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Hoang VT, Nguyen QT, Phan TTK, Pham TH, Dinh NTH, Anh LPH, Dao LTM, Bui VD, Dao H, Le DS, Ngo ATL, Le Q, Nguyen Thanh L. Tissue Engineering and Regenerative Medicine: Perspectives and Challenges. MedComm (Beijing) 2025; 6:e70192. [PMID: 40290901 PMCID: PMC12022429 DOI: 10.1002/mco2.70192] [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: 07/06/2024] [Revised: 12/30/2024] [Accepted: 03/04/2025] [Indexed: 04/30/2025] Open
Abstract
From the pioneering days of cell therapy to the achievement of bioprinting organs, tissue engineering, and regenerative medicine have seen tremendous technological advancements, offering solutions for restoring damaged tissues and organs. However, only a few products and technologies have received United States Food and Drug Administration approval. This review highlights significant progress in cell therapy, extracellular vesicle-based therapy, and tissue engineering. Hematopoietic stem cell transplantation is a powerful tool for treating many diseases, especially hematological malignancies. Mesenchymal stem cells have been extensively studied. The discovery of induced pluripotent stem cells has revolutionized disease modeling and regenerative applications, paving the way for personalized medicine. Gene therapy represents an innovative approach to the treatment of genetic disorders. Additionally, extracellular vesicle-based therapies have emerged as rising stars, offering promising solutions in diagnostics, cell-free therapeutics, drug delivery, and targeted therapy. Advances in tissue engineering enable complex tissue constructs, further transforming the field. Despite these advancements, many technical, ethical, and regulatory challenges remain. This review addresses the current bottlenecks, emphasizing novel technologies and interdisciplinary research to overcome these hurdles. Standardizing practices and conducting clinical trials will balance innovation and regulation, improving patient outcomes and quality of life.
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Affiliation(s)
- Van T. Hoang
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quyen Thi Nguyen
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang Thi Kieu Phan
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Trang H. Pham
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Nhung Thi Hong Dinh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Le Phuong Hoang Anh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Lan Thi Mai Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Van Dat Bui
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- School of Chemical EngineeringCollege of EngineeringSungkyunkwan University (SKKU)SuwonRepublic of Korea
| | - Hong‐Nhung Dao
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Duc Son Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Anh Thi Lan Ngo
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Quang‐Duong Le
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene TechnologyCollege of Health SciencesVinUniversityVinhomes Ocean ParkHanoiVietnam
- Vinmec Health Care SystemHanoiVietnam
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Liu L, Chen H, Zhao X, Han Q, Xu Y, Liu Y, Zhang A, Li Y, Zhang W, Chen B, Wang J. Advances in the application and research of biomaterials in promoting bone repair and regeneration through immune modulation. Mater Today Bio 2025; 30:101410. [PMID: 39811613 PMCID: PMC11731593 DOI: 10.1016/j.mtbio.2024.101410] [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: 07/06/2024] [Revised: 12/02/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025] Open
Abstract
With the ongoing development of osteoimmunology, increasing evidence indicates that the local immune microenvironment plays a critical role in various stages of bone formation. Consequently, modulating the immune inflammatory response triggered by biomaterials to foster a more favorable immune microenvironment for bone regeneration has emerged as a novel strategy in bone tissue engineering. This review first examines the roles of various immune cells in bone tissue injury and repair. Then, the contributions of different biomaterials, including metals, bioceramics, and polymers, in promoting osteogenesis through immune regulation, as well as their future development directions, are discussed. Finally, various design strategies, such as modifying the physicochemical properties of biomaterials and integrating bioactive substances, to optimize material design and create an immune environment conducive to bone formation, are explored. In summary, this review comprehensively covers strategies and approaches for promoting bone tissue regeneration through immune modulation. It offers a thorough understanding of current research trends in biomaterial-based immune regulation, serving as a theoretical reference for the further development and clinical application of biomaterials in bone tissue engineering.
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Affiliation(s)
- Li Liu
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Hao Chen
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Xue Zhao
- Department of Endocrinology, The First Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Qing Han
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Yongjun Xu
- Department of Orthopedics Surgery, Wangqing County People's Hospital, Yanbian, 133000, Jilin, China
| | - Yang Liu
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Aobo Zhang
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Yongyue Li
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Weilong Zhang
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Bingpeng Chen
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
| | - Jincheng Wang
- Department of Orthopedic Surgery, The Second Hospital of Jilin University, Changchun, 130000, Jilin, China
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Emami A, Arabpour Z, Izadi E. Extracellular vesicles: essential agents in critical bone defect repair and therapeutic enhancement. Mol Biol Rep 2025; 52:113. [PMID: 39798011 DOI: 10.1007/s11033-024-10209-0] [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: 12/09/2024] [Accepted: 12/29/2024] [Indexed: 01/13/2025]
Abstract
Bone serves as a fundamental structural component in the body, playing pivotal roles in support, protection, mineral supply, and hormonal regulation. However, critical-sized bone injuries have become increasingly prevalent, necessitating extensive medical interventions due to limitations in the body's capacity for self-repair. Traditional approaches, such as autografts, allografts, and xenografts, have yielded unsatisfactory results. Stem cell therapy emerges as a promising avenue, but challenges like immune rejection and low cell survival rates hinder its widespread clinical implementation. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have garnered attention for their regenerative capabilities, which surpass those of MSCs themselves. EVs offer advantages such as reduced immunogenicity, enhanced stability, and simplified storage, positioning them as a promising tool in stem cell-based therapies. This review explores the potential of EV-based therapy in bone tissue regeneration, delving into their biological characteristics, communication mechanisms, and preclinical applications across various physiological and pathological conditions. The mechanisms underlying EV-mediated bone regeneration, including angiogenesis, osteoblast proliferation, mineralization, and immunomodulation, are elucidated. Preclinical studies demonstrate the efficacy of EVs in promoting bone repair and neovascularization, even in pathological conditions like osteoporosis. EVs hold promise as a potential alternative for regenerating bone tissue, particularly in the context of critical-sized bone defects, offering new avenues for effective bone defect repair and management.
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Affiliation(s)
- Asrin Emami
- Iranian Tissue Bank and Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| | - Zohreh Arabpour
- Department of Ophthalmology and Visual Science and University of Illinois, Chicago, IL, 60612, USA
| | - Elaheh Izadi
- Pediatric Cell, and Gene Therapy Research Center Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Li G, Wu J, Cheng X, Pei X, Wang J, Xie W. Nanoparticle-Mediated Gene Delivery for Bone Tissue Engineering. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024:e2408350. [PMID: 39623813 DOI: 10.1002/smll.202408350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/13/2024] [Indexed: 03/17/2025]
Abstract
Critical-sized bone defects represent an urgent clinical problem, necessitating innovative treatment approaches. Gene-activated grafts for bone tissue engineering have emerged as a promising solution. However, traditional gene delivery methods are constrained by limited osteogenic efficacy and safety concerns. Recently, organic and inorganic nanoparticle (NP) vectors have attracted significant attention in bone tissue engineering for their safe, stable, and controllable gene delivery. Targeted gene delivery guided by insights into bone healing mechanisms, coupled with the multifunctional design of NPs, is crucial for enhancing therapeutic outcomes. Here, the theoretical foundations underlying NP-mediated gene therapy for enhancing bone healing across different histological stages are elucidated. Furthermore, the distinct attributes of functionalized NP vectors are discussed, and cutting-edge strategies aimed at optimizing gene delivery efficiency throughout the therapeutic process are highlighted. Additionally, the review addresses the unresolved challenges and prospects of this technology. This review may contribute to the continued development and clinical application of NP-mediated gene delivery for treating critical-sized bone defects.
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Affiliation(s)
- Guangzhao Li
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jiaxin Wu
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xinting Cheng
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Disease, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou, 310006, China
| | - Xibo Pei
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jian Wang
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Wenjia Xie
- State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China
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Wu Y, Song P, Wang M, Liu H, Jing Y, Su J. Extracellular derivatives for bone metabolism. J Adv Res 2024; 66:329-347. [PMID: 38218580 PMCID: PMC11674789 DOI: 10.1016/j.jare.2024.01.011] [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: 11/03/2023] [Revised: 12/13/2023] [Accepted: 01/09/2024] [Indexed: 01/15/2024] Open
Abstract
BACKGROUND Bone metabolism can maintain the normal homeostasis and function of bone tissue. Once the bone metabolism balance is broken, it will cause osteoporosis, osteoarthritis, bone defects, bone tumors, or other bone diseases. However, such orthopedic diseases still have many limitations in clinical treatment, such as drug restrictions, drug tolerance, drug side effects, and implant rejection. AIM OF REVIEW In complex bone therapy and bone regeneration, extracellular derivatives have become a promising research focus to solve the problems of bone metabolic diseases. These derivatives, which include components such as extracellular matrix, growth factors, and extracellular vesicles, have significant therapeutic potential. It has the advantages of good biocompatibility, low immune response, and dynamic demand for bone tissue. The purpose of this review is to provide a comprehensive perspective on extracellular derivatives for bone metabolism and elucidate the intrinsic properties and versatility of extracellular derivatives. Further discussion of them as innovative advanced orthopedic materials for improving the effectiveness of bone therapy and regeneration processes. KEY SCIENTIFIC CONCEPTS OF REVIEW In this review, we first listed the types and functions of three extracellular derivatives. Then, we discussed the effects of extracellular derivatives of different cell sources on bone metabolism. Subsequently, we collected applications of extracellular derivatives in the treatment of bone metabolic diseases and summarized the advantages and challenges of extracellular derivatives in clinical applications. Finally, we prospected the extracellular derivatives in novel orthopedic materials and clinical applications. We hope that the comprehensive understanding of extracellular derivatives in bone metabolism will provide new solutions to bone diseases.
