therapy publications in OP, providing an objective and comprehensive overview of the field and a valuable reference for researchers in this domain.
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Affiliation(s)
- He Lv
- Faculty of Postgraduate, Guangxi University of Chinese Medicine, Nanning, China
| | - Zhe Feng
- Joint & Sports Medicine Surgery Division, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Xingyu Chen
- Faculty of Postgraduate, Guangxi University of Chinese Medicine, Nanning, China
| | - Zhenyu Zhang
- Gynecology Department, Guangdong Medical University Shunde Women and Children’s Hospital, Foshan, China
| | - Tianhao Zhou
- Faculty of Postgraduate, Guangxi University of Chinese Medicine, Nanning, China
| | - Jihu Wei
- Faculty of Postgraduate, Guangxi University of Chinese Medicine, Nanning, China
| | - Lin Feng
- Faculty of Postgraduate, Guangxi University of Chinese Medicine, Nanning, China
| | - Yizi Tao
- Faculty of Postgraduate, Guangxi University of Chinese Medicine, Nanning, China
| | - Feng Chen
- Spine Surgery Division, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Shijin Lu
- Centre for Translational Medical Research in Integrative Chinese and Western Medicine, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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13
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Larbi A. From Genesis to Old Age: Exploring the Immune System One Cell at a Time with Flow Cytometry. Biomedicines 2024; 12:1469. [PMID: 39062042 PMCID: PMC11275137 DOI: 10.3390/biomedicines12071469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 06/21/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
The immune system is a highly complex and tightly regulated system that plays a crucial role in protecting the body against external threats, such as pathogens, and internal abnormalities, like cancer cells. It undergoes development during fetal stages and continuously learns from each encounter with pathogens, allowing it to develop immunological memory and provide a wide range of immune protection. Over time, after numerous encounters and years of functioning, the immune system can begin to show signs of erosion, which is commonly named immunosenescence. In this review, we aim to explore how the immune system responds to initial encounters with antigens and how it handles persistent stimulations throughout a person's lifetime. Our understanding of the immune system has greatly benefited from advanced technologies like flow cytometry. In this context, we will discuss the valuable contribution of flow cytometry in enhancing our knowledge of the immune system behavior in aging, with a specific focus on T-cells. Moreover, we will expand our discussion to the flow cytometry-based assessment of extracellular vesicles, a recently discovered communication channel in biology, and their implications for immune system functioning.
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Affiliation(s)
- Anis Larbi
- Medical and Scientific Affairs, Beckman Coulter Life Sciences, 22 Avenue des Nations, 93420 Villepinte, France;
- Department of Medicine, Division of Geriatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada
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14
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Zhu F, Wang T, Wang G, Yan C, He B, Qiao B. The Exosome-Mediated Bone Regeneration: An Advanced Horizon Toward the Isolation, Engineering, Carrying Modalities, and Mechanisms. Adv Healthc Mater 2024; 13:e2400293. [PMID: 38426417 DOI: 10.1002/adhm.202400293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Indexed: 03/02/2024]
Abstract
Exosomes, nanoparticles secreted by various cells, composed of a bilayer lipid membrane, and containing bioactive substances such as proteins, nucleic acids, metabolites, etc., have been intensively investigated in tissue engineering owing to their high biocompatibility and versatile biofunction. However, there is still a lack of a high-quality review on bone defect regeneration potentiated by exosomes. In this review, the biogenesis and isolation methods of exosomes are first introduced. More importantly, the engineered exosomes of the current state of knowledge are discussed intensively in this review. Afterward, the biomaterial carriers of exosomes and the mechanisms of bone repair elucidated by compelling evidence are presented. Thus, future perspectives and concerns are revealed to help devise advanced modalities based on exosomes to overcome the challenges of bone regeneration. It is totally believed this review will attract special attention from clinicians and provide promising ideas for their future works.
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Affiliation(s)
- Fukang Zhu
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Chongqing, 400010, P. R. China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400010, P. R. China
| | - Taiyou Wang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Chongqing, 400010, P. R. China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400010, P. R. China
| | - Guangjian Wang
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Chongqing, 400010, P. R. China
- Department of Orthopaedics, The People's Hospital of Rongchang District, Chongqing, 402460, P. R. China
| | - Caiping Yan
- Department of Orthopaedics, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, P. R. China
| | - Bin He
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Chongqing, 400010, P. R. China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400010, P. R. China
| | - Bo Qiao
- Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Rd, Chongqing, 400010, P. R. China
- Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400010, P. R. China
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15
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He L, Zhang H, Zhao N, Liao L. A novel approach in biomedical engineering: The use of polyvinyl alcohol hydrogel encapsulating human umbilical cord mesenchymal stem cell-derived exosomes for enhanced osteogenic differentiation and angiogenesis in bone regeneration. Int J Biol Macromol 2024; 270:132116. [PMID: 38723803 DOI: 10.1016/j.ijbiomac.2024.132116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 04/09/2024] [Accepted: 05/04/2024] [Indexed: 05/19/2024]
Abstract
Developing effective methods for alveolar bone defect regeneration is a significant challenge in orthopedics. Exosomes from human umbilical cord mesenchymal stem cells (HUMSC-Exos) have shown potential in bone repair but face limitations due to undefined application methods and mechanisms. To address this, HUMSC-Exos were encapsulated in polyvinyl alcohol (PVA) hydrogel (Exo@PVA) to create a novel material for alveolar bone repair. This combination enhanced the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) more effectively than Exos alone. Additionally, Exo@PVA significantly improved alveolar bone regeneration and defect repair in rats. The microRNA-21-5p (miR-21-5p) in Exo@PVA, identified through the GEO database and analyzed via in silico methods, played a crucial role. miR-21-5p promoted BMSC osteogenic differentiation by inhibiting WWP1-mediated KLF5 ubiquitination and enhanced HUVEC angiogenesis by targeting ATP2B4. These findings underscore the potential of an Exo-based approach with PVA hydrogel scaffolds for bone defect repair, operating through the miR-21-5p/WWP1/ATP2B4 signaling axis.
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Affiliation(s)
- Longlong He
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China; Department of Implant Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Hengwei Zhang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Ningbo Zhao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China; Department of Implant Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China
| | - Lifan Liao
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China; Department of Implant Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi'an 710004, PR China.
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16
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Cui H, Wang Y, Ma J, Zhou L, Li G, Li Y, Sun Y, Shen J, Ma T, Wang Q, Feng X, Dong B, Yang P, Li Y, Ma X. Advances in exosome modulation of ferroptosis for the treatment of orthopedic diseases. Pathol Res Pract 2024; 257:155312. [PMID: 38663177 DOI: 10.1016/j.prp.2024.155312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/09/2024] [Accepted: 04/15/2024] [Indexed: 05/12/2024]
Abstract
Current treatments for orthopaedic illnesses frequently result in poor prognosis, treatment failure, numerous relapses, and other unpleasant outcomes that have a significant impact on patients' quality of life. Cell-free therapy has emerged as one of the most promising options in recent decades for improving the status quo. As a result, using exosomes produced from various cells to modulate ferroptosis has been proposed as a therapeutic method for the condition. Exosomes are extracellular vesicles that secrete various bioactive chemicals that influence disease treatment and play a role in the genesis and progression of orthopaedic illnesses. Ferroptosis is a recently defined kind of controlled cell death typified by large iron ion buildup and lipid peroxidation. An increasing number of studies indicate that ferroptosis plays a significant role in orthopaedic illnesses. Exosomes, as intercellular information transfer channels, have been found to play a significant role in the regulation of ferroptosis processes. Furthermore, accumulating research suggests that exosomes can influence the course of many diseases by regulating ferroptosis in injured cells. In order to better understand the processes by which exosomes govern ferroptosis in the therapy of orthopaedic illnesses. This review discusses the biogenesis, secretion, and uptake of exosomes, as well as the mechanisms of ferroptosis and exosomes in the therapy of orthopaedic illnesses. It focuses on recent research advances and exosome mechanisms in regulating iron death for the therapy of orthopaedic illnesses. The present state of review conducted both domestically and internationally is elucidated and anticipated as a viable avenue for future therapy in the field of orthopaedics.
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Affiliation(s)
- Hongwei Cui
- Tianjin Medical University Orthopedic Clinical College, Tianjin 300050, China; Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Yan Wang
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Jianxiong Ma
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China.
| | - Liyun Zhou
- Tianjin Medical University Orthopedic Clinical College, Tianjin 300050, China; Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Guang Li
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Yiyang Li
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Yadi Sun
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Jiahui Shen
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Tiancheng Ma
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Qiyu Wang
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Xiaotian Feng
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Benchao Dong
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Peichuan Yang
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Yan Li
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
| | - Xinlong Ma
- Tianjin Hospital of Tianjin University (Tianjin Hospital), Tianjin 300211, China; Tianjin Orthopedic Institute, Tianjin 300050, China; Tianjin Key Laboratory of Orthopedic Biomechanics and Medical Engineering, Tianjin 300050, China
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17
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Li S, Guan X, Yu W, Zhao Z, Sun Y, Bai Y. Effect of human periodontal ligament stem cell-derived exosomes on cementoblast activity. Oral Dis 2024; 30:2511-2522. [PMID: 37448205 DOI: 10.1111/odi.14671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023]
Abstract
OBJECTIVES Exosomes derived from stem cells are a potential cell-free tool for tissue regeneration with therapeutic potential. However, its application in cementum repair is unclear. This study aimed to investigate the effect of human periodontal ligament stem cell-derived exosomes on the biological activity of cementoblasts, the main effector cells in cementum synthesis. MATERIALS AND METHODS OCCM-30 cementoblasts were cultured with various human periodontal ligament stem cell-derived exosome concentrations. OCCM-30 cells proliferation, migration, and cementogenic mineralization were examined, along with the gene and protein expression of factors associated with cementoblastic mineralization. RESULTS Exosomal promoted the migration, proliferation, and mineralization of OCCM-30 cells. The exosome-treated group significantly increased the expression of cementogenic-related genes and proteins. Furthermore, the expression of p-PI3K and p-AKT was enhanced by exosome administration. Treatment with a PI3K/AKT inhibitor markedly attenuated the gene and protein expression of cementoblastic factors, and this effect was partially reversed by exosome administration. CONCLUSIONS Human periodontal ligament stem cell-derived exosomes can promote the activity of cementoblasts via the PI3K/AKT signaling pathway, providing a scientific basis for promoting the repair process in orthodontically induced inflammatory root resorption.