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Affiliation(s)
- Yan Wu
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Peiran Song
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Miaomiao Wang
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Department of Rehabilitation Medicine, Shanghai Zhongye Hospital, Shanghai 200941, China
| | - Han Liu
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Organoid Research Center, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
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Košuthová H, Fecskeová LK, Matejová J, Slovinská L, Morávek M, Bártová Z, Harvanová D. Effects of Replicative Senescence of Human Chorionic MSCs on their EV-miRNA Profile. Stem Cell Rev Rep 2024; 20:2318-2335. [PMID: 39305404 PMCID: PMC11554840 DOI: 10.1007/s12015-024-10790-8] [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] [Accepted: 09/15/2024] [Indexed: 11/12/2024]
Abstract
Chorionic mesenchymal stromal cells (CHO-MSCs) and their extracellular vesicles (EVs) are becoming increasingly popular, since chorion is ethically harmless and an easily accessible source of MSCs. However, until now there is only a limited number of studies with a thorough characterization of CHO-MSCs derived EVs and their miRNA profile. In this study, we monitored changes in the EV-miRNA profile between early and late passage of human CHO-MSCs. First, senescence of CHO-MSCs was induced by serial passaging and confirmed by morphological changes, shortened telomeres and changes in the expression of selected genes. The expression of MSCs-specific surface markers CD73, CD90, CD105 did not change with increasing passages. Next, EVs and their miRNA profiles were compared between early vs late passage cells. Number of EVs and their size were not significantly changed. Seven of the top 10 most expressed EV-miRNAs were common to both early and late passages. A differential expression study between early and late passages identified 37 significantly differentially expressed EV-miRNAs, out of which 23 were found to be associated with pathways of cellular senescence based on KEGG pathway analysis. A set of 9 miRNAs were identified as the most frequently associated with senescence and/or with the most altered expression between early and late passages, out of which miR-145-5p, miR-335-5p and miR-199b-3p were the most significant downregulated miRNAs in late passages. The most upregulated EV-miRNAs were miR-1307-3p, miR-3615 and miR320b. Targeting these miRNAs in future experiments may prolong the therapeutic potential of CHO-MSCs and their EVs.
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Affiliation(s)
- Hedviga Košuthová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Lívia K Fecskeová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia.
| | - Jana Matejová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Lucia Slovinská
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Marko Morávek
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
| | - Zuzana Bártová
- Institute of Geotechnics of the Slovak Academy of Sciences, Watsonova 45, 040 01, Kosice, Slovakia
| | - Denisa Harvanová
- Associated Tissue Bank, Faculty of Medicine, Pavol Jozef Safarik University and Louis Pasteur University Hospital, Trieda SNP 1, 04011, Kosice, Slovakia
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Peng B, Wang L, Han G, Cheng Y. Mesenchymal stem cell-derived exosomes: a potential cell-free therapy for orthodontic tooth stability management. Stem Cell Res Ther 2024; 15:342. [PMID: 39354604 PMCID: PMC11446149 DOI: 10.1186/s13287-024-03962-3] [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: 08/28/2024] [Accepted: 09/25/2024] [Indexed: 10/03/2024] Open
Abstract
Orthodontic relapse (OR) occurs at a rate of over 70%. Retention is the current attempt at prevention, but it requires a considerable amount of time and cannot fully block OR. It's imperative to find a safe and effective method for managing post-orthodontic tooth stability. Periodontal bone remodeling is one crucial biological foundation of OR. Mesenchymal stem cell-derived exosomes (MSC-Exo) show promise in relapse management by regulating periodontal bone remodeling. MSC-Exo can prevent relapse by regulating periodontal ligament function, osteoclast activity, osteoblast differentiation, macrophage polarization, and periodontal microcirculation. In recent years, exosome-loaded hydrogels, which achieve controlled exosome release, have demonstrated efficacy in promoting bone regeneration and remodeling, offering promising prospects for OR management. This review aims to highlight the use of MSC-Exo-based therapy for preventing OR, offering new insights for future research focused on improving tooth stability and enhancing orthodontic anchorage.
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Affiliation(s)
- Boyuan Peng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China
| | - Lianhao Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China
| | - Guangli Han
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China.
- Department of Orthodontics Division II, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
| | - Yong Cheng
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, No.237, Luo Yu Road, Hongshan District, Wuhan City, 430079, China.
- Department of Oral Radiology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
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Hu X, Yang S, Zhao W, Zhang Z, Qiao L, Wu H, Su Q, Che L, Zhou K, Li K, He J. Novel multi-functional microsphere scaffold with shape memory function for bone regeneration. BIOMATERIALS ADVANCES 2024; 163:213958. [PMID: 39053385 DOI: 10.1016/j.bioadv.2024.213958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/09/2024] [Accepted: 07/12/2024] [Indexed: 07/27/2024]
Abstract
Irregular bone defects caused by trauma and bone diseases provide a complex implant environment for surgery. Traditional implants often fail to integrate well with the surrounding bone defect interface, therefore, developing an artificial bone scaffold that can adapt to irregular bone defect boundaries is of significant importance for bone defect repair. This study successfully utilized a shape memory ternary copolymer polylactic acid-trimethylene carbonate-hydroxyacetic acid (PLLA-TMC-GA) and dopamine-modified nano-hydroxyapatite (PHA) composite to construct a temperature-responsive bone repair scaffold (PTG/PHA), thereby enhancing the interface compatibility between the implant and the surrounding environment. The addition of PHA has effectively improved the hydrophilicity of the stent and significantly increased its mechanical strength. Furthermore, the Sodium alginate (SA) hydrogel loaded with Icariin (Ica) coated on the stent surface promotes the growth and differentiation of bone cells through the drug-scaffold synergistic effect. Both in vivo and in vitro experiments have shown that the synergistic effect of the composite stent with Icariin significantly enhances the repair of bone defects. This study provides a promising tissue engineering method for the repair of irregular bone defects.
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Affiliation(s)
- Xulin Hu
- Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan 610081, China; Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shuhao Yang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Weiming Zhao
- Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan 610081, China
| | - Zhen Zhang
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liang Qiao
- Henan Univ Sci & Technol, Affiliated Hosp 1, Key Lab Neuromol Biol, Coll Clin Med, Luoyang, Henan 471003, China
| | - Haoming Wu
- Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan 610081, China
| | - Qiao Su
- West China School of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lanyu Che
- Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan 610081, China
| | - Kai Zhou
- Department of Orthopedics and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
| | - Kainan Li
- Clinical Medical College and Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan 610081, China.
| | - Jian He
- College of Basic Medicine and Forensic Medicine, Henan University of Science and Technology, Luoyang, Henan 471000, China.
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Chen R, Tong Y, Hu X, Wang W, Liao F. circSLTM knockdown attenuates chondrocyte inflammation, apoptosis and ECM degradation in osteoarthritis by regulating the miR-515-5p/VAPB axis. Int Immunopharmacol 2024; 138:112435. [PMID: 38981227 DOI: 10.1016/j.intimp.2024.112435] [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: 02/24/2024] [Revised: 05/20/2024] [Accepted: 06/05/2024] [Indexed: 07/11/2024]
Abstract
Osteoarthritis (OA) is a prevalent joint disorder characterized by cartilage degeneration. Circular RNAs (circRNAs) have emerged as pivotal players in OA progression, orchestrating various biological processes such as proliferation, apoptosis, inflammation, and extracellular matrix (ECM) reorganization. Among these circRNAs, circSLTM exhibits aberrant expression in OA, yet its precise regulatory mechanism remains elusive. This study aimed to elucidate the regulatory mechanisms of circSLTM in OA pathogenesis, with a focus on its role as a competing endogenous RNA (ceRNA). Human cartilage tissues were procured from both OA patients and non-OA individuals, while human chondrocyte cells were subjected to lipopolysaccharide (LPS) treatment to mimic OA-like conditions. Our findings revealed upregulation of circSLTM in OA patients and LPS-treated chondrocytes. Loss-of-function assays were conducted, demonstrating that silencing circSLTM via shRNAs mitigated LPS-induced effects on chondrocytes, as evidenced by enhanced proliferation, reduced apoptosis, and inflammatory factors, and altered expression of extracellular matrix proteins. Further exploration into the regulatory mechanism of circSLTM unveiled its interaction with microRNA-515-5p (miR-515-5p) to modulate vesicle-associated membrane protein (VAPB) expression in chondrocytes. VAPB, also upregulated in OA, was positively regulated by circSLTM. Rescue assays corroborated that VAPB overexpression reinstated the protective effects of circSLTM knockdown on LPS-treated chondrocytes. Moreover, concurrent knockdown of both circSLTM and VAPB demonstrated synergistic protection against LPS-induced chondrocyte injury. Additionally, we delineated that LPS triggered the activation of the NF-κB pathway in chondrocytes, which was counteracted by circSLTM silencing. To assess the effects of circSLTM on OA in vivo, anterior cruciate ligament transection (ACLT) mouse models were established, revealing that circSLTM deficiency ameliorated cartilage defects in vivo. In conclusion, circSLTM exacerbates osteoarthritis progression by orchestrating the miR-515-5p/VAPB axis and activating the NF-κB pathway, providing novel insights for targeted therapy in OA management.
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Affiliation(s)
- Rijiang Chen
- Department of Orthopedics, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian 364000, China.
| | - Yan Tong
- Department of Endocrine, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian 364000, China.
| | - Xiunian Hu
- Department of Orthopedics, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian 364000, China.
| | - Wantao Wang
- Department of Orthopedics, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian 364000, China.
| | - Fake Liao
- Department of Orthopedics, Longyan First Affiliated Hospital of Fujian Medical University, Longyan, Fujian 364000, China.
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Wan X, Zhang W, Dai L, Chen L. The Role of Extracellular Vesicles in Bone Regeneration and Associated Bone Diseases. Curr Issues Mol Biol 2024; 46:9269-9285. [PMID: 39329900 PMCID: PMC11430372 DOI: 10.3390/cimb46090548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 08/18/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024] Open
Abstract
Extracellular vesicles (EVs) are nanoscale particles with a lipid bilayer membrane structure secreted by various cell types. Nearly all human cells secrete EVs, primarily mediating intercellular communication. In recent years, scientists have discovered that EVs can carry multiple biological cargos, such as DNA, non-coding RNAs (ncRNAs), proteins, cytokines, and lipids, and mediate intercellular signal transduction. Bone is a connective tissue with a nerve supply and high vascularization. The repair process after injury is highly complex, involving interactions among multiple cell types and biological signaling pathways. Bone regeneration consists of a series of coordinated osteoconductive and osteoinductive biological processes. As mediators of intercellular communication, EVs can promote bone regeneration by regulating osteoblast-mediated bone formation, osteoclast-mediated bone resorption, and other pathways. This review summarizes the biogenesis of EVs and the mechanisms by which EV-mediated intercellular communication promotes bone regeneration. Additionally, we focus on the research progress of EVs in various diseases related to bone regeneration. Finally, based on the above research, we explore the clinical applications of engineered EVs in the diagnosis and treatment of bone regeneration-related diseases.
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Affiliation(s)
- Xinyue Wan
- School of Medicine, Chongqing University, Chongqing 400030, China; (X.W.); (W.Z.); (L.D.)
| | - Wenjie Zhang
- School of Medicine, Chongqing University, Chongqing 400030, China; (X.W.); (W.Z.); (L.D.)
| | - Lingyan Dai
- School of Medicine, Chongqing University, Chongqing 400030, China; (X.W.); (W.Z.); (L.D.)
| | - Liang Chen
- School of Medicine, Chongqing University, Chongqing 400030, China; (X.W.); (W.Z.); (L.D.)
- Department of Bone and Soft Tissue Oncology, Chongqing University Cancer Hospital, Chongqing University School of Medicine, Chongqing 400030, China
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11
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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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12
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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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Hu L, Chen W, Qian A, Li YP. Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and disease. Bone Res 2024; 12:39. [PMID: 38987555 PMCID: PMC11237130 DOI: 10.1038/s41413-024-00342-8] [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: 12/10/2023] [Revised: 04/27/2024] [Accepted: 05/12/2024] [Indexed: 07/12/2024] Open
Abstract
Wnts are secreted, lipid-modified proteins that bind to different receptors on the cell surface to activate canonical or non-canonical Wnt signaling pathways, which control various biological processes throughout embryonic development and adult life. Aberrant Wnt signaling pathway underlies a wide range of human disease pathogeneses. In this review, we provide an update of Wnt/β-catenin signaling components and mechanisms in bone formation, homeostasis, and diseases. The Wnt proteins, receptors, activators, inhibitors, and the crosstalk of Wnt signaling pathways with other signaling pathways are summarized and discussed. We mainly review Wnt signaling functions in bone formation, homeostasis, and related diseases, and summarize mouse models carrying genetic modifications of Wnt signaling components. Moreover, the therapeutic strategies for treating bone diseases by targeting Wnt signaling, including the extracellular molecules, cytosol components, and nuclear components of Wnt signaling are reviewed. In summary, this paper reviews our current understanding of the mechanisms by which Wnt signaling regulates bone formation, homeostasis, and the efforts targeting Wnt signaling for treating bone diseases. Finally, the paper evaluates the important questions in Wnt signaling to be further explored based on the progress of new biological analytical technologies.
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Affiliation(s)
- Lifang Hu
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China
| | - Wei Chen
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA
| | - Airong Qian
- Laboratory for Bone Metabolism, Xi'an Key Laboratory of Special Medicine and Health Engineering, Key Laboratory for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, 710072, China.
| | - Yi-Ping Li
- Division in Cellular and Molecular Medicine, Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, Tulane University, New Orleans, LA, 70112, USA.
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14
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Zhao Q, Zhang X, Li Y, He Z, Qin K, Buhl EM, Mert Ü, Horst K, Hildebrand F, Balmayor ER, Greven J. Porcine Mandibular Bone Marrow-Derived Mesenchymal Stem Cell (BMSC)-Derived Extracellular Vesicles Can Promote the Osteogenic Differentiation Capacity of Porcine Tibial-Derived BMSCs. Pharmaceutics 2024; 16:279. [PMID: 38399333 PMCID: PMC10893405 DOI: 10.3390/pharmaceutics16020279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/02/2024] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
OBJECTIVE Existing research suggests that bone marrow-derived mesenchymal stem cells (BMSCs) may promote endogenous bone repair. This may be through the secretion of factors that stimulate repair processes or directly through differentiation into osteoblast-progenitor cells. However, the osteogenic potential of BMSCs varies among different tissue sources (e.g., mandibular versus long BMSCs). The main aim of this study was to investigate the difference in osteogenic differentiation capacity between mandibular BMSCs (mBMSCs) and tibial BMSCs (tBMSCs). MATERIALS AND METHODS Bioinformatics analysis of the GSE81430 dataset taken from the Gene Expression Omnibus (GEO) database was performed using GEO2R. BMSCs were isolated from mandibular and tibial bone marrow tissue samples. Healthy pigs (n = 3) (registered at the State Office for Nature, Environment, and Consumer Protection, North Rhine-Westphalia (LANUV) 81-02.04.2020.A215) were used for this purpose. Cell morphology and osteogenic differentiation were evaluated in mBMSCs and tBMSCs. The expression levels of toll-like receptor 4 (TLR4) and nuclear transcription factor κB (NF-κB) were analyzed using quantitative polymerase chain reaction (qPCR) and Western blot (WB), respectively. In addition, mBMSC-derived extracellular vesicles (mBMSC-EVs) were gained and used as osteogenic stimuli for tBMSCs. Cell morphology and osteogenic differentiation capacity were assessed after mBMSC-EV stimulation. RESULTS Bioinformatic analysis indicated that the difference in the activation of the TLR4/NF-κB pathway was more pronounced compared to all other examined genes. Specifically, this demonstrated significant downregulation, whereas only 5-7 upregulated genes displayed significant variances. The mBMSC group showed stronger osteogenic differentiation capacity compared to the tBMSC group, confirmed via ALP, ARS, and von Kossa staining. Furthermore, qPCR and WB analysis revealed a significant decrease in the expression of the TLR4/NF-κB pathway in the mBMSC group compared to the tBMSC group (TLR4 fold changes: mBMSCs vs. tBMSCs p < 0.05; NF-κB fold changes: mBMSCs vs. tBMSCs p < 0.05). The osteogenic differentiation capacity was enhanced, and qPCR and WB analysis revealed a significant decrease in the expression of TLR4 and NF-κB in the tBMSC group with mBMSC-EVs added compared to tBMSCs alone (TLR4 fold changes: p < 0.05; NF-κB fold changes: p < 0.05). CONCLUSION Our results indicate that mBMSC-EVs can promote the osteogenic differentiation of tBMSCs in vitro. The results also provide insights into the osteogenic mechanism of mBMSCs via TLR4/NF-κB signaling pathway activation. This discovery promises a fresh perspective on the treatment of bone fractures or malunions, potentially offering a novel therapeutic method.
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Affiliation(s)
- Qun Zhao
- Experimental Orthopedics and Trauma Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Xing Zhang
- Experimental Orthopedics and Trauma Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - You Li
- Experimental Orthopedics and Trauma Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Zhizhen He
- Experimental Orthopedics and Trauma Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Kang Qin
- Experimental Orthopedics and Trauma Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Department of Shoulder and Elbow Surgery, Center for Orthopedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, China
| | - Eva Miriam Buhl
- Electron Microscopy Facility, Institute of Pathology and Medical Clinic II, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Ümit Mert
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Klemens Horst
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Frank Hildebrand
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Elizabeth R. Balmayor
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Johannes Greven
- Experimental Orthopedics and Trauma Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
- Department of Orthopedics, Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
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15
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Shi H, Yang Y, Xing H, Jia J, Xiong W, Guo S, Yang S. Exosomal non-coding RNAs: Emerging insights into therapeutic potential and mechanisms in bone healing. J Tissue Eng 2024; 15:20417314241286606. [PMID: 39371940 PMCID: PMC11456177 DOI: 10.1177/20417314241286606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 09/10/2024] [Indexed: 10/08/2024] Open
Abstract
Exosomes are nano-sized extracellular vesicles (EVs) released by diverse types of cells, which affect the functions of targeted cells by transporting bioactive substances. As the main component of exosomes, non-coding RNA (ncRNA) is demonstrated to impact multiple pathways participating in bone healing. Herein, this review first introduces the biogenesis and secretion of exosomes, and elucidates the role of the main cargo in exosomes, ncRNAs, in mediating intercellular communication. Subsequently, the potential molecular mechanism of exosomes accelerating bone healing is elucidated from the following four aspects: macrophage polarization, vascularization, osteogenesis and osteoclastogenesis. Then, we systematically introduce construction strategies based on modified exosomes in bone regeneration field. Finally, the clinical trials of exosomes for bone healing and the challenges of exosome-based therapies in the biomedical field are briefly introduced, providing solid theoretical frameworks and optimization methods for the clinical application of exosomes in orthopedics.
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Affiliation(s)
- Huixin Shi
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yang Yang
- Department of Rehabilitation, The First Hospital of China Medical University, Shenyang, China
| | - Hao Xing
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Jialin Jia
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Wei Xiong
- Department of Plastic Surgery, The First Affiliated Hospital of Medical College of Shihezi University, Shihezi, Xinjiang, China
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Shude Yang
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
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16
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Khaledi M, Zandi B, Mohsenipour Z. The Effect of Mesenchymal Stem Cells on the Wound Infection. Curr Stem Cell Res Ther 2024; 19:1084-1092. [PMID: 37815189 DOI: 10.2174/011574888x252482230926104342] [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: 03/08/2023] [Revised: 07/10/2023] [Accepted: 08/17/2023] [Indexed: 10/11/2023]
Abstract
Wound infection often requires a long period of care and an onerous treatment process. Also, the rich environment makes the wound an ideal niche for microbial growth. Stable structures, like biofilm, and drug-resistant strains cause a delay in the healing process, which has become one of the important challenges in wound treatment. Many studies have focused on alternative methods to deal the wound infections. One of the novel and highly potential ways is mesenchymal stromal cells (MSCs). MSCs are mesoderm-derived pluripotent adult stem cells with the capacity for self-renewal, multidirectional differentiation, and immunological control. Also, MSCs have anti-inflammatory and antiapoptotic effects. MScs, as pluripotent stromal cells, differentiate into many mature cells. Also, MSCs produce antimicrobial compounds, such as antimicrobial peptides (AMP), as well as secrete immune modulators, which are two basic features considered in wound healing. Despite the advantages, preserving the structure and activity of MSCs is considered one of the most important points in the treatment. MSCs' antimicrobial effects on microorganisms involved in wound infection have been confirmed in various studies. In this review, we aimed to discuss the antimicrobial and therapeutic applications of MSCs in the infected wound healing processes.