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Affiliation(s)
- Shengnan Li
- Department of Orthodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Xiuchen Guan
- Department of Orthodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Wenting Yu
- Department of Orthodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Zeqing Zhao
- Department of Orthodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Yaxi Sun
- Department of Orthodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
| | - Yuxing Bai
- Department of Orthodontics, Beijing Stomatological Hospital, School of Stomatology, Capital Medical University, Beijing, China
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18
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Anvari Y, Afrashteh A, Pourkaveh S, Salek SB, Al-Numan L, Khademnezhad S. Emerging role of mesenchymal stem cell-derived extracellular vesicles in periodontal regeneration. J Taibah Univ Med Sci 2024; 19:390-402. [PMID: 38380419 PMCID: PMC10876597 DOI: 10.1016/j.jtumed.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/17/2023] [Accepted: 01/25/2024] [Indexed: 02/22/2024] Open
Abstract
Periodontitis is a prevalent oral ailment that harms both hard and soft tissues of the periodontium, leading to loosening and eventual removal of the teeth. Current clinical treatments have limitations in achieving complete periodontal tissue regeneration. Mesenchymal stem cells (MSCs) have garnered attention due to their unique characteristics and potential as a promising new therapy for periodontitis. Research suggests that the role of MSCs in regenerative medicine primarily occurs through the paracrine pathway, involving the emission of particles encased by lipids called extracellular vesicles (EVs) abundant in bioactive compounds. These EVs play a vital function in controlling the activities of periodontal tissues and immune system cells, and by influencing the immediate surrounding, thus fostering the healing of periodontal damage and renewal of tissues. EVs obtained from MSCs (MSC-EVs), in the form of a cell-free treatment, offer advantages in terms of stability, reduced immune rejection, and ethical considerations, elevating their potential as a hopeful choice for broad clinical applications. This concise overview highlights the mechanisms of MSC-EVs and the possibilities they hold in clinical application for periodontal regeneration.
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Affiliation(s)
- Yaldasadat Anvari
- Department of Dentistry, School of Dentistry, Near East University, Nicosia, Cyprus
| | - Ahmad Afrashteh
- Department of Periodontics, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sajjad Pourkaveh
- Department of Periodontics, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samira B. Salek
- Department of Periodontics, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Lelaw Al-Numan
- Department of Dentistry, School of Dentistry, Near East University, Nicosia, Cyprus
| | - Sahar Khademnezhad
- Department of Oral and Maxillofacial Medicine, School of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
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Hassanzadeh A, Shomali N, Kamrani A, Nasiri H, Ahmadian Heris J, Pashaiasl M, Sadeghi M, Sadeghvand S, Valedkarimi Z, Akbari M. Detailed role of mesenchymal stem cell (MSC)-derived exosome therapy in cardiac diseases. EXCLI JOURNAL 2024; 23:401-420. [PMID: 38741729 PMCID: PMC11089093 DOI: 10.17179/excli2023-6538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/05/2024] [Indexed: 05/16/2024]
Abstract
Coronary heart disease (CHD) continues to be the leading cause of morbidity and mortality. There are numerous therapeutic reperfusion methods, including thrombolytic therapy, primary percutaneous coronary intervention, and anti-remodeling drugs like angiotensin-converting enzyme inhibitors and beta-blockers. Despite this, there is no pharmacological treatment that can effectively stop cardiomyocyte death brought on by myocardial ischemia/reperfusion (I/R) injury. For the purpose of regenerating cardiac tissue, mesenchymal stem cell (MSC) therapy has recently gained more attention. The pleiotropic effects of MSCs are instead arbitrated by the secretion of soluble paracrine factors and are unrelated to their capacity for differentiation. One of these paracrine mediators is the extracellular vesicle known as an exosome. Exosomes deliver useful cargo to recipient cells from MSCs, including peptides, proteins, cytokines, lipids, miRNA, and mRNA molecules. Exosomes take part in intercellular communication processes and help tissues and organs that have been injured or are ill heal. Exosomes alone were found to be the cause of MSCs' therapeutic effects in a variety of animal models, according to studies. Here, we have focused on the recent development in the therapeutic capabilities of exosomal MSCs in cardiac diseases.
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Affiliation(s)
- Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Navid Shomali
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Kamrani
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hadi Nasiri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Pashaiasl
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
- Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, P.O. Box 51376563833, Tabriz, Iran
| | - Mohammadreza Sadeghi
- Department of Molecular Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahram Sadeghvand
- Pediatrics Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Valedkarimi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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20
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He X, Guo C, Wang Y, Ma S, Liu X, Wei Y, Xu H, Liang Z, Hu Y, Zhao L, Lian X, Huang D. Enhancing osseointegration of titanium implants through MC3T3-E1 protein-gelatin polyelectrolyte multilayers. J Biomed Mater Res B Appl Biomater 2024; 112:e35373. [PMID: 38359169 DOI: 10.1002/jbm.b.35373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 12/01/2023] [Accepted: 01/02/2024] [Indexed: 02/17/2024]
Abstract
Titanium and its alloys have found extensive use in the biomedical field, however, implant loosening due to weak osseointegration remains a concern. Improved surface morphology and chemical composition can enhance the osseointegration of the implant. Bioactive molecules have been utilized to modify the surface of the titanium-based material to achieve rapid and efficient osseointegration between the implant and bone tissues. In this study, the bioactive substance MC3T3-E1 protein-gelatin polyelectrolyte multilayers were constructed on the surface of the titanium implants by means of layer-by-layer self-assembly to enhance the strength of the bond between the bone tissue and the implant. The findings of the study indicate that the layer-by-layer self-assembly technique can enhance surface roughness and hydrophilicity to a considerable extent. Compared to pure titanium, the hydrophilicity of TiOH LBL was significantly increased with a water contact angle of 75.0 ± $$ \pm $$ 2.4°. The modified titanium implant exhibits superior biocompatibility and wound healing ability upon co-culture with cells. MC3T3-E1 cells were co-cultured with TiOH LBL for 1, 3, and 5 days and their viability was higher than 85%. In addition, the wound healing results demonstrate that TiOH LBL exhibited the highest migratory ability (243 ± 10 μm). Furthermore, after 7 days of osteogenic induction, the modified titanium implant significantly promotes osteoblast differentiation.
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Affiliation(s)
- Xuhong He
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
| | - Chaiqiong Guo
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
| | - Yuhui Wang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
| | - Shilong Ma
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
| | - Xuanyu Liu
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
| | - Yan Wei
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
- Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan, China
| | - Haofeng Xu
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
| | - Ziwei Liang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
- Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan, China
| | - Yinchun Hu
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
- Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan, China
| | - Liqin Zhao
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
- Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan, China
| | - Xiaojie Lian
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
- Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan, China
| | - Di Huang
- Department of Biomedical Engineering, Research Center for Nano-biomaterials & Regenerative Medicine, College of Biomedical Engineering, Shanxi Key Laboratory of Materials Strength & Structural Impact, Taiyuan University of Technology, Taiyuan, China
- Shanxi-Zheda Institute of Advanced Materials and Chemical Engineering, Taiyuan, China
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21
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Ma Y, Wang S, Wang H, Chen X, Shuai Y, Wang H, Mao Y, He F. Mesenchymal stem cells and dental implant osseointegration during aging: from mechanisms to therapy. Stem Cell Res Ther 2023; 14:382. [PMID: 38124153 PMCID: PMC10734190 DOI: 10.1186/s13287-023-03611-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023] Open
Abstract
Dental implants are widely used to replace missing teeth, providing patients with unparalleled levels of effectiveness, convenience, and affordability. The biological basis for the clinical success of dental implants is osseointegration. Bone aging is a high-risk factor for the reduced osseointegration and survival rates of dental implants. In aged individuals, mesenchymal stem cells (MSCs) in the bone marrow show imbalanced differentiation with a reduction in osteogenesis and an increase in adipogenesis. This leads to impaired osseointegration and implant failure. This review focuses on the molecular mechanisms underlying the dysfunctional differentiation of aged MSCs, which primarily include autophagy, transcription factors, extracellular vesicle secretion, signaling pathways, epigenetic modifications, microRNAs, and oxidative stress. Furthermore, this review addresses the pathological changes in MSCs that affect osseointegration and discusses potential therapeutic interventions to enhance osseointegration by manipulating the mechanisms underlying MSC aging.
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Affiliation(s)
- Yang Ma
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Siyuan Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Hui Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Xiaoyu Chen
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China
| | - Yi Shuai
- Nanjing Jinling Hospital: East Region Military Command General Hospital, Nanjing, China
| | - Huiming Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China.
| | - Yingjie Mao
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China.
| | - Fuming He
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, China.
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22
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Yeo M, Sarkar A, Singh YP, Derman ID, Datta P, Ozbolat IT. Synergistic coupling between 3D bioprinting and vascularization strategies. Biofabrication 2023; 16:012003. [PMID: 37944186 PMCID: PMC10658349 DOI: 10.1088/1758-5090/ad0b3f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 09/27/2023] [Accepted: 11/09/2023] [Indexed: 11/12/2023]
Abstract
Three-dimensional (3D) bioprinting offers promising solutions to the complex challenge of vascularization in biofabrication, thereby enhancing the prospects for clinical translation of engineered tissues and organs. While existing reviews have touched upon 3D bioprinting in vascularized tissue contexts, the current review offers a more holistic perspective, encompassing recent technical advancements and spanning the entire multistage bioprinting process, with a particular emphasis on vascularization. The synergy between 3D bioprinting and vascularization strategies is crucial, as 3D bioprinting can enable the creation of personalized, tissue-specific vascular network while the vascularization enhances tissue viability and function. The review starts by providing a comprehensive overview of the entire bioprinting process, spanning from pre-bioprinting stages to post-printing processing, including perfusion and maturation. Next, recent advancements in vascularization strategies that can be seamlessly integrated with bioprinting are discussed. Further, tissue-specific examples illustrating how these vascularization approaches are customized for diverse anatomical tissues towards enhancing clinical relevance are discussed. Finally, the underexplored intraoperative bioprinting (IOB) was highlighted, which enables the direct reconstruction of tissues within defect sites, stressing on the possible synergy shaped by combining IOB with vascularization strategies for improved regeneration.
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Affiliation(s)
- Miji Yeo
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, United States of America
- Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, United States of America
| | - Anwita Sarkar
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal 700054, India
| | - Yogendra Pratap Singh
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, United States of America
- Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, United States of America
| | - Irem Deniz Derman
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, United States of America
- Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, United States of America
| | - Pallab Datta
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal 700054, India
| | - Ibrahim T Ozbolat
- The Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, United States of America
- Engineering Science and Mechanics Department, Penn State University, University Park, PA 16802, United States of America
- Department of Biomedical Engineering, Penn State University, University Park, PA 16802, United States of America
- Materials Research Institute, Penn State University, University Park, PA 16802, United States of America
- Department of Neurosurgery, Penn State College of Medicine, Hershey, PA 17033, United States of America
- Penn State Cancer Institute, Penn State University, Hershey, PA 17033, United States of America
- Biotechnology Research and Application Center, Cukurova University, Adana 01130, Turkey
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23
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Ball JR, Shelby T, Hernandez F, Mayfield CK, Lieberman JR. Delivery of Growth Factors to Enhance Bone Repair. Bioengineering (Basel) 2023; 10:1252. [PMID: 38002376 PMCID: PMC10669014 DOI: 10.3390/bioengineering10111252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 10/20/2023] [Accepted: 10/25/2023] [Indexed: 11/26/2023] Open
Abstract
The management of critical-sized bone defects caused by nonunion, trauma, infection, malignancy, pseudoarthrosis, and osteolysis poses complex reconstruction challenges for orthopedic surgeons. Current treatment modalities, including autograft, allograft, and distraction osteogenesis, are insufficient for the diverse range of pathology encountered in clinical practice, with significant complications associated with each. Therefore, there is significant interest in the development of delivery vehicles for growth factors to aid in bone repair in these settings. This article reviews innovative strategies for the management of critical-sized bone loss, including novel scaffolds designed for controlled release of rhBMP, bioengineered extracellular vesicles for delivery of intracellular signaling molecules, and advances in regional gene therapy for sustained signaling strategies. Improvement in the delivery of growth factors to areas of significant bone loss has the potential to revolutionize current treatment for this complex clinical challenge.
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Affiliation(s)
- Jacob R. Ball
- Department of Orthopaedic Surgery, University of Southern California Keck School of Medicine, 1500 San Pablo St., Los Angeles, CA 90033, USA
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24
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Wang W, Xu Z, Liu M, Cai M, Liu X. Prospective applications of extracellular vesicle-based therapies in regenerative medicine: implications for the use of dental stem cell-derived extracellular vesicles. Front Bioeng Biotechnol 2023; 11:1278124. [PMID: 37936823 PMCID: PMC10627172 DOI: 10.3389/fbioe.2023.1278124] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/06/2023] [Indexed: 11/09/2023] Open
Abstract
In the 21st century, research on extracellular vesicles (EVs) has made remarkable advancements. Recently, researchers have uncovered the exceptional biological features of EVs, highlighting their prospective use as therapeutic targets, biomarkers, innovative drug delivery systems, and standalone therapeutic agents. Currently, mesenchymal stem cells stand out as the most potent source of EVs for clinical applications in tissue engineering and regenerative medicine. Owing to their accessibility and capability of undergoing numerous differentiation inductions, dental stem cell-derived EVs (DSC-EVs) offer distinct advantages in the field of tissue regeneration. Nonetheless, it is essential to note that unmodified EVs are currently unsuitable for use in the majority of clinical therapeutic scenarios. Considering the high feasibility of engineering EVs, it is imperative to modify these EVs to facilitate the swift translation of theoretical knowledge into clinical practice. The review succinctly presents the known biotherapeutic effects of odontogenic EVs and the underlying mechanisms. Subsequently, the current state of functional cargo loading for engineered EVs is critically discussed. For enhancing EV targeting and in vivo circulation time, the review highlights cutting-edge engineering solutions that may help overcome key obstacles in the clinical application of EV therapeutics. By presenting innovative concepts and strategies, this review aims to pave the way for the adaptation of DSC-EVs in regenerative medicine within clinical settings.
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Affiliation(s)
- Wenhao Wang
- School of Stomatology, Jinan University, Guangzhou, China
- Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zinan Xu
- School of Stomatology, Jinan University, Guangzhou, China
- Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Minyi Liu
- Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
- Clinical Research Platform for Interdiscipline, Jinan University, Guangzhou, China
| | - Mingxiang Cai
- School of Stomatology, Jinan University, Guangzhou, China
- Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiangning Liu
- School of Stomatology, Jinan University, Guangzhou, China
- Center of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou, China
- Clinical Research Platform for Interdiscipline, Jinan University, Guangzhou, China
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25
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Wu T, Jiang Y, Shi W, Wang Y, Li T. Endoplasmic reticulum stress: a novel targeted approach to repair bone defects by regulating osteogenesis and angiogenesis. J Transl Med 2023; 21:480. [PMID: 37464413 PMCID: PMC10353205 DOI: 10.1186/s12967-023-04328-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/06/2023] [Indexed: 07/20/2023] Open
Abstract
Bone regeneration therapy is clinically important, and targeted regulation of endoplasmic reticulum (ER) stress is important in regenerative medicine. The processing of proteins in the ER controls cell fate. The accumulation of misfolded and unfolded proteins occurs in pathological states, triggering ER stress. ER stress restores homeostasis through three main mechanisms, including protein kinase-R-like ER kinase (PERK), inositol-requiring enzyme 1ɑ (IRE1ɑ) and activating transcription factor 6 (ATF6), collectively known as the unfolded protein response (UPR). However, the UPR has both adaptive and apoptotic effects. Modulation of ER stress has therapeutic potential for numerous diseases. Repair of bone defects involves both angiogenesis and bone regeneration. Here, we review the effects of ER stress on osteogenesis and angiogenesis, with emphasis on ER stress under high glucose (HG) and inflammatory conditions, and the use of ER stress inducers or inhibitors to regulate osteogenesis and angiogenesis. In addition, we highlight the ability for exosomes to regulate ER stress. Recent advances in the regulation of ER stress mediated osteogenesis and angiogenesis suggest novel therapeutic options for bone defects.
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Affiliation(s)
- Tingyu Wu
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China
| | - Yaping Jiang
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Weipeng Shi
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China
| | - Yingzhen Wang
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China
| | - Tao Li
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, No. 59, Haier Road, Qingdao, 266003, China.
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26
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He Y, Liang L, Luo C, Zhang ZY, Huang J. Strategies for in situ tissue engineering of vascularized bone regeneration (Review). Biomed Rep 2023; 18:42. [PMID: 37325184 PMCID: PMC10265129 DOI: 10.3892/br.2023.1625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 04/03/2023] [Indexed: 06/17/2023] Open
Abstract
Numerous physiological processes occur following bone fracture, including inflammatory cell recruitment, vascularization, and callus formation and remodeling. In particular circumstances, such as critical bone defects or osteonecrosis, the regenerative microenvironment is compromised, rendering endogenous stem/progenitor cells incapable of fully manifesting their reparative potential. Consequently, external interventions, such as grafting or augmentation, are frequently necessary. In situ bone tissue engineering (iBTE) employs cell-free scaffolds that possess microenvironmental cues, which, upon implantation, redirect the behavior of endogenous stem/progenitor cells towards a pro-regenerative inflammatory response and reestablish angiogenesis-osteogenesis coupling. This process ultimately results in vascularized bone regeneration (VBR). In this context, a comprehensive review of the current techniques and modalities in VBR-targeted iBTE technology is provided.
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Affiliation(s)
- Yijun He
- Department of Osteoarthropathy and Sports Medicine, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong 511400, P.R. China
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Lin Liang
- Department of Osteoarthropathy and Sports Medicine, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong 511400, P.R. China
| | - Cheng Luo
- Department of Osteoarthropathy and Sports Medicine, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong 511400, P.R. China
| | - Zhi-Yong Zhang
- Translational Research Centre of Regenerative Medicine and 3D Printing of Guangzhou Medical University, Guangdong Province Engineering Research Center for Biomedical Engineering, State Key Laboratory of Respiratory Disease, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, P.R. China
| | - Jiongfeng Huang
- Department of Osteoarthropathy and Sports Medicine, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong 511400, P.R. China
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27
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Song X, Okabe K, Ohta Y, Ohara G, Toyama N, Chang Q, Wang Y, Hibi H. Family with sequence similarity 20 member B regulates osteogenic differentiation of bone marrow mesenchymal stem cells on titanium surfaces. Acta Biomater 2023; 161:298-308. [PMID: 36871775 DOI: 10.1016/j.actbio.2023.02.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/14/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023]
Abstract
Successful bone regeneration on titanium (Ti) surfaces is a key process in dental implant treatment. Bone marrow mesenchymal stem cells (BMSCs) are fundamental cellular components of this process, and their early recruitment, proliferation, and differentiation into bone-forming osteoblasts are crucial. A proteoglycan (PG)-rich layer has been reported to exist between Ti surfaces and bones; however, the molecules that could potentially affect the formation of this layer remain unknown. Family with sequence similarity 20 member B (FAM20B) is a newly identified kinase that regulates the synthesis of glycosaminoglycans, an important component of the PG-rich layer. Because FAM20B is also closely associated with bone development, in this study, we examined the function of FAM20B in osteogenic differentiation of BMSCs on Ti surfaces. For this, BMSC cell lines with knocked down FAM20B (shBMSCs) were cultured on Ti surfaces. The results showed that the depletion of FAM20B reduced the formation of a PG-rich layer between the Ti surfaces and cells. The shBMSCs exhibited downregulated expression of osteogenic marker genes (ALP and OCN) and decreased mineral deposition. Moreover, shBMSCs reduced the molecular levels of p-ERK1/2, which plays an important role in MSC osteogenesis. The nuclear translocation of RUNX2, an important transcription factor for osteogenic differentiation, on the Ti surfaces is inhibited by the depletion of FAM20B in BMSCs. Moreover, the depletion of FAM20B reduced the transcriptional activity of RUNX2, which is important in regulating the expression of osteogenic genes. STATEMENT OF SIGNIFICANCE: Bone healing and regeneration on implanted titanium surfaces is a cell-material interaction. Such an interaction is enabled by bone marrow mesenchymal stem cells (BMSCs), and their early recruitment, proliferation, and differentiation into bone-forming osteoblasts are essential for bone healing and osseointegration. In this study, we found that the family with sequence similarity 20-B influenced the formation of a proteoglycan rich layer between BMSCs and the titanium surface and regulated the differentiation of BMSCs into bone-forming osteoblasts. We believe that our study contributes significantly to the further exploration of bone healing and osseointegration mechanisms on implanted titanium surfaces.