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Affiliation(s)
- Mansoor Khaledi
- Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
- Department of Microbiology and Immunology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Bita Zandi
- Department of Microbiology, Faculty of advanced science and technology, Tehran medical science, Islamic Azad University, Tehran, Iran
| | - Zeinab Mohsenipour
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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17
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Liu R, Wu S, Liu W, Wang L, Dong M, Niu W. microRNAs delivered by small extracellular vesicles in MSCs as an emerging tool for bone regeneration. Front Bioeng Biotechnol 2023; 11:1249860. [PMID: 37720323 PMCID: PMC10501734 DOI: 10.3389/fbioe.2023.1249860] [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: 06/29/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023] Open
Abstract
Bone regeneration is a dynamic process that involves angiogenesis and the balance of osteogenesis and osteoclastogenesis. In bone tissue engineering, the transplantation of mesenchymal stem cells (MSCs) is a promising approach to restore bone homeostasis. MSCs, particularly their small extracellular vesicles (sEVs), exert therapeutic effects due to their paracrine capability. Increasing evidence indicates that microRNAs (miRNAs) delivered by sEVs from MSCs (MSCs-sEVs) can alter gene expression in recipient cells and enhance bone regeneration. As an ideal delivery vehicle of miRNAs, MSCs-sEVs combine the high bioavailability and stability of sEVs with osteogenic ability of miRNAs, which can effectively overcome the challenge of low delivery efficiency in miRNA therapy. In this review, we focus on the recent advancements in the use of miRNAs delivered by MSCs-sEVs for bone regeneration and disorders. Additionally, we summarize the changes in miRNA expression in osteogenic-related MSCs-sEVs under different microenvironments.
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Affiliation(s)
| | | | | | | | - Ming Dong
- School of Stomatology, Dalian Medical University, Dalian, China
| | - Weidong Niu
- School of Stomatology, Dalian Medical University, Dalian, China
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18
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Kandeel M, Morsy MA, Alkhodair KM, Alhojaily S. Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities. Biomolecules 2023; 13:1250. [PMID: 37627315 PMCID: PMC10452295 DOI: 10.3390/biom13081250] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/11/2023] [Accepted: 08/14/2023] [Indexed: 08/27/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.
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Affiliation(s)
- Mahmoud Kandeel
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
| | - Mohamed A. Morsy
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, Egypt
| | - Khalid M. Alkhodair
- Department of Anatomy, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
| | - Sameer Alhojaily
- Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
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19
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Jiang T, Su W, Li Y, Jiang M, Zhang Y, Xian CJ, Zhai Y. Research Progress on Nanomaterials for Tissue Engineering in Oral Diseases. J Funct Biomater 2023; 14:404. [PMID: 37623649 PMCID: PMC10455101 DOI: 10.3390/jfb14080404] [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: 05/29/2023] [Revised: 06/25/2023] [Accepted: 07/25/2023] [Indexed: 08/26/2023] Open
Abstract
Due to their superior antibacterial properties, biocompatibility and high conductivity, nanomaterials have shown a broad prospect in the biomedical field and have been widely used in the prevention and treatment of oral diseases. Also due to their small particle sizes and biodegradability, nanomaterials can provide solutions for tissue engineering, especially for oral tissue rehabilitation and regeneration. At present, research on nanomaterials in the field of dentistry focuses on the biological effects of various types of nanomaterials on different oral diseases and tissue engineering applications. In the current review, we have summarized the biological effects of nanoparticles on oral diseases, their potential action mechanisms and influencing factors. We have focused on the opportunities and challenges to various nanomaterial therapy strategies, with specific emphasis on overcoming the challenges through the development of biocompatible and smart nanomaterials. This review will provide references for potential clinical applications of novel nanomaterials in the field of oral medicine for the prevention, diagnosis and treatment of oral diseases.
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Affiliation(s)
- Tong Jiang
- School of Stomatology, Henan University, Kaifeng 475000, China; (T.J.)
- Kaifeng Key Laboratory of Periodontal Tissue Engineering, Kaifeng 475000, China
| | - Wen Su
- School of Stomatology, Henan University, Kaifeng 475000, China; (T.J.)
- Kaifeng Key Laboratory of Periodontal Tissue Engineering, Kaifeng 475000, China
| | - Yan Li
- Department of Pharmacy, Huaihe Hospital, Henan University, Kaifeng 475000, China
| | - Mingyuan Jiang
- School of Stomatology, Henan University, Kaifeng 475000, China; (T.J.)
- Kaifeng Key Laboratory of Periodontal Tissue Engineering, Kaifeng 475000, China
| | - Yonghong Zhang
- Department of Orthopaedics, The 2nd Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Cory J. Xian
- UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, Australia
| | - Yuankun Zhai
- School of Stomatology, Henan University, Kaifeng 475000, China; (T.J.)
- Kaifeng Key Laboratory of Periodontal Tissue Engineering, Kaifeng 475000, China
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20
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Pan L, Zhang C, Zhang H, Ke T, Bian M, Yang Y, Chen L, Tan J. Osteoclast-Derived Exosomal miR-5134-5p Interferes with Alveolar Bone Homeostasis by Targeting the JAK2/STAT3 Axis. Int J Nanomedicine 2023; 18:3727-3744. [PMID: 37441084 PMCID: PMC10335290 DOI: 10.2147/ijn.s413692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Background In chronic periodontitis, exosomes transport various informative substances between osteoclasts and osteoblasts in alveolar bone. Herein, we aimed to investigate the effect of exosomal micro-ribonucleic acid (miRNA/miR)-5134-5p derived from osteoclasts on osteoblastic proliferation and differentiation and the development of periodontitis in vivo and in vitro. Methods The effects of OC-Exos on the proliferation and differentiation of osteoblasts were identified by Real-time quantitative reverse polymerase chain reaction (qRT-PCR), Western blot(WB), alkaline phosphatase(ALP) staining, etc. Exosomal miRNA expression was analyzed by sequencing. The sites of miRNA action were predicted through TargetScan and tested by double luciferase assay. After transfecting miR-5134-5p mimic/inhibitor into osteoblasts, we measured the proliferation and differentiation of osteoblasts by ALP staining and WB, etc. Furthermore, OC-Exos were injected into the gingival sulcus at the ligation site. Inflammation was observed by Hematoxylin-eosin (H&E) staining, the expression of inflammatory factors were detected by qRT-PCR, the resorption of alveolar bone was observed by Micro CT. Results Osteoblastic proliferation and differentiation were negatively regulated by OC-Exos in vitro. miRNA sequencing analysis revealed that miR-5134-5p expression was significantly elevated in OC-Exos, which also increased in osteoblasts following OC-Exo intervention. The dual-luciferase assay revealed that miR-5134-5p and Janus kinase 2 (JAK2) had binding sites. miR-5134-5p-mimics could upregulate miR-5134-5p expression in osteoblasts while downregulating Runt-related transcription factor 2(Runx2), phosphorylated-JAK2 (p-JAK2), and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) expression and inhibited osteogenic differentiation. However, miR-5134-5p-inhibitor had the opposite effect. In vivo, the OC-Exo group demonstrated morphological disruption of periodontal tissue, massive inflammatory cell infiltration, upregulation of inflammatory factors mRNA expression, a significant decrease in BV/TV, and an increase in the cementoenamel junction and alveolar bone crest distance. Conclusion Osteoclast-derived exosomal miR-5134-5p inhibits osteoblastic proliferation and differentiation via the JAK2/STAT3 pathway. OC-Exos exacerbate periodontal tissue inflammation and accelerate alveolar bone resorption in mice with experimental periodontitis.
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Affiliation(s)
- Lai Pan
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
| | - Chenyi Zhang
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
| | - Haizheng Zhang
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
| | - Ting Ke
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
| | - Mengyao Bian
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
| | - Yuxuan Yang
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
| | - Lili Chen
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
| | - Jingyi Tan
- Department of Periodontology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, People’s Republic of China
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21
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Torrecillas-Baena B, Pulido-Escribano V, Dorado G, Gálvez-Moreno MÁ, Camacho-Cardenosa M, Casado-Díaz A. Clinical Potential of Mesenchymal Stem Cell-Derived Exosomes in Bone Regeneration. J Clin Med 2023; 12:4385. [PMID: 37445420 DOI: 10.3390/jcm12134385] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/19/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Bone metabolism is regulated by osteoblasts, osteoclasts, osteocytes, and stem cells. Pathologies such as osteoporosis, osteoarthritis, osteonecrosis, and traumatic fractures require effective treatments that favor bone formation and regeneration. Among these, cell therapy based on mesenchymal stem cells (MSC) has been proposed. MSC are osteoprogenitors, but their regenerative activity depends in part on their paracrine properties. These are mainly mediated by extracellular vesicle (EV) secretion. EV modulates regenerative processes such as inflammation, angiogenesis, cell proliferation, migration, and differentiation. Thus, MSC-EV are currently an important tool for the development of cell-free therapies in regenerative medicine. This review describes the current knowledge of the effects of MSC-EV in the different phases of bone regeneration. MSC-EV has been used by intravenous injection, directly or in combination with different types of biomaterials, in preclinical models of bone diseases. They have shown great clinical potential in regenerative medicine applied to bone. These findings should be confirmed through standardization of protocols, a better understanding of the mechanisms of action, and appropriate clinical trials. All that will allow the translation of such cell-free therapy to human clinic applications.