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Affiliation(s)
- Xinman Song
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
| | - Kazuto Okabe
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
| | - Yuya Ohta
- Department of Oral and Maxillofacial Surgery, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
| | - Go Ohara
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
| | - Naoto Toyama
- Department of Oral and Maxillofacial Surgery, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
| | - Qi Chang
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
| | - Yilin Wang
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
| | - Hideharu Hibi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan; Department of Oral and Maxillofacial Surgery, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
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28
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Song X, Xu L, Zhang W. Biomimetic synthesis and optimization of extracellular vesicles for bone regeneration. J Control Release 2023; 355:18-41. [PMID: 36706840 DOI: 10.1016/j.jconrel.2023.01.057] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/29/2023]
Abstract
Critical-size bone defect repair is in high demand but is difficult to treat. Modern therapies, such as autograft and cell-based treatments, face limitations, including potential immunological rejection and tumorigenesis. Therefore, extracellular vesicle (EV)-based strategies have been proposed as a novel approach for tissue regeneration owing to EVs' complex composition of lipids, proteins, and nucleic acids, as well as their low immunogenicity and congenital cell-targeting features. Despite these remarkable features of EVs, biomimetic synthesis and optimization of natural EVs can lead to enhanced bioactivity, increased cellular uptake, and specific cell targeting, aiming to achieve optimal therapeutic efficacy. To maximize their function, these nanoparticles can be integrated into bone graft biomaterials for superior bone regeneration. Herein, we summarize the role of naturally occurring EVs from distinct cell types in bone regeneration, the current strategies for optimizing biomimetic synthetic EVs in bone regeneration, and discuss the recent advances in applying bone graft biomaterials for the delivery of EVs to bone defect repair. We focused on distinct strategies for optimizing EVs with different functions and the most recent research on achieving time-controlled release of nanoparticles from EV-loaded biomaterials. Furthermore, we thoroughly discuss several current challenges and proposed solutions, aiming to provide insight into current progress, inspiration for future development directions, and incentives for clinical application in this field.
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Affiliation(s)
- Xinyu Song
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China
| | - Ling Xu
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China.
| | - Wenjie Zhang
- Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China; College of Stomatology, Shanghai Jiao Tong University, Shanghai, China; National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai, China.
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29
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The Roles of Exosomes in Metastasis of Sarcoma: From Biomarkers to Therapeutic Targets. Biomolecules 2023; 13:biom13030456. [PMID: 36979391 PMCID: PMC10046038 DOI: 10.3390/biom13030456] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
Sarcoma is a heterogeneous group of mesenchymal neoplasms with a high rate of lung metastasis. The cellular mechanisms responsible for sarcoma metastasis remain poorly understood. Furthermore, there are limited efficacious therapeutic strategies for treating metastatic sarcoma. Improved diagnostic and therapeutic modalities are of increasing importance for the treatment of sarcoma due to their high mortality in the advanced stages of the disease. Recent evidence demonstrates that the exosome, a type of extracellular vesicle released by virtually all cells in the body, is an important facilitator of intercellular communication between the cells and the surrounding environment. The exosome is gaining significant attention among the medical research community, but there is little knowledge about how the exosome affects sarcoma metastasis. In this review, we summarize the multifaceted roles of sarcoma-derived exosomes in promoting the process of metastasis via the formation of pre-metastatic niche (PMN), the regulation of immunity, angiogenesis, vascular permeability, and the migration of sarcoma cells. We also highlight the potential of exosomes as innovative diagnostic and prognostic biomarkers as well as therapeutic targets in sarcoma metastasis.
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30
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Gerami MH, Khorram R, Rasoolzadegan S, Mardpour S, Nakhaei P, Hashemi S, Al-Naqeeb BZT, Aminian A, Samimi S. Emerging role of mesenchymal stem/stromal cells (MSCs) and MSCs-derived exosomes in bone- and joint-associated musculoskeletal disorders: a new frontier. Eur J Med Res 2023; 28:86. [PMID: 36803566 PMCID: PMC9939872 DOI: 10.1186/s40001-023-01034-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 01/26/2023] [Indexed: 02/22/2023] Open
Abstract
Exosomes are membranous vesicles with a 30 to 150 nm diameter secreted by mesenchymal stem/stromal cells (MSCs) and other cells, such as immune cells and cancer cells. Exosomes convey proteins, bioactive lipids, and genetic components to recipient cells, such as microRNAs (miRNAs). Consequently, they have been implicated in regulating intercellular communication mediators under physiological and pathological circumstances. Exosomes therapy as a cell-free approach bypasses many concerns regarding the therapeutic application of stem/stromal cells, including undesirable proliferation, heterogeneity, and immunogenic effects. Indeed, exosomes have become a promising strategy to treat human diseases, particularly bone- and joint-associated musculoskeletal disorders, because of their characteristics, such as potentiated stability in circulation, biocompatibility, low immunogenicity, and toxicity. In this light, a diversity of studies have indicated that inhibiting inflammation, inducing angiogenesis, provoking osteoblast and chondrocyte proliferation and migration, and negative regulation of matrix-degrading enzymes result in bone and cartilage recovery upon administration of MSCs-derived exosomes. Notwithstanding, insufficient quantity of isolated exosomes, lack of reliable potency test, and exosomes heterogeneity hurdle their application in clinics. Herein, we will deliver an outline respecting the advantages of MSCs-derived exosomes-based therapy in common bone- and joint-associated musculoskeletal disorders. Moreover, we will have a glimpse the underlying mechanism behind the MSCs-elicited therapeutic merits in these conditions.
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Affiliation(s)
- Mohammad Hadi Gerami
- grid.412571.40000 0000 8819 4698Bone and Joint Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Roya Khorram
- grid.412571.40000 0000 8819 4698Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheil Rasoolzadegan
- grid.411600.2Department of Surgery, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeid Mardpour
- grid.411705.60000 0001 0166 0922Department of Radiology, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Pooria Nakhaei
- grid.411705.60000 0001 0166 0922Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Soheyla Hashemi
- grid.411036.10000 0001 1498 685XObstetrician, Gynaecology & Infertility Department, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Amir Aminian
- Bone and Joint Reconstruction Research Center, Shafa Orthopedic Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Sahar Samimi
- Tehran University of Medical Sciences, Tehran, Iran.
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31
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Cha KY, Cho W, Park S, Ahn J, Park H, Baek I, Lee M, Lee S, Arai Y, Lee SH. Generation of bioactive MSC-EVs for bone tissue regeneration by tauroursodeoxycholic acid treatment. J Control Release 2023; 354:45-56. [PMID: 36586671 DOI: 10.1016/j.jconrel.2022.12.053] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 12/24/2022] [Accepted: 12/26/2022] [Indexed: 01/02/2023]
Abstract
Extracellular vesicles (EVs) are nano-sized carriers that reflect the parent cell's information and are known to mediate cell-cell communication. In order to overcome the disadvantages of mesenchymal stem cells (MSCs) in cell therapy, such as unexpected differentiation leading to tumorization, immune rejection, and other side effects, EVs derived from MSCs (MSC-EVs) with the tissue regenerative function have been studied as new cell-free therapeutics. However, therapeutic applications of EVs require overcoming several challenges. First, the production efficiency of MSC-EVs should be increased at least as much as the quantity of them are required to their clinical application; second, MSC-EVs needs to show various functionality further, thereby increasing tissue regeneration efficiency. In this study, we treated tauroursodeoxycholic acid (TUDCA), a biological derivative known to regulate cholesterol, to MSCs and investigated whether TUDCA treatment would be able to increase EV production efficiency and tissue regenerative capacity of EVs. Indeed, it appears that TUDCA priming to MSC increases the yield of MSC-EVs >2 times by reducing the cellular cholesterol level in MSCs and increasing the exocytosis-related CAV1 expression. Interestingly, it was found that the EVs derived from TUDCA-primed MSCs (T-EV) contained higher amounts of anti-inflammatory cytokines (IL1RN, IL6, IL10, and IL11) and osteogenic proteins (ALP, RUNX2, BMP2, BMPR1, and BMPR2) than those in control MSC-EVs (C-EV). Besides, it was shown that T-EV not only regulated M1/M2 macrophages differentiation of monocytes, also effectively increased the osteogenic differentiation of MSCs as well as bone tissue regeneration in a bone defect rat model. Based on these results, it is concluded that TUDCA treatment to MSC as a new approach endows EV with high-yield production and functionality. Thus, we strongly believe T-EV would be a powerful therapeutic material for bone tissue regeneration and potentially could be expanded to other types of tissue regeneration for clinical applications.
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Affiliation(s)
- Kyung-Yup Cha
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Woongjin Cho
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Sunghyun Park
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Jinsung Ahn
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Hyoeun Park
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Inho Baek
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Minju Lee
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Sunjun Lee
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea
| | - Yoshie Arai
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea.
| | - Soo-Hong Lee
- Department of Medical Biotechnology, Dongguk University-Seoul, 04620 Seoul, South Korea.
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BMSC-Derived Exosomal CircHIPK3 Promotes Osteogenic Differentiation of MC3T3-E1 Cells via Mitophagy. Int J Mol Sci 2023; 24:ijms24032785. [PMID: 36769123 PMCID: PMC9917928 DOI: 10.3390/ijms24032785] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/20/2023] [Accepted: 01/28/2023] [Indexed: 02/05/2023] Open
Abstract
Exosome-based therapy is emerging as a promising strategy to promote bone regeneration due to exosomal bioactive cargos, among which circular RNA (circRNA) has recently been recognized as the key effector. The role of exosomal circRNA derived from bone marrow mesenchymal stem cells (BMSCs) has not been well-defined. The present study aimed to clarify the regulatory function and molecular mechanism of BMSC-derived exosomal circRNA in osteogenesis. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) were isolated and identified. BMSC-Exos' pro-osteogenic effect on MC3T3-E1 cells was validated by alkaline phosphatase (ALP) activity and Alizarin Red staining. Through bioinformatic analysis and molecular experiments, circHIPK3 was selected and verified as the key circRNA of BMSC-Exos to promote osteoblast differentiation of MC3T3-E1 cells. Mechanistically, circHIPK3 acted as an miR-29a-5p sponge and functioned in mitophagy via targeting miR-29a-5p and PINK1. Additionally, we showed that the mitophagy level of MC3T3-E1 cells were mediated by BMSC-Exos, which promoted the osteogenic differentiation. Collectively, our results revealed an important role for BMSC-derived exosomal circHIPK3 in osteogenesis. These findings provide a potentially effective therapeutic strategy for bone regeneration.
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Ju Y, Hu Y, Yang P, Xie X, Fang B. Extracellular vesicle-loaded hydrogels for tissue repair and regeneration. Mater Today Bio 2023; 18:100522. [PMID: 36593913 PMCID: PMC9803958 DOI: 10.1016/j.mtbio.2022.100522] [Citation(s) in RCA: 175] [Impact Index Per Article: 87.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/04/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Extracellular vesicles (EVs) are a collective term for nanoscale or microscale vesicles secreted by cells that play important biological roles. Mesenchymal stem cells are a class of cells with the potential for self-healing and multidirectional differentiation. In recent years, numerous studies have shown that EVs, especially those secreted by mesenchymal stem cells, can promote the repair and regeneration of various tissues and, thus, have significant potential in regenerative medicine. However, due to the rapid clearance capacity of the circulatory system, EVs are barely able to act persistently at specific sites for repair of target tissues. Hydrogels have good biocompatibility and loose and porous structural properties that allow them to serve as EV carriers, thereby prolonging the retention in certain specific areas and slowing the release of EVs. When EVs are needed to function at specific sites, the EV-loaded hydrogels can stand as an excellent approach. In this review, we first introduce the sources, roles, and extraction and characterization methods of EVs and describe their current application status. We then review the different types of hydrogels and discuss factors influencing their abilities to carry and release EVs. We summarize several strategies for loading EVs into hydrogels and characterizing EV-loaded hydrogels. Furthermore, we discuss application strategies for EV-loaded hydrogels and review their specific applications in tissue regeneration and repair. This article concludes with a summary of the current state of research on EV-loaded hydrogels and an outlook on future research directions, which we hope will provide promising ideas for researchers.
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Key Words
- 4-arm-PEG-MAL, four-armed polyethylene glycol (PEG) functionalized with maleimide group
- AD/CS/RSF, alginate-dopamine chondroitin sulfate and regenerated silk fibroin
- ADSC, Adipose derived mesenchymal stem cells
- ADSC-EVs, adipose mesenchymal stem cells derived EVs
- ADSC-Exos, adipose mesenchymal stem cells derived exosomes
- ATRP, Atom transfer radical polymerization
- BCA, bicinchoninic acid
- BMSC, Bone marrow mesenchymal stem cells
- BMSC-EVs, bone marrow mesenchymal stem cells derived EVs
- BMSC-Exos, bone marrow mesenchymal stem cells derived exosomes
- CGC, chitosan-gelatin-chondroitin sulfate
- CL, chitosan lactate
- CNS, central nervous system
- CPCs, cardiac progenitor cells
- CS-g-PEG, chitosan-g-PEG
- DPSC-Exos, dental pulp stem cells derived exosomes
- ECM, extracellular matrix
- EGF, epidermal growth factor
- EVMs, extracellular vesicles mimetics
- EVs, Extracellular vesicles
- Exos, Exosomes
- Exosome
- Extracellular vesicle
- FEEs, functionally engineered EVs
- FGF, fibroblast growth factor
- GelMA, Gelatin methacryloyl
- HA, Hyaluronic acid
- HAMA, Hyaluronic acid methacryloyl
- HG, nano-hydroxyapatite-gelatin
- HIF-1 α, hypoxia-inducible factor-1 α
- HS-HA, hypoxia-sensitive hyaluronic acid
- HUVEC, human umbilical vein endothelial cell
- Hydrogel
- LAP, Lithium Phenyl (2,4,6-trimethylbenzoyl) phosphinate
- LSCM, laser scanning confocal microscopy
- MC-CHO, Aldehyde methylcellulose
- MMP, matrix metalloproteinase
- MNs, microneedles
- MSC-EVs, mesenchymal stem cells derived EVs
- MSC-Exos, mesenchymal stem cells derived exosomes
- MSCs, mesenchymal stem cells
- NPCs, neural progenitor cells
- NTA, nanoparticle tracking analysis
- OHA, oxidized hyaluronic acid
- OSA, oxidized sodium alginate
- PDA, Polydopamine
- PDLLA, poly(D l-lactic acid)
- PDNPs-PELA, Polydopamine nanoparticles incorporated poly (ethylene glycol)-poly(ε-cap-rolactone-co-lactide)
- PEG, Polyethylene glycol
- PF-127, Pluronic F-127
- PHEMA, phenoxyethyl methacrylate
- PIC, photo-induced imine crosslinking
- PKA, protein kinase A system
- PLA, Poly lactic acid
- PLGA, polylactic acid-hydroxy acetic acid copolymer
- PLLA, poly(l-lactic acid)
- PPy, polypyrrole
- PVA, polyvinyl alcohol
- RDRP, Reversible deactivation radical polymerization
- Regeneration
- SCI, spinal cord injury
- SEM, Scanning electron microscopy
- SF, Silk fibroin
- SPT, single-particle tracking
- TEM, transmission electron microscopy
- Tissue repair
- UMSC, umbilical cord mesenchymal stem cells
- UMSC-EVs, umbilical cord mesenchymal stem cells derived EVs
- UMSC-Exos, umbilical cord mesenchymal stem cells derived exosomes
- UV, ultraviolet
- VEGF, vascular endothelial growth factor
- VEGF-R, vascular endothelial growth factor receptor
- WB, western blotting
- dECM, decellularized ECM
- hiPS-MSC-Exos, human induced pluripotent stem cell-MSC-derived exosomes
- iPS-CPCs, pluripotent stem cell-derived cardiac progenitors
- nHP, nanohydroxyapatite/poly-ε-caprolactone
- sEVs, small extracellular vesicles
- β-TCP, β-Tricalcium Phosphate
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Affiliation(s)
- Yikun Ju
- Department of Plastic and Aesthetic (Burn) Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China
| | - Yue Hu
- School of Clinical Medicine, North Sichuan Medical College, Nanchong, 637000, People's Republic of China
| | - Pu Yang
- Department of Plastic and Aesthetic (Burn) Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China
| | - Xiaoyan Xie
- Department of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China
| | - Bairong Fang
- Department of Plastic and Aesthetic (Burn) Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, People's Republic of China
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Liu F, Sun T, An Y, Ming L, Li Y, Zhou Z, Shang F. The potential therapeutic role of extracellular vesicles in critical-size bone defects: Spring of cell-free regenerative medicine is coming. Front Bioeng Biotechnol 2023; 11:1050916. [PMID: 36733961 PMCID: PMC9887316 DOI: 10.3389/fbioe.2023.1050916] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023] Open
Abstract
In recent years, the incidence of critical-size bone defects has significantly increased. Critical-size bone defects seriously affect patients' motor functions and quality of life and increase the need for additional clinical treatments. Bone tissue engineering (BTE) has made great progress in repairing critical-size bone defects. As one of the main components of bone tissue engineering, stem cell-based therapy is considered a potential effective strategy to regenerate bone tissues. However, there are some disadvantages including phenotypic changes, immune rejection, potential tumorigenicity, low homing efficiency and cell survival rate that restrict its wider clinical applications. Evidence has shown that the positive biological effects of stem cells on tissue repair are largely mediated through paracrine action by nanostructured extracellular vesicles (EVs), which may overcome the limitations of traditional stem cell-based treatments. In addition to stem cell-derived extracellular vesicles, the potential therapeutic roles of nonstem cell-derived extracellular vesicles in critical-size bone defect repair have also attracted attention from scholars in recent years. Currently, the development of extracellular vesicles-mediated cell-free regenerative medicine is still in the preliminary stage, and the specific mechanisms remain elusive. Herein, the authors first review the research progress and possible mechanisms of extracellular vesicles combined with bone tissue engineering scaffolds to promote bone regeneration via bioactive molecules. Engineering modified extracellular vesicles is an emerging component of bone tissue engineering and its main progression and clinical applications will be discussed. Finally, future perspectives and challenges of developing extracellular vesicle-based regenerative medicine will be given. This review may provide a theoretical basis for the future development of extracellular vesicle-based biomedicine and provide clinical references for promoting the repair of critical-size bone defects.