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Affiliation(s)
- Bárbara Torrecillas-Baena
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Victoria Pulido-Escribano
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Gabriel Dorado
- Department Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, 14071 Córdoba, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), 14004 Córdoba, Spain
| | - María Ángeles Gálvez-Moreno
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Marta Camacho-Cardenosa
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
| | - Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición-GC17, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, 14004 Córdoba, Spain
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), 14004 Córdoba, Spain
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22
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Man K, Eisenstein NM, Hoey DA, Cox SC. Bioengineering extracellular vesicles: smart nanomaterials for bone regeneration. J Nanobiotechnology 2023; 21:137. [PMID: 37106449 PMCID: PMC10134574 DOI: 10.1186/s12951-023-01895-2] [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: 01/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
In the past decade, extracellular vesicles (EVs) have emerged as key regulators of bone development, homeostasis and repair. EV-based therapies have the potential to circumnavigate key issues hindering the translation of cell-based therapies including functional tissue engraftment, uncontrolled differentiation and immunogenicity issues. Due to EVs' innate biocompatibility, low immunogenicity, and high physiochemical stability, these naturally-derived nanoparticles have garnered growing interest as potential acellular nanoscale therapeutics for a variety of diseases. Our increasing knowledge of the roles these cell-derived nanoparticles play, has made them an exciting focus in the development of novel pro-regenerative therapies for bone repair. Although these nano-sized vesicles have shown promise, their clinical translation is hindered due to several challenges in the EV supply chain, ultimately impacting therapeutic efficacy and yield. From the biochemical and biophysical stimulation of parental cells to the transition to scalable manufacture or maximising vesicles therapeutic response in vivo, a multitude of techniques have been employed to improve the clinical efficacy of EVs. This review explores state of the art bioengineering strategies to promote the therapeutic utility of vesicles beyond their native capacity, thus maximising the clinical potential of these pro-regenerative nanoscale therapeutics for bone repair.
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Affiliation(s)
- Kenny Man
- School of Chemical Engineering, University of Birmingham, Birmingham, B15 2TT, UK
| | - Neil M Eisenstein
- Research and Clinical Innovation, Royal Centre for Defence Medicine, ICT Centre, Vincent Drive, Birmingham, B15 2SQ, UK
- Institute of Translational Medicine, University of Birmingham, Heritage Building, Mindelsohn Way, Birmingham, B15 2TH, UK
| | - David A Hoey
- Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College, Dublin, D02 R590, Ireland
- Dept. of Mechanical, Manufacturing, and Biomedical Engineering, School of Engineering, Trinity College, Dublin 2, D02 DK07, Dublin, Ireland
- Advanced Materials and Bioengineering Research Centre, Trinity College Dublin & RCSI, Dublin 2, D02 VN51, Dublin, Ireland
| | - Sophie C Cox
- School of Chemical Engineering, University of Birmingham, Birmingham, B15 2TT, UK.
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23
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Man K, Brunet MY, Lees R, Peacock B, Cox SC. Epigenetic Reprogramming via Synergistic Hypomethylation and Hypoxia Enhances the Therapeutic Efficacy of Mesenchymal Stem Cell Extracellular Vesicles for Bone Repair. Int J Mol Sci 2023; 24:ijms24087564. [PMID: 37108726 PMCID: PMC10142722 DOI: 10.3390/ijms24087564] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/11/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are a promising cell population for regenerative medicine applications, where paracrine signalling through the extracellular vesicles (EVs) regulates bone tissue homeostasis and development. MSCs are known to reside in low oxygen tension, which promotes osteogenic differentiation via hypoxia-inducible factor-1α activation. Epigenetic reprogramming has emerged as a promising bioengineering strategy to enhance MSC differentiation. Particularly, the process of hypomethylation may enhance osteogenesis through gene activation. Therefore, this study aimed to investigate the synergistic effects of inducing hypomethylation and hypoxia on improving the therapeutic efficacy of EVs derived from human bone marrow MSCs (hBMSCs). The effects of the hypoxia mimetic agent deferoxamine (DFO) and the DNA methyltransferase inhibitor 5-azacytidine (AZT) on hBMSC viability was assessed by quantifying the DNA content. The epigenetic functionality was evaluated by assessing histone acetylation and histone methylation. hBMSC mineralisation was determined by quantifying alkaline phosphate activity, collagen production and calcium deposition. EVs were procured from AZT, DFO or AZT/DFO-treated hBMSCs over a two-week period, with EV size and concentration defined using transmission electron microscopy, nanoflow cytometry and dynamic light scattering. The effects of AZT-EVs, DFO-EVs or AZT/DFO-EVs on the epigenetic functionality and mineralisation of hBMSCs were evaluated. Moreover, the effects of hBMSC-EVs on human umbilical cord vein endothelial cells (HUVECs) angiogenesis was assessed by quantifying pro-angiogenic cytokine release. DFO and AZT caused a time-dose dependent reduction in hBMSC viability. Pre-treatment with AZT, DFO or AZT/DFO augmented the epigenetic functionality of the MSCs through increases in histone acetylation and hypomethylation. AZT, DFO and AZT/DFO pre-treatment significantly enhanced extracellular matrix collagen production and mineralisation in hBMSCs. EVs derived from AZT/DFO-preconditioned hBMSCs (AZT/DFO-EVs) enhanced the hBMSC proliferation, histone acetylation and hypomethylation when compared to EVs derived from AZT-treated, DFO-treated and untreated hBMSCs. Importantly, AZT/DFO-EVs significantly increased osteogenic differentiation and mineralisation of a secondary hBMSC population. Furthermore, AZT/DFO-EVs enhanced the pro-angiogenic cytokine release of HUVECs. Taken together, our findings demonstrate the considerable utility of synergistically inducing hypomethylation and hypoxia to improve the therapeutic efficacy of the MSC-EVs as a cell-free approach for bone regeneration.
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Affiliation(s)
- Kenny Man
- School of Chemical Engineering, University of Birmingham, Birmingham B15 2TT, UK
| | - Mathieu Y Brunet
- School of Chemical Engineering, University of Birmingham, Birmingham B15 2TT, UK
| | | | | | - Sophie C Cox
- School of Chemical Engineering, University of Birmingham, Birmingham B15 2TT, UK
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24
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Mao X, Li Z, Gu S, Song W, Zhang M, Tan X, Mao Z. MicroRNA-211-5p in extracellular vesicles derived from BMSCs facilitates the repair of rat frozen shoulder via regulating KDM2B/LACC1 axis. Tissue Cell 2023; 81:102006. [PMID: 36610229 DOI: 10.1016/j.tice.2022.102006] [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: 07/06/2022] [Revised: 12/21/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022]
Abstract
OBJECTIVE This study aims to explore the mechanism of miR-211-5p in extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) in improving frozen shoulder (FS) in rat models. METHODS Rat BMSCs and EVs derived from rat BMSCs were isolated, identified, and then injected into rats to assess the expression of TGF-β, MMP1, MMP3, MMP12, GAP43, and PGP9.5 in shoulder capsule tissues. The range of motion of bilateral glenohumeral joints was assessed and pathological changes of shoulder capsule tissues were observed after hematoxylin-eosin staining. The binding sites of miR-211-5p to KDM2B and LACC1 to H3K4me3 were measured. FS rat models with LACC1 highly expressed were established to assess the motion of bilateral glenohumeral joints and expression of arthritis related factors in rats. RESULTS EVs were successfully extracted from BMSCs. Injection of BMSCs-EVs could improve the activity of bilateral glenohumeral joints and the pathological condition of joint capsule in rats. Elevated expression of miR-211-5p was found in rats injected with BMSCs-EVs. Dual luciferase assay showed that miR-211-5p had a binding site with KDM2B. ChIP, qRT-PCR, and western blot experiments showed BMSCs-EVs injection resulted in elevated enrichment of LACC1 promoter in shoulder capsule tissues of FS rats, and decreased mRNA and protein expression of KDM2B and increased H3K4me3 methylation. Overexpression of LACC1 could also improve the pathological condition of joint capsule tissue. CONCLUSION miR-211-5p in EVs derived from BMSCs increased H3K4me3 methylation in shoulder capsule tissue of rats by binding KDM2B, resulting in up-regulated transcription level of LACC1 and improving FS. AVAILABILITY OF DATA AND MATERIALS The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
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Affiliation(s)
- Xiaodong Mao
- Department of Orthopedics & Traumatology, Department of Joint Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha Eighth Hospital, Changsha, Hunan 410008, PR China
| | - Zhi Li
- Department of Orthopedics & Traumatology, Department of Joint Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha Eighth Hospital, Changsha, Hunan 410008, PR China
| | - Shaofang Gu
- Department of Orthopedics & Traumatology, Department of Joint Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha Eighth Hospital, Changsha, Hunan 410008, PR China
| | - Wei Song
- Department of Orthopedics & Traumatology, Department of Joint Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha Eighth Hospital, Changsha, Hunan 410008, PR China
| | - Mimi Zhang
- Department of Orthopedics & Traumatology, Department of Joint Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha Eighth Hospital, Changsha, Hunan 410008, PR China
| | - Xiao Tan
- Department of Orthopedics & Traumatology, Department of Joint Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha Eighth Hospital, Changsha, Hunan 410008, PR China
| | - Ziqing Mao
- Department of Orthopedics & Traumatology, Department of Joint Surgery, Changsha Hospital of Traditional Chinese Medicine, Changsha Eighth Hospital, Changsha, Hunan 410008, PR China.
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25
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Huo KL, Yang TY, Zhang WW, Shao J. Mesenchymal stem/stromal cells-derived exosomes for osteoporosis treatment. World J Stem Cells 2023; 15:83-89. [PMID: 37007454 PMCID: PMC10052342 DOI: 10.4252/wjsc.v15.i3.83] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/17/2023] [Accepted: 03/17/2023] [Indexed: 03/23/2023] Open
Abstract
Osteoporosis is a systemic bone disease, which leads to decreased bone mass and an increased risk of fragility fractures. Currently, there are many anti-resorption drugs and osteosynthesis drugs, which are effective in the treatment of osteoporosis, but their usage is limited due to their contraindications and side effects. In regenerative medicine, the unique repair ability of mesenchymal stem cells (MSCs) has been favored by researchers. The exosomes secreted by MSCs have signal transduction and molecular delivery mechanisms, which may have therapeutic effects. In this review, we describe the regulatory effects of MSCs-derived exosomes on osteoclasts, osteoblasts, and bone immunity. We aim to summarize the preclinical studies of exosome therapy in osteoporosis. Furthermore, we speculate that exosome therapy can be a future direction to improve bone health.
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Affiliation(s)
- Kai-Lun Huo
- Postgraduate Training Base in Shanghai Gongli Hospital, Ningxia Medical University, Yinchuan 750004, the Ningxia Hui Autonomous Region, China
| | - Tie-Yi Yang
- Department of Orthopedics, Pudong New Area Gongli Hospital, School of Medical Technology, University of Shanghai for Science and Technology, Shanghai 200135, China
| | - Wei-Wei Zhang
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jin Shao
- Department of Orthopedics, Pudong New Area Gongli Hospital, School of Medical Technology, University of Shanghai for Science and Technology, Shanghai 200135, China
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26
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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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27
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Ren S, Lin Y, Liu W, Yang L, Zhao M. MSC-Exos: Important active factor of bone regeneration. Front Bioeng Biotechnol 2023; 11:1136453. [PMID: 36814713 PMCID: PMC9939647 DOI: 10.3389/fbioe.2023.1136453] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 01/24/2023] [Indexed: 02/08/2023] Open
Abstract
Bone defect and repair is a common but difficult problem in restorative and reconstructive surgery. Bone tissue defects of different sizes caused by different reasons bring functional limitations and cosmetic deformities to patients. Mesenchymal stem cells (MSC), a major hotspot in the field of regeneration in recent years, have been widely used in various studies on bone tissue regeneration. Numerous studies have shown that the bone regenerative effects of MSC can be achieved through exosome-delivered messages. Although its osteogenic mechanism is still unclear, it is clear that MSC-Exos can directly or indirectly support the action of bone regeneration. It can act directly on various cells associated with osteogenesis, or by carrying substances that affect cellular activators or the local internal environment in target cells, or it can achieve activation of the osteogenic framework by binding to materials. Therefore, this review aims to summarize the types and content of effective contents of MSC-Exos in bone regeneration, as well as recent advances in the currently commonly used methods to enable the binding of MSC-Exos to the framework and to conclude that MSC-Exos is effective in promoting osteogenesis.
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Affiliation(s)
- Sihang Ren
- Department of Plastic Surgery, The Second Hospital of Dalian Medical University, Dalian, China,Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China,NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Affiliated Reproductive Hospital of China Medical University), Shenyang, China
| | - Yuyang Lin
- Department of Plastic Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Wenyue Liu
- Department of Plastic Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Liqun Yang
- NHC Key Laboratory of Reproductive Health and Medical Genetics (China Medical University), Liaoning Research Institute of Family Planning (The Affiliated Reproductive Hospital of China Medical University), Shenyang, China,Department of Biomaterials, Shengjing Hospital of China Medical University, Shenyang, China,*Correspondence: Liqun Yang, ; Muxin Zhao,
| | - Muxin Zhao
- Department of Plastic Surgery, The Second Hospital of Dalian Medical University, Dalian, China,*Correspondence: Liqun Yang, ; Muxin Zhao,
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28
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Wong PF, Dharmani M, Ramasamy TS. Senotherapeutics for mesenchymal stem cell senescence and rejuvenation. Drug Discov Today 2023; 28:103424. [PMID: 36332835 DOI: 10.1016/j.drudis.2022.103424] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 10/04/2022] [Accepted: 10/27/2022] [Indexed: 11/06/2022]
Abstract
Mesenchymal stem cells (MSCs) are susceptible to replicative senescence and senescence-associated functional decline, which hampers their use in regenerative medicine. Senotherapeutics are drugs that target cellular senescence through senolytic and senomorphic functions to induce apoptosis and suppress chronic inflammation caused by the senescence-associated secreted phenotype (SASP), respectively. Therefore, senotherapeutics could delay aging-associated degeneration. They could also be used to eliminate senescent MSCs during in vitro expansion or bioprocessing for transplantation. In this review, we discuss the role of senotherapeutics in MSC senescence, rejuvenation, and transplantation, with examples of some tested compounds in vitro. The prospects, challenges, and the way forward in clinical applications of senotherapeutics in cell-based therapeutics are also discussed.
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Affiliation(s)
- Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Murugan Dharmani
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, 50603 Wilayah Persekutuan Kuala Lumpur, Malaysia.
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29
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Breulmann FL, Hatt LP, Schmitz B, Wehrle E, Richards RG, Della Bella E, Stoddart MJ. Prognostic and therapeutic potential of microRNAs for fracture healing processes and non-union fractures: A systematic review. Clin Transl Med 2023; 13:e1161. [PMID: 36629031 PMCID: PMC9832434 DOI: 10.1002/ctm2.1161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Approximately 10% of all bone fractures result in delayed fracture healing or non-union; thus, the identification of biomarkers and prognostic factors is of great clinical interest. MicroRNAs (miRNAs) are known to be involved in the regulation of the bone healing process and may serve as functional markers for fracture healing. AIMS AND METHODS This systematic review aimed to identify common miRNAs involved in fracture healing or non-union fractures using a qualitative approach. A systematic literature search was performed with the keywords 'miRNA and fracture healing' and 'miRNA and non-union fracture'. Any original article investigating miRNAs in fracture healing or non-union fractures was screened. Eventually, 82 studies were included in the qualitative analysis for 'miRNA and fracture healing', while 19 were selected for the 'miRNA and fracture non-union' category. RESULTS AND CONCLUSIONS Out of 151 miRNAs, miR-21, miR-140 and miR-214 were the most investigated miRNAs in fracture healing in general. miR-31-5p, miR-221 and miR-451-5p were identified to be regulated specifically in non-union fractures. Large heterogeneity was detected between studies investigating the role of miRNAs in fracture healing or non-union in terms of patient population, sample types and models used. Nonetheless, our approach identified some miRNAs with the potential to serve as biomarkers for non-union fractures, including miR-31-5p, miR-221 and miR-451-5p. We provide a discussion of involved pathways and suggest on alignment of future research in the field.
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Affiliation(s)
- Franziska Lioba Breulmann
- AO Research Institute DavosDavos PlatzSwitzerland
- Department of Orthopedic Sports MedicineKlinikum Rechts der IsarTechnical University of MunichMunichGermany
| | - Luan Phelipe Hatt
- AO Research Institute DavosDavos PlatzSwitzerland
- Institute for BiomechanicsETH ZürichZurichSwitzerland
| | - Boris Schmitz
- Department of Rehabilitation SciencesFaculty of HealthUniversity of Witten/HerdeckeWittenGermany
- DRV Clinic KönigsfeldCenter for Medical RehabilitationEnnepetalGermany
| | - Esther Wehrle
- AO Research Institute DavosDavos PlatzSwitzerland
- Institute for BiomechanicsETH ZürichZurichSwitzerland
| | - Robert Geoff Richards
- AO Research Institute DavosDavos PlatzSwitzerland
- Faculty of MedicineMedical Center‐Albert‐Ludwigs‐University of FreiburgAlbert‐Ludwigs‐University of FreiburgFreiburgGermany
| | | | - Martin James Stoddart
- AO Research Institute DavosDavos PlatzSwitzerland
- Faculty of MedicineMedical Center‐Albert‐Ludwigs‐University of FreiburgAlbert‐Ludwigs‐University of FreiburgFreiburgGermany
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30
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Smolinska V, Csobonyeiova M, Zamborsky R, Danisovic L. Stem Cells and Their Derivatives: An Implication for the Regeneration of Nonunion Fractures. Cell Transplant 2023; 32:9636897231183530. [PMID: 37462248 PMCID: PMC10363876 DOI: 10.1177/09636897231183530] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 07/20/2023] Open
Abstract
Despite advances in biomedical research, fracture nonunion rates have remained stable throughout the years. Long-bone fractures have a high likelihood of nonunion, but the specific biological pathways involved in this severe consequence are unknown. Fractures often heal in an organized sequence, including the production of a hematoma and an early stage of inflammation, the development of a soft callus and hard callus, and eventually the stage of bone remodeling. Deficient healing can result in a persistent bone defect with instability, discomfort, and loss of function. In the treatment of nonunions, mesenchymal stem cells (MSCs) prove to be a promising and safe alternative to the standard therapeutic strategies. Moreover, novel scaffolds are being created in order to use a synergistic biomimetic technique to rapidly generate bone tissue. MSCs respond to acellular biomimetic matrices by regenerating bone. Extracellular vesicles (EVs) derived from MSCs have recently gained interest in the field of musculoskeletal regeneration. Although many of these techniques and technologies are still in the preclinical stage and have not yet been approved for use in humans, novel approaches to accelerate bone healing via MSCs and/or MSC derivatives have the potential to reduce the physical, economic, and social burdens associated with nonhealing fractures and bone defects. In this review, we focus on providing an up-to-date summary of recent scientific studies dealing with the treatment of nonunion fractures in clinical and preclinical settings employing MSC-based therapeutic techniques.
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Affiliation(s)
- Veronika Smolinska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
- National Institute of Rheumatic Diseases, Piestany, Slovakia
| | - Maria Csobonyeiova
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Institute of Histology and Embryology, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Radoslav Zamborsky
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Department of Orthopaedics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
- National Institute of Children’s Diseases, Bratislava, Slovakia
- Centre for Tissue Engineering and Regenerative Medicine–Translational Research Unit, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Lubos Danisovic
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
- National Institute of Rheumatic Diseases, Piestany, Slovakia
- Centre for Tissue Engineering and Regenerative Medicine–Translational Research Unit, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
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31
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Huang G, Zhao Q, Li W, Jiao J, Zhao X, Feng D, Tang W. Exosomes: A new option for osteoporosis treatment. Medicine (Baltimore) 2022; 101:e32402. [PMID: 36595975 PMCID: PMC9803424 DOI: 10.1097/md.0000000000032402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Osteoporosis is a systemic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. However, the pathogenesis and molecular mechanisms of this disease remain unclear. Extracellular vesicles, structures originating from the plasma membrane and ranging from 30 nm to 5 µm in diameter, play an important role in intercellular communication in the bone microenvironment. Exosomes are extracellular vesicles that deliver cargo molecules, including endogenous proteins, lipids and nucleic acids. These cargo molecules are encapsulated in a lipid bilayer and internalized by target cells through receptor-ligand interactions or lipid membrane fusion. With the advancement of exosome research, exosome therapy for osteoporosis is fast becoming a research hotspot for researchers. This review aims to discuss the role of exosomes in the pathogenesis of osteoporosis. In addition, emerging diagnostic and therapeutic properties of exosomes are described to highlight the potential role of exosomes in osteoporosis.