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Affiliation(s)
- Fen Liu
- Department of Periodontology, Shenzhen Stomatological Hospital (Pingshan), Southern Medical University, Shenzhen, Guangdong, China
| | - Tianyu Sun
- Department of Periodontology, Stomatological Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ying An
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture and Department of Periodontology, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Leiguo Ming
- Department of Research and Development, Shaanxi Zhonghong Institute of Regenerative Medicine, Xi’an, Shaanxi, China
| | - Yinghui Li
- Department of Orthodontics, Stomatological Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhifei Zhou
- Department of Stomatology, General Hospital of Tibetan Military Command, Lhasa, Tibet, China,*Correspondence: Fengqing Shang, ; Zhifei Zhou,
| | - Fengqing Shang
- Department of Stomatology, Air Force Medical Center, Fourth Military Medical University, Beijing, China,*Correspondence: Fengqing Shang, ; Zhifei Zhou,
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Cai R, Wang L, Zhang W, Liu B, Wu Y, Pang J, Ma C. The role of extracellular vesicles in periodontitis: pathogenesis, diagnosis, and therapy. Front Immunol 2023; 14:1151322. [PMID: 37114060 PMCID: PMC10126335 DOI: 10.3389/fimmu.2023.1151322] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 03/28/2023] [Indexed: 04/29/2023] Open
Abstract
Periodontitis is a prevalent disease and one of the leading causes of tooth loss. Biofilms are initiating factor of periodontitis, which can destroy periodontal tissue by producing virulence factors. The overactivated host immune response is the primary cause of periodontitis. The clinical examination of periodontal tissues and the patient's medical history are the mainstays of periodontitis diagnosis. However, there is a lack of molecular biomarkers that can be used to identify and predict periodontitis activity precisely. Non-surgical and surgical treatments are currently available for periodontitis, although both have drawbacks. In clinical practice, achieving the ideal therapeutic effect remains a challenge. Studies have revealed that bacteria produce extracellular vesicles (EVs) to export virulence proteins to host cells. Meanwhile, periodontal tissue cells and immune cells produce EVs that have pro- or anti-inflammatory effects. Accordingly, EVs play a critical role in the pathogenesis of periodontitis. Recent studies have also presented that the content and composition of EVs in saliva and gingival crevicular fluid (GCF) can serve as possible periodontitis diagnostic indicators. In addition, studies have indicated that stem cell EVs may encourage periodontal regeneration. In this article, we mainly review the role of EVs in the pathogenesis of periodontitis and discuss their diagnostic and therapeutic potential.
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Affiliation(s)
- Rong Cai
- Department of Stomatology, Air Force Medical Center, The Fourth Military Medical University, Beijing, China
| | - Lu Wang
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Wei Zhang
- Department of Stomatology, Air Force Medical Center, The Fourth Military Medical University, Beijing, China
| | - Bing Liu
- Department of Stomatology, Air Force Medical Center, The Fourth Military Medical University, Beijing, China
| | - Yiqi Wu
- Department of Critical Care Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Jianliang Pang
- Department of Stomatology, Air Force Medical Center, The Fourth Military Medical University, Beijing, China
- *Correspondence: Chufan Ma, ; Jianliang Pang,
| | - Chufan Ma
- Department of Stomatology, Air Force Medical Center, The Fourth Military Medical University, Beijing, China
- *Correspondence: Chufan Ma, ; Jianliang Pang,
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Wang S, Liu Z, Yang S, Huo N, Qiao B, Zhang T, Xu J, Shi Q. Extracellular vesicles secreted by human gingival mesenchymal stem cells promote bone regeneration in rat femoral bone defects. Front Bioeng Biotechnol 2023; 11:1098172. [PMID: 36896013 PMCID: PMC9989199 DOI: 10.3389/fbioe.2023.1098172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/10/2023] [Indexed: 02/25/2023] Open
Abstract
Extracellular vesicles (EVs), important components of paracrine secretion, are involved in various pathological and physiological processes of the body. In this study, we researched the benefits of EVs secreted by human gingival mesenchymal stem cells (hGMSC-derived EVs) in promoting bone regeneration, thereby providing new ideas for EVs-based bone regeneration therapy. Here, we successfully demonstrated that hGMSC-derived EVs could enhance the osteogenic ability of rat bone marrow mesenchymal stem cells and the angiogenic capability of human umbilical vein endothelial cells. Then, femoral defect rat models were created and treated with phosphate-buffered saline, nanohydroxyapatite/collagen (nHAC), a grouping of nHAC/hGMSCs, and a grouping of nHAC/EVs. The results of our study indicated that the combination of hGMSC-derived EVs and nHAC materials could significantly promote new bone formation and neovascularization with a similar effect to that of the nHAC/hGMSCs group. Our outcomes provide new messages on the role of hGMSC-derived EVs in tissue engineering, which exhibit great potential in bone regeneration treatment.
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Affiliation(s)
- Situo Wang
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.,Orthopedic Laboratory of PLA General Hospital, Beijing, China
| | - Ziwei Liu
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China.,Orthopedic Laboratory of PLA General Hospital, Beijing, China.,Medical School of Chinese PLA, Beijing, China
| | - Shuo Yang
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Na Huo
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Bo Qiao
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Tong Zhang
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Juan Xu
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Quan Shi
- Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Shi Y, Shao J, Zhang Z, Zhang J, Lu H. Effect of condylar chondrocyte exosomes on condylar cartilage osteogenesis in rats under tensile stress. Front Bioeng Biotechnol 2022; 10:1061855. [PMID: 36561044 PMCID: PMC9766957 DOI: 10.3389/fbioe.2022.1061855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Background: Functional orthoses are commonly used to treat skeletal Class II malocclusion, but the specific mechanism through which they do this has been a challenging topic in orthodontics. In the present study, we aimed to explore the effect of tensile stress on the osteogenic differentiation of condylar chondrocytes from an exosomal perspective. Methods: We cultured rat condylar chondrocytes under resting and tensile stress conditions and subsequently extracted cellular exosomes from them. We then screened miRNAs that were differentially expressed between the two exosome extracts by high-throughput sequencing and performed bioinformatics analysis and osteogenesis-related target gene prediction using the TargetScan and miRanda softwares. Exosomes cultured under resting and tensile stress conditions were co-cultured with condylar chondrocytes for 24 h to form the Control-Exo and Force-Exo exosome groups, respectively. Quantitative real time PCR(RT-qPCR) and western blotting were then used to determine the mRNA and protein expression levels of Runx2 and Sox9 in condylar chondrocytes. Results: The mRNA and protein expression levels of Runx2 and Sox9 in the Force-Exo group were significantly higher than those in the Control-Exo group (p < 0.05). The differential miRNA expression results were consistent with our sequencing results. Bioinformatics analysis and target gene prediction results showed that the main biological processes and molecular functions involved in differential miRNA expression in exosomes under tensile stress were biological processes and protein binding, respectively. Kyoto Gene and Genome Data Bank (KEGG) pathway enrichment analysis showed significant enrichment of differentially expressed miRNAs in the mTOR signaling pathway. The differentially expressed miRNAs were found to target osteogenesis-related genes. Conclusion: These results suggest that stimulation of rat condylar chondrocytes with tensile stress can alter the expression levels of certain miRNAs in their exosomes and promote their osteogenic differentiation. Exosomes under tensile stress culture conditions thus have potential applications in the treatment of Osteoarthritis (OA).
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Affiliation(s)
- Yuan Shi
- Department of Stomatology, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiaqi Shao
- Department of Stomatology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, China
| | - Zanzan Zhang
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, China
| | - Jianan Zhang
- Department of Dentistry, Center of Orthodontics, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou, China
| | - Haiping Lu
- Department of Stomatology, Zhejiang Chinese Medical University, Hangzhou, China,*Correspondence: Haiping Lu,
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The effect of mesenchymal stem cells-derived exosomes on the prostate, bladder, and renal cancer cell lines. Sci Rep 2022; 12:20924. [PMID: 36463254 PMCID: PMC9719468 DOI: 10.1038/s41598-022-23204-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/26/2022] [Indexed: 12/07/2022] Open
Abstract
We aimed to explain the role of mesenchymal stem cells (MSC-exosomes) on gene expressions of epithelial to mesenchymal transition (EMT), angiogenesis, and apoptosis. Four different cell lines were employed, including ACHN, 5637, LNCaP, and PC3, as well-known representatives for renal, bladder, hormone-sensitive, and hormone-refractory prostate cancers, respectively. Cell lines were exposed to diverse concentrations of mesenchymal stem cells-derived exosomes to find IC50 values. Percentages of apoptotic cells were evaluated by Annexin/P.I. staining. Micro Culture Tetrazolium Test assessed proliferative inhibitory effect; and prostate biomarker (KLK2), EMT (E-cadherin and Snail), angiogenesis genes (VEGF-A/VEGF-C), apoptosis genes (BAX/BCL2, P53) and Osteopontin variants (OPNa/b, and c) mRNA levels were studied by realtime PCR method. All 5637, LNCaP, and PC3 following treatment with exosomes illustrated specific responses with changes in expression of different genes. The increased TP53 and decreased BCL2 expressions were seen in 5637, LNCaP, and PC3. In PC3, OPNb and OPNc have raised more than P53; in LNCap, the increase was in VEGF-c. In 5637 cells, more than TP53 and BCL2 changes, two other genes, VEGFa and B.A.X., have decreased, suggesting exosomes' anti-apoptotic and anti-angiogenic effects. The kidney tumor cell line saw no significant gene expression change in ten targeted genes. MSC-exosomes therapy has augmented some interesting antitumor effects on prostate, bladder, and kidney cancer cell lines. This effect which originates from exosomes' potency to persuade apoptosis and prevent the proliferation of cancer cells simultaneously, was more substantial in bladder cancer, moderate in prostate cancer, and mild in renal cancer.