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Affiliation(s)
- Guijiang Huang
- The First Affiliated Hospital of Kunming Medical University, Kunming City, China
| | - Qianhao Zhao
- Kunming Children’s Hospital, Kunming City, China
| | - Wenhu Li
- Kunming Medical University, Kunming City, China
| | | | - Xin Zhao
- The First Affiliated Hospital of Kunming Medical University, Kunming City, China
| | - Dan Feng
- The First Affiliated Hospital of Kunming Medical University, Kunming City, China
| | - Wei Tang
- The First Affiliated Hospital of Kunming Medical University, Kunming City, China
- *Correspondence: Wei Tang, The First Affiliated Hospital of Kunming Medical University, Kunming City, Yunnan Province, China (e-mail: )
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32
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Zeng ZL, Xie H. Mesenchymal stem cell-derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review. BIOMATERIALS TRANSLATIONAL 2022; 3:175-187. [PMID: 36654775 PMCID: PMC9840092 DOI: 10.12336/biomatertransl.2022.03.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/19/2022] [Accepted: 08/02/2022] [Indexed: 01/20/2023]
Abstract
Accumulating evidence suggests that the therapeutic role of mesenchymal stem cells (MSCs) in bone diseases is closely related to paracrine-generated extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) carry proteins, nucleic acids, and lipids to the extracellular space and affect the bone microenvironment. They have similar biological functions to MSCs, such as the ability to repair organ and tissue damage. In addition, MSC-EVs also have the advantages of long half-life, low immunogenicity, attractive stability, ability to pass through the blood-brain barrier, and demonstrate excellent performance with potential practical applications in bone diseases. In this review, we summarise the current applications and mechanisms of MSC-EVs in osteoporosis, osteoarthritis, bone tumours, osteonecrosis of the femoral head, and fractures, as well as the development of MSC-EVs combined with materials science in the field of orthopaedics. Additionally, we explore the critical challenges involved in the clinical application of MSC-EVs in orthopaedic diseases.
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Affiliation(s)
- Zhao-Lin Zeng
- Department of Metabolism and Endocrinology, The First Affliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China,Department of Clinical Medicine, The First Affliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan Province, China
| | - Hui Xie
- Department of Orthopaedics, Movement System Injury and Repair Research Centre, Xiangya Hospital, Central South University, Changsha, Hunan Province, China,Corresponding author: Hui Xie,
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33
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Wang J, Cui Y, Liu H, Li S, Sun S, Xu H, Peng C, Wang Y, Wu D. MicroRNA-loaded biomaterials for osteogenesis. Front Bioeng Biotechnol 2022; 10:952670. [PMID: 36199361 PMCID: PMC9527286 DOI: 10.3389/fbioe.2022.952670] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022] Open
Abstract
The large incidence of bone defects in clinical practice increases not only the demand for advanced bone transplantation techniques but also the development of bone substitute materials. A variety of emerging bone tissue engineering materials with osteogenic induction ability are promising strategies for the design of bone substitutes. MicroRNAs (miRNAs) are a class of non-coding RNAs that regulate intracellular protein expression by targeting the non-coding region of mRNA3′-UTR to play an important role in osteogenic differentiation. Several miRNA preparations have been used to promote the osteogenic differentiation of stem cells. Therefore, multiple functional bone tissue engineering materials using miRNA as an osteogenic factor have been developed and confirmed to have critical efficacy in promoting bone repair. In this review, osteogenic intracellular signaling pathways mediated by miRNAs are introduced in detail to provide a clear understanding for future clinical treatment. We summarized the biomaterials loaded with exogenous cells engineered by miRNAs and biomaterials directly carrying miRNAs acting on endogenous stem cells and discussed their advantages and disadvantages, providing a feasible method for promoting bone regeneration. Finally, we summarized the current research deficiencies and future research directions of the miRNA-functionalized scaffold. This review provides a summary of a variety of advanced miRNA delivery system design strategies that enhance bone regeneration.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Dankai Wu
- *Correspondence: Yanbing Wang, ; Dankai Wu,
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34
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Could BMPs Therapy Be Improved if BMPs Were Used in Composition Acting during Bone Formation in Endochondral Ossification? Int J Mol Sci 2022; 23:ijms231810327. [PMID: 36142232 PMCID: PMC9499665 DOI: 10.3390/ijms231810327] [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: 07/27/2022] [Revised: 09/01/2022] [Accepted: 09/04/2022] [Indexed: 11/28/2022] Open
Abstract
The discovery of bone morphogenetic proteins (BMPs) inspired hope for the successful treatment of bone disorders, but side effects worsening the clinical effects were eventually observed. BMPs exert a synergistic effect, stimulating osteogenesis; however, predicting the best composition of growth factors for use in humans is difficult. Chondrocytes present within the growth plate produce growth factors stored in calcified cartilage adhering to metaphysis. These factors stimulate initial bone formation in metaphysis. We have previously determined the growth factors present in bovine calcified cartilage and produced by rat epiphyseal chondrocytes. The results suggest that growth factors stimulating physiological ossification are species dependent. The collection of human calcified cartilage for growth factors determination does not appear feasible, but chondrocytes for mRNA determination could be obtained. Their collection from young recipients, in view of the Academy of Medical Royal Colleges Recommendation, would be ethical. The authors of this review do not have facilities to conduct such a study and can only appeal to competent institutions to undertake the task. The results could help to formulate a better recipe for the stimulation of bone formation and improve clinical results.
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35
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Zhang W, Qiu H, Han F, Liu L, Jin H, Shang H. Bone Marrow Mesenchymal Stem Cells Exert Anti-Inflammatory and Chondrocyte Activity in Rats with Knee Arthritis. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
This study investigates whether bone marrow mesenchymal stem cells (BMSCS) exert antiinflammatory and chondrocyte activity in rats with knee arthritis. 36 SD rats were randomly divided into Health group (H group), knee arthritis group (K group), methotrexate group (M group), BMSCs group
(B Group), with 9 rats in each group followed by analysis of the levels of TNF-α, IL-6 and IL-1, morphology of knee cartilage by H&E staining, chondrocyte activity by MTT assay, and the expression of NO, ERα and cGMP by Western Blot. H&E staining showed that
the surface of knee cartilage in group H was smooth and the morphology of chondrocytes was normal. In group K, bone fissure was formed on articular cartilage surface, and the hyperplasia of deep cells was disorder. The surface of articular cartilage in group B and GROUP M gradually became
smooth. Compared with group H, the levels of TNF-α, IL-6 and IL-1 were increased and chondrocytes activity was decreased in group K (P < 0.05) with decreased TNF-α, IL-6 and IL-1 levels and increased chondrocytes activity in group M and B (P <
0.05). The levels of NO, ERα and cGMP in knee cartilage of group K were decreased (P < 0.05) and increased in group M and group B (P < 0.05). Bone marrow mesenchymal cells can down-regulate the levels of IL-6, IL-1 and TNF-α, enhance the activity
of chondrocytes, and up-regulate the levels of NO, ERα and cGMP, thus providing a new idea for the treatment of knee arthritis.
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Affiliation(s)
- Wanbiao Zhang
- Department of Muscle Injury, Shenzhen Luohu Hospital of Traditional Chinese Medicine, Shenzhen, Guangdong, 518000, China
| | - Haiyan Qiu
- Shenzhen Pingle Orthopaedic Hospital, Shenzhen, Guangdong, 518000, China
| | - Fangmiao Han
- Department of Muscle Injury, Shenzhen Luohu Hospital of Traditional Chinese Medicine, Shenzhen, Guangdong, 518000, China
| | - Liming Liu
- Department of Muscle Injury, Shenzhen Luohu Hospital of Traditional Chinese Medicine, Shenzhen, Guangdong, 518000, China
| | - Haibo Jin
- Department of Muscle Injury, Shenzhen Luohu Hospital of Traditional Chinese Medicine, Shenzhen, Guangdong, 518000, China
| | - Hongsheng Shang
- Department of Muscle Injury, Shenzhen Luohu Hospital of Traditional Chinese Medicine, Shenzhen, Guangdong, 518000, China
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36
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Ren YZ, Ding SS, Jiang YP, Wen H, Li T. Application of exosome-derived noncoding RNAs in bone regeneration: Opportunities and challenges. World J Stem Cells 2022; 14:473-489. [PMID: 36157529 PMCID: PMC9350624 DOI: 10.4252/wjsc.v14.i7.473] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 05/15/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
With advances in the fields of regenerative medicine, cell-free therapy has received increased attention. Exosomes have a variety of endogenous properties that provide stability for molecular transport across biological barriers to cells, as a form of cell-to-cell communication that regulates function and phenotype. In addition, exosomes are an important component of paracrine signaling in stem-cell-based therapy and can be used as a stand-alone therapy or as a drug delivery system. The remarkable potential of exosomes has paved the pathway for cell-free treatment in bone regeneration. Exosomes are enriched in distinct noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs and circular RNAs. Different ncRNAs have multiple functions. Altered expression of ncRNA in exosomes is associated with the regenerative potential and development of various diseases, such as femoral head osteonecrosis, myocardial infarction, and cancer. Although there is increasing evidence that exosome-derived ncRNAs (exo-ncRNAs) have the potential for bone regeneration, the detailed mechanisms are not fully understood. Here, we review the biogenesis of exo-ncRNA and the effects of ncRNAs on angiogenesis and osteoblast- and osteoclast-related pathways in different diseases. However, there are still many unsolved problems and challenges in the clinical application of ncRNA; for instance, production, storage, targeted delivery and therapeutic potency assessment. Advancements in exo-ncRNA methods and design will promote the development of therapeutics, revolutionizing the present landscape.