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Wang W, Liang X, Zheng K, Ge G, Chen X, Xu Y, Bai J, Pan G, Geng D. Horizon of exosome-mediated bone tissue regeneration: The all-rounder role in biomaterial engineering. Mater Today Bio 2022; 16:100355. [PMID: 35875196 PMCID: PMC9304878 DOI: 10.1016/j.mtbio.2022.100355] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 12/02/2022] Open
Abstract
Bone injury repair has always been a tricky problem in clinic, the recent emergence of bone tissue engineering provides a new direction for the repair of bone injury. However, some bone tissue processes fail to achieve satisfactory results mainly due to insufficient vascularization or cellular immune rejection. Exosomes with the ability of vesicle-mediated intercellular signal transmission have gained worldwide attention and can achieve cell-free therapy. Exosomes are small vesicles that are secreted by cells, which contain genetic material, lipids, proteins and other substances. It has been found to play the function of material exchange between cells. It is widely used in bone tissue engineering to achieve cell-free therapy because it not only does not produce some immune rejection like cells, but also can play a cell-like function. Exosomes from different sources can bind to scaffolds in various ways and affect osteoblast, angioblast, and macrophage polarization in vivo to promote bone regeneration. This article reviews the recent research progress of exosome-loaded tissue engineering, focusing on the mechanism of exosomes from different sources and the application of exosome-loaded scaffolds in promoting bone regeneration. Finally, the existing deficiencies and challenges, future development directions and prospects are summarized.
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Affiliation(s)
- Wentao Wang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China
| | - Xiaolong Liang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China
| | - Kai Zheng
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China
| | - Gaoran Ge
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China
| | - Xu Chen
- Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu, China
| | - Yaozeng Xu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China
| | - Jiaxiang Bai
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China
| | - Guoqing Pan
- Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu, China
| | - Dechun Geng
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, Jiangsu, China
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Effects of Human Deciduous Dental Pulp-Derived Mesenchymal Stem Cell-Derived Conditioned Medium on the Metabolism of HUVECs, Osteoblasts, and BMSCs. Cells 2022; 11:cells11203222. [PMID: 36291089 PMCID: PMC9600042 DOI: 10.3390/cells11203222] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022] Open
Abstract
In this study, we assessed the effects of human deciduous dental pulp-derived mesenchymal stem cell-derived conditioned medium (SHED-CM) on the properties of various cell types. The effects of vascular endothelial growth factor (VEGF) in SHED-CM on the luminal architecture, proliferative ability, and angiogenic potential of human umbilical vein endothelial cells (HUVECs) were determined. We also investigated the effects of SHED-CM on the proliferation of human-bone-marrow mesenchymal stem cells (hBMSCs) and mouse calvarial osteoblastic cells (MC3T3-E1) as well as the expression of ALP, OCN, and RUNX2. The protein levels of ALP were examined using Western blot analysis. VEGF blockade in SHED-CM suppressed the proliferative ability and angiogenic potential of HUVECs, indicating that VEGF in SHED-CM contributes to angiogenesis. The culturing of hBMSCs and MC3T3-E1 cells with SHED-CM accelerated cell growth and enhanced mRNA expression of bone differentiation markers. The addition of SHED-CM enhanced ALP protein expression in hBMSCs and MT3T3-E1 cells compared with that of the 0% FBS group. Furthermore, SHED-CM promoted the metabolism of HUVECs, MC3T3-E1 cells, and hBMSCs. These findings indicate the potential benefits of SHED-CM in bone tissue regeneration.
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Jahangiri B, Saei AK, Obi PO, Asghari N, Lorzadeh S, Hekmatirad S, Rahmati M, Velayatipour F, Asghari MH, Saleem A, Moosavi MA. Exosomes, autophagy and ER stress pathways in human diseases: Cross-regulation and therapeutic approaches. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166484. [PMID: 35811032 DOI: 10.1016/j.bbadis.2022.166484] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 06/01/2022] [Accepted: 07/03/2022] [Indexed: 02/08/2023]
Abstract
Exosomal release pathway and autophagy together maintain homeostasis and survival of cells under stressful conditions. Autophagy is a catabolic process through which cell entities, such as malformed biomacromolecules and damaged organelles, are degraded and recycled via the lysosomal-dependent pathway. Exosomes, a sub-type of extracellular vesicles (EVs) formed by the inward budding of multivesicular bodies (MVBs), are mostly involved in mediating communication between cells. The unfolded protein response (UPR) is an adaptive response that is activated to sustain survival in the cells faced with the endoplasmic reticulum (ER) stress through a complex network that involves protein synthesis, exosomes secretion and autophagy. Disruption of the critical crosstalk between EVs, UPR and autophagy may be implicated in various human diseases, including cancers and neurodegenerative diseases, yet the molecular mechanism(s) behind the coordination of these communication pathways remains obscure. Here, we review the available information on the mechanisms that control autophagy, ER stress and EV pathways, with the view that a better understanding of their crosstalk and balance may improve our knowledge on the pathogenesis and treatment of human diseases, where these pathways are dysregulated.
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Affiliation(s)
- Babak Jahangiri
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Ali Kian Saei
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Patience O Obi
- Applied Health Sciences, University of Manitoba, Winnipeg R3T 2N2, Canada; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg R3T 2N2, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg R3E 3P4, Canada
| | - Narjes Asghari
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Shirin Hekmatirad
- Department of Pharmacology and Toxicology, School of Medicine, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Marveh Rahmati
- Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Velayatipour
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Mohammad Hosseni Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Ayesha Saleem
- Applied Health Sciences, University of Manitoba, Winnipeg R3T 2N2, Canada; Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg R3T 2N2, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg R3E 3P4, Canada.
| | - Mohammad Amin Moosavi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran.
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Treatment Effect of Platelet Gel on Reconstructing Bone Defects and Nonunions: A Review of In Vivo Human Studies. Int J Mol Sci 2022; 23:ijms231911377. [PMID: 36232679 PMCID: PMC9570043 DOI: 10.3390/ijms231911377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/19/2022] [Accepted: 09/23/2022] [Indexed: 11/21/2022] Open
Abstract
In ideal circumstances, a fractured bone can heal properly by itself or with the aid of clinical interventions. However, around 5% to 10% of bone fractures fail to heal properly within the expected time even with the aid of clinical interventions, resulting in nonunions. Platelet gel is a blood-derived biomaterial used in regenerative medicine aiming to promote wound healing and regeneration of damaged tissues. The purpose of this paper is to review relevant articles in an attempt to explore the current consensus on the treatment effect of platelet gel on reconstructing bone defects and nonunions, hoping to provide a valuable reference for clinicians to make treatment decisions in clinical practice. Based on the present review, most of the studies applied the combination of platelet gel and bone graft to reconstruct bone defects and nonunions, and most of the results were positive, suggesting that this treatment strategy could promote successful reconstruction of bone defects and nonunions. Only two studies tried to apply platelet gel alone to reconstruct bone defects and nonunions, therefore a convincing conclusion could not be made yet regarding the treatment effect of platelet gel alone on reconstructing bone defects and nonunions. Only one study applied platelet gel combined with extracorporeal shock wave therapy to reconstruct nonunions, and the results were positive; the hypothetical mechanism of this treatment strategy is reasonable and sound, and more future clinical studies are encouraged to further justify the effectiveness of this promising treatment strategy. In conclusion, the application of platelet gel could be a promising and useful treatment method for reconstructing bone defects and nonunions, and more future clinical studies are encouraged to further investigate the effectiveness of this promising treatment method.
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Aimaletdinov AM, Gomzikova MO. Tracking of Extracellular Vesicles' Biodistribution: New Methods and Approaches. Int J Mol Sci 2022; 23:11312. [PMID: 36232613 PMCID: PMC9569979 DOI: 10.3390/ijms231911312] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/15/2022] [Accepted: 09/21/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are nanosized lipid bilayer vesicles that are released by almost all cell types. They range in diameter from 30 nm to several micrometres and have the ability to carry biologically active molecules such as proteins, lipids, RNA, and DNA. EVs are natural vectors and play an important role in many physiological and pathological processes. The amount and composition of EVs in human biological fluids serve as biomarkers and are used for diagnosing diseases and monitoring the effectiveness of treatment. EVs are promising for use as therapeutic agents and as natural vectors for drug delivery. However, the successful use of EVs in clinical practice requires an understanding of their biodistribution in an organism. Numerous studies conducted so far on the biodistribution of EVs show that, after intravenous administration, EVs are mostly localized in organs rich in blood vessels and organs associated with the reticuloendothelial system, such as the liver, lungs, spleen, and kidneys. In order to improve resolution, new dyes and labels are being developed and detection methods are being optimized. In this work, we review all available modern methods and approaches used to assess the biodistribution of EVs, as well as discuss their advantages and limitations.
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Affiliation(s)
| | - Marina O. Gomzikova
- Laboratory of Intercellular Communication, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
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Ji W, Lu Y, Ma Z, Gan K, Liu Y, Cheng Y, Xu J, Liu S, Guo Y, Han S, Zhao Z, Xu H, Qi W. Triptolide attenuates inhibition of ankylosing spondylitis-derived mesenchymal stem cells on the osteoclastogenesis through modulating exosomal transfer of circ-0110634. J Orthop Translat 2022; 36:132-144. [PMID: 36185580 PMCID: PMC9489540 DOI: 10.1016/j.jot.2022.05.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 03/30/2022] [Accepted: 05/19/2022] [Indexed: 10/25/2022] Open
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Ma S, Li X, Hu H, Ma X, Zhao Z, Deng S, Wang J, Zhang L, Wu C, Liu Z, Wang Y. Synergetic osteogenesis of extracellular vesicles and loading RGD colonized on 3D-printed titanium implants. Biomater Sci 2022; 10:4773-4784. [PMID: 35849688 DOI: 10.1039/d2bm00725h] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Titanium (Ti) and its alloys have been universally used as surgical implants, and the clinical need for modifying titanium surfaces to accelerate early stage osseointegration and prevent implant loosening is in huge demand. 3D printing technology is an accurate and controllable method to create titanium implants with complex nanostructures, which provide enough space to react and fit in the microenvironment of cells. Recently, extracellular vesicles (EVs) have attracted attention in promoting osteogenesis. The vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) have been proved to pack osteogenic-relative RNAs thereby regulating the osteogenic differentiation and mineralization of the target BMSCs. Arg-Gly-Asp (RGD)-derived peptides are typical peptides used to improve cell attachment and proliferation in bone tissue engineering. A novel strategy is proposed to load RGD-derived peptides on EVs with a fusion peptide (EVsRGD) and colonize EVsRGD on the titanium surface via a specific bonding peptide. In this study, we verify that the presence of EVsRGD enables the realization of the synergetic effect of EVs and RGD, enhancing the osteogenic differentiation and mineralization of BMSCs in vitro, resulting in satisfactory osseointegration around implants in vivo.
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Affiliation(s)
- Shiqing Ma
- Department of Stomotology, Tianjin Medical University Second Hospital, 23 Pingjiang Road, Hexi District, Tianjin, 300211, China
| | - Xuewen Li
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Han Hu
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Xinying Ma
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Zhezhe Zhao
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Shu Deng
- Department of Stomotology, Tianjin Medical University Second Hospital, 23 Pingjiang Road, Hexi District, Tianjin, 300211, China
| | - Jie Wang
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Leyu Zhang
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Chenxuan Wu
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Zihao Liu
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
| | - Yonglan Wang
- School and Hospital of Stomatology, Tianjin Medical University, 12 Observatory Road, Tianjin, 030070, China.
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Zhang L, Lin Y, Zhang X, Shan C. Research progress of exosomes in orthopedics. Front Genet 2022; 13:915141. [PMID: 36081990 PMCID: PMC9445804 DOI: 10.3389/fgene.2022.915141] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 07/05/2022] [Indexed: 11/30/2022] Open
Abstract
Exosomes are nano-extracellular vesicles secreted by a variety of cells. They are composed of a double-layer membrane that can transport a variety of proteins, coding and non-coding genes, and bioactive substances. Exosomes participate in information transmission between cells and regulate processes such as cell proliferation, migration, angiogenesis, and phenotypic transformation. They have broad prospects in the occurrence, development, and treatment of many diseases including orthopedics. Exosomes derived from different types of bone cells such as mesenchymal stem cells, osteoblasts, osteoclasts, and their precursors are recognized to play pivotal roles in bone remodeling processes including osteogenesis, osteoclastogenesis, and angiogenesis. This articlesummarizes the characteristics of exosomes and their research progress in bone remodeling, bone tumors, vascular skeletal muscle injury, spinal cord injury, degenerative disc diseases, cartilage degeneration, osteoarthritis, necrosis of the femoral head, and osteoporosis.
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Effects of Extracellular Vesicles from Osteogenic Differentiated Human BMSCs on Osteogenic and Adipogenic Differentiation Capacity of Naïve Human BMSCs. Cells 2022; 11:cells11162491. [PMID: 36010568 PMCID: PMC9406723 DOI: 10.3390/cells11162491] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 11/29/2022] Open
Abstract
Osteoporosis, or steroid-induced osteonecrosis of the hip, is accompanied by increased bone marrow adipogenesis. Such a disorder of adipogenic/osteogenic differentiation, affecting bone-marrow-derived mesenchymal stem cells (BMSCs), contributes to bone loss during aging. Here, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on the osteogenic and adipogenic differentiation capacity of naïve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of naïve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of naïve hBMSCs more effectively than EVs derived from naïve hBMSCs (naïve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of naïve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and naïve EVs contained distinct protein profiles, with pro-osteogenic and anti-adipogenic proteins encapsulated in osteogenic EVs. We speculate that osteogenic EVs could serve as an intercellular communication system between bone- and bone-marrow adipose tissue, for transporting osteogenic factors and thus favoring pro-osteogenic processes. Our data may support the theory of an endocrine circuit with the skeleton functioning as a ductless gland.
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Ma TL, Chen JX, Ke ZR, Zhu P, Hu YH, Xie J. Targeting regulation of stem cell exosomes: Exploring novel strategies for aseptic loosening of joint prosthesis. Front Bioeng Biotechnol 2022; 10:925841. [PMID: 36032702 PMCID: PMC9399432 DOI: 10.3389/fbioe.2022.925841] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/11/2022] [Indexed: 12/03/2022] Open
Abstract
Periprosthetic osteolysis is a major long-term complication of total joint replacement. A series of biological reactions caused by the interaction of wear particles at the prosthesis bone interface and surrounding bone tissue cells after artificial joint replacement are vital reasons for aseptic loosening. Disorder of bone metabolism and aseptic inflammation induced by wear particles are involved in the occurrence and development of aseptic loosening of the prosthesis. Promoting osteogenesis and angiogenesis and mediating osteoclasts and inflammation may be beneficial in preventing the aseptic loosening of the prosthesis. Current research about the prevention and treatment of aseptic loosening of the prosthesis focuses on drug, gene, and stem cell therapy and has not yet achieved satisfactory clinical efficacy or has not been used in clinical practice. Exosomes are a kind of typical extracellular vehicle. In recent years, stem cell exosomes (Exos) have been widely used to regulate bone metabolism, block inflammation, and have broad application prospects in tissue repair and cell therapy.
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Affiliation(s)
- Tian-Liang Ma
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Biomedical Metal and Ceramic Impants, Xiangya Hospital, Central South University, Changsha, China
- XiangYa School of Medicine, Central South University, Changsha, China
| | - Jing-Xian Chen
- XiangYa School of Medicine, Central South University, Changsha, China
| | - Zhuo-Ran Ke
- XiangYa School of Medicine, Central South University, Changsha, China
| | - Peng Zhu
- XiangYa School of Medicine, Central South University, Changsha, China
| | - Yi-He Hu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Biomedical Metal and Ceramic Impants, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Yi-He Hu, ; Jie Xie,
| | - Jie Xie
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- Hunan Engineering Research Center of Biomedical Metal and Ceramic Impants, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Yi-He Hu, ; Jie Xie,
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Wang D, Cao H, Hua W, Gao L, Yuan Y, Zhou X, Zeng Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Bone Defect Repair. MEMBRANES 2022; 12:716. [PMID: 35877919 PMCID: PMC9315966 DOI: 10.3390/membranes12070716] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/12/2022]
Abstract
The repair of critical bone defects is a hotspot of orthopedic research. With the development of bone tissue engineering (BTE), there is increasing evidence showing that the combined application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes, with hydrogels, scaffolds, and other bioactive materials has made great progress, exhibiting a good potential for bone regeneration. Recent studies have found that miRNAs, proteins, and other cargo loaded in EVs are key factors in promoting osteogenesis and angiogenesis. In BTE, the expression profile of the intrinsic cargo of EVs can be changed by modifying the gene expression of MSCs to obtain EVs with enhanced osteogenic activity and ultimately enhance the osteoinductive ability of bone graft materials. However, the current research on MSC-EVs for repairing bone defects is still in its infancy, and the underlying mechanism remains unclear. Therefore, in this review, the effect of bioactive materials such as hydrogels and scaffolds combined with MSC-EVs in repairing bone defects is summarized, and the mechanism of MSC-EVs promoting bone defect repair by delivering active molecules such as internal miRNAs is further elucidated, which provides a theoretical basis and reference for the clinical application of MSC-EVs in repairing bone defects.
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Affiliation(s)
- Dongxue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Hong Cao
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Weizhong Hua
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Lu Gao
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
| | - Yu Yuan
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Xuchang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; (H.C.); (Y.Y.)
| | - Zhipeng Zeng
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China; (D.W.); (W.H.); (L.G.)
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50
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Zhu Y, Zhao S, Cheng L, Lin Z, Zeng M, Ruan Z, Sun B, Luo Z, Tang Y, Long H. Mg 2+ -mediated autophagy-dependent polarization of macrophages mediates the osteogenesis of bone marrow stromal stem cells by interfering with macrophage-derived exosomes containing miR-381. J Orthop Res 2022; 40:1563-1576. [PMID: 34727384 DOI: 10.1002/jor.25189] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/02/2021] [Accepted: 09/30/2021] [Indexed: 02/04/2023]
Abstract
Magnesium ion (Mg2+ ) has received increased attention due to the roles it plays in promoting osteogenesis and preventing inflammation. This study was designed to investigate the mechanism by which Mg2+ influences the osteoblastic differentiation of bone marrow stromal stem cells (BMSCs). The polarization of Mø (macrophages) was measured after treatment with Mg2+ . Meanwhile, autophagy in Mø was measured by detecting LC3B expression. Mø-derived exosomes were isolated and cocultured with BMSCs; after which, osteogenic differentiation was evaluated by Alizarin Red staining and detection of alkaline phosphatase (ALP). Our results showed that Mg2+ could induce autophagy in macrophages and modulate the M1/M2 polarization of macrophages. Mg2+ -mediated macrophages could facilitate the osteogenic differentiation of BMSCs by regulating autophagy, and this facilitation by Mg2+ -mediated macrophages was closely related to macrophage-derived exosomes, and especially exosomes containing miR-381. However, miR-381 in macrophages did not influence autophagy or the polarization of Mg2+ -mediated macrophages. Furthermore, macrophage-derived exosomes containing miR-381 mainly determined the osteogenic differentiation of BMSCs. Mg2+ -mediated macrophages were shown to promote the osteogenic differentiation of BMSCs via autophagy through reducing miR-381 in macrophage-derived exosomes. In conclusion, our results suggest Mg2+ -mediated macrophage-derived exosomes containing miR-381 as novel vehicles for promoting the osteogenic differentiation of BMSCs.
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Affiliation(s)
- Yong Zhu
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Shushan Zhao
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Liang Cheng
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Zhangyuan Lin
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Min Zeng
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Zhe Ruan
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Buhua Sun
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Zhongwei Luo
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
| | - Yifu Tang
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China.,Department of Orthopaedics, Xiangya Third Hospital of Central South University, Changsha, Hunan, PR China
| | - Haitao Long
- Department of Orthopaedics, Xiangya Hospital of Central South University, Changsha, Hunan, PR China
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