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Affiliation(s)
- Yuan-Zhong Ren
- Department of Emergency Trauma Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471000, Henan Province, China
| | - Shan-Shan Ding
- Department of Geriatrics, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471000, Henan Province, China
| | - Ya-Ping Jiang
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Hui Wen
- Department of Emergency Trauma Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471000, Henan Province, China
| | - Tao Li
- Department of Joint Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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37
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Chen P, Liu Y, Liu W, Wang Y, Liu Z, Rong M. Impact of High-Altitude Hypoxia on Bone Defect Repair: A Review of Molecular Mechanisms and Therapeutic Implications. Front Med (Lausanne) 2022; 9:842800. [PMID: 35620712 PMCID: PMC9127390 DOI: 10.3389/fmed.2022.842800] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 04/15/2022] [Indexed: 11/23/2022] Open
Abstract
Reaching areas at altitudes over 2,500–3,000 m above sea level has become increasingly common due to commerce, military deployment, tourism, and entertainment. The high-altitude environment exerts systemic effects on humans that represent a series of compensatory reactions and affects the activity of bone cells. Cellular structures closely related to oxygen-sensing produce corresponding functional changes, resulting in decreased tissue vascularization, declined repair ability of bone defects, and longer healing time. This review focuses on the impact of high-altitude hypoxia on bone defect repair and discusses the possible mechanisms related to ion channels, reactive oxygen species production, mitochondrial function, autophagy, and epigenetics. Based on the key pathogenic mechanisms, potential therapeutic strategies have also been suggested. This review contributes novel insights into the mechanisms of abnormal bone defect repair in hypoxic environments, along with therapeutic applications. We aim to provide a foundation for future targeted, personalized, and precise bone regeneration therapies according to the adaptation of patients to high altitudes.
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Affiliation(s)
- Pei Chen
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Yushan Liu
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Wenjing Liu
- Department of Prosthodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Yarong Wang
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Ziyi Liu
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Mingdeng Rong
- Department of Periodontology and Implantology, Stomatological Hospital, Southern Medical University, Guangzhou, China
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38
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Sarvar DP, Effatpanah H, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived extracellular vesicles: novel approach in hematopoietic stem cell transplantation. Stem Cell Res Ther 2022; 13:202. [PMID: 35578300 PMCID: PMC9109321 DOI: 10.1186/s13287-022-02875-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 12/24/2021] [Indexed: 11/24/2022] Open
Abstract
Bone marrow mesenchymal stromal cells (MSCs) play a crucial role in the regulation of hematopoiesis. These cells affect the process through direct cell–cell contact, as well as releasing various trophic factors and extracellular vehicles (EVs) into the bone marrow microenvironment. MSC-derived EVs (MSC-EVs) are prominent intercellular communication tolls enriched with broad-spectrum bioactive factors such as proteins, cytokines, lipids, miRNAs, and siRNAs. They mimic some effects of MSCs by direct fusion with hematopoietic stem cells (HSC) membranes in the bone marrow (BM), thereby affecting HSC fate. MSC-EVs are attractive scope in cell-free therapy because of their unique capacity to repair BM tissue and regulate proliferation and differentiation of HSCs. These vesicles modulate the immune system responses and inhibit graft-versus-host disease following hematopoietic stem cell transplantation (HSCT). Recent studies have demonstrated that MSC-EVs play an influential role in the BM niches because of their unprecedented capacity to regulate HSC fate. Therefore, the existing paper intends to speculate upon the preconditioned MSC-EVs as a novel approach in HSCT.
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Affiliation(s)
| | | | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Tabriz University of Medical Science, Tabriz, Iran
| | - Karim Shamsasenjan
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Hu CH, Sui BD, Liu J, Dang L, Chen J, Zheng CX, Shi S, Zhao N, Dang MY, He XN, Zhang LQ, Gao PP, Chen N, Kuang HJ, Chen K, Xu XL, Yu XR, Zhang G, Jin Y. Sympathetic Neurostress Drives Osteoblastic Exosomal MiR-21 Transfer to Disrupt Bone Homeostasis and Promote Osteopenia. SMALL METHODS 2022; 6:e2100763. [PMID: 35312228 DOI: 10.1002/smtd.202100763] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/19/2021] [Indexed: 06/14/2023]
Abstract
Innervation and extracellular vesicle secretion co-exist in the local tissue microenvironment for message transfer, but whether they are interconnected to regulate organ homeostasis remains unknown. Sympatho-adrenergic activation is implicated in stress-induced depression and leads to bone loss, but the mechanisms and therapeutics are incompletely elucidated. Here, it is revealed that sympathetic neurostress through the β1/2 -adrenergic receptor (β1/2-AR) signaling triggers the transcription response of a microRNA, miR-21, in osteoblasts, which is transferred to osteoclast progenitors via exosomes for dictating osteoclastogenesis. After confirming that miR-21 deficiency retards the β1/2-AR agonist isoproterenol (ISO)-induced osteopenia, it is shown that the pharmacological inhibition of exosome release by two clinically-relevant drugs, dimethyl amiloride and omeprazole, suppresses osteoblastic miR-21 transfer and ameliorates bone loss under both ISO and chronic variable stress (CVS)-induced depression conditions. A targeted delivery approach to specifically silence osteoblastic miR-21 is further applied, which is effective in rescuing the bone remodeling balance and ameliorating ISO- and CVS-induced osteopenias. These results decipher a previously unrecognized paradigm that neural cues drive exosomal microRNA communication to regulate organ homeostasis and help to establish feasible strategies to counteract bone loss under psychological stresses.
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Affiliation(s)
- Cheng-Hu Hu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710032, China
| | - Bing-Dong Sui
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Jin Liu
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Lei Dang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Ji Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Songtao Shi
- South China Center of Craniofacial Stem Cell Research, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Na Zhao
- Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710032, China
| | - Min-Yan Dang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Xiao-Ning He
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Li-Qiang Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Ping-Ping Gao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Nan Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Hui-Juan Kuang
- Institute for Stem Cell and Regenerative Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710032, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Kai Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Xiao-Lin Xu
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
| | - Xiao-Rui Yu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710032, China
| | - Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
- Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China
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40
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Educating EVs to Improve Bone Regeneration: Getting Closer to the Clinic. Int J Mol Sci 2022; 23:ijms23031865. [PMID: 35163787 PMCID: PMC8836395 DOI: 10.3390/ijms23031865] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/28/2022] [Accepted: 02/05/2022] [Indexed: 12/11/2022] Open
Abstract
The incidence of bone-related disorders is continuously growing as the aging of the population in developing countries continues to increase. Although therapeutic interventions for bone regeneration exist, their effectiveness is questioned, especially under certain circumstances, such as critical size defects. This gap of curative options has led to the search for new and more effective therapeutic approaches for bone regeneration; among them, the possibility of using extracellular vesicles (EVs) is gaining ground. EVs are secreted, biocompatible, nano-sized vesicles that play a pivotal role as messengers between donor and target cells, mediated by their specific cargo. Evidence shows that bone-relevant cells secrete osteoanabolic EVs, whose functionality can be further improved by several strategies. This, together with the low immunogenicity of EVs and their storage advantages, make them attractive candidates for clinical prospects in bone regeneration. However, before EVs reach clinical translation, a number of concerns should be addressed. Unraveling the EVs’ mode of action in bone regeneration is one of them; the molecular mediators driving their osteoanabolic effects in acceptor cells are now beginning to be uncovered. Increasing the functional and bone targeting abilities of EVs are also matters of intense research. Here, we summarize the cell sources offering osteoanabolic EVs, and the current knowledge about the molecular cargos that mediate bone regeneration. Moreover, we discuss strategies under development to improve the osteoanabolic and bone-targeting potential of EVs.
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Mi B, Chen L, Xiong Y, Yang Y, Panayi AC, Xue H, Hu Y, Yan C, Hu L, Xie X, Lin Z, Zhou W, Cao F, Xiao X, Feng Q, Liu G. Osteoblast/Osteoclast and Immune Cocktail Therapy of an Exosome/Drug Delivery Multifunctional Hydrogel Accelerates Fracture Repair. ACS NANO 2022; 16:771-782. [PMID: 34979087 DOI: 10.1021/acsnano.1c08284] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The osteoblast/osteoclast and M1/M2 macrophage ratios play critical roles in delayed fracture healing. Robust osteoblast differentiation and M2 macrophage polarization can substantiality promote fracture repair; however, the combined effect of these strategies has not been previously studied. In this study, we constructed a cocktail therapy to simultaneously regulate the osteoblast/osteoclast and M1/M2 macrophage balance. The cocktail therapy composed of a natural polymer hyaluronic-acid-based hydrogel (HA hydrogel, which has a tissue-adhesive, injectable, self-healing, anti-inflammation profile), engineered endothelial cell-derived exosomes (EC-ExosmiR-26a-5p), and APY29, an IRE-1α inhibitor. This allowed for specific delivery of EC-ExosmiR-26a-5p and APY29 for osteoblast/osteoclast and macrophage regulation, respectively. The results suggested that the cocktail therapy exerted pro-fracture repair effects with each of its components established as indispensable. The assessed cocktail therapy provides insight into synergistic strategies and is useful for developing more suitable pro-fracture repair therapy.
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Affiliation(s)
- Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Lang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yuan Xiong
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yayan Yang
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
| | - Adriana C Panayi
- Department of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts 02152, United States
| | - Hang Xue
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Yiqiang Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Chenchen Yan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Liangcong Hu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Xudong Xie
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Ze Lin
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Wu Zhou
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Faqi Cao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
| | - Xiufeng Xiao
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
| | - Qian Feng
- College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou 350007, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Guohui Liu
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan 430022, China
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HPV16 E6 enhances the radiosensitivity in HPV-positive human head and neck squamous cell carcinoma by regulating the miR-27a-3p/SMG1 axis. Infect Agent Cancer 2021; 16:56. [PMID: 34389030 PMCID: PMC8361787 DOI: 10.1186/s13027-021-00397-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/29/2021] [Indexed: 01/13/2023] Open
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is the 6th most common malignant cancer type worldwide. Radiosensitivity has been shown to be significantly increased in patients with human papillomavirus (HPV)-positive HNSCC compared with HPV-negative patients. However, the clinical significance of HPV and its regulatory mechanisms in HNSCC are largely unknown. The aim of our study was to explore the regulatory mechanism of miR-27a-3p in the radiosensitivity of HPV-positive HNSCC cells. Methods E6-overexpressing and E6-knockdown HNSCC cell lines were generated and the transfection efficiencies were evaluated by quantitative real-time PCR (RT-qPCR) and western blotting. The expression of miR-27a-3p and DiGeorge syndrome critical region 8 (DGCR8) was examined by RT-qPCR after transfection with E6 overexpressing plasmid or E6 siRNA. The effects of miR-27a-3p on the radiosensitivity of HNSCC cells were explored by a colony formation and TUNEL staining assays. Bioinformatic tools and luciferase reporter assays were used to identify that SMG1 is the direct target of miR-27a-3p. Furthermore, the effect of E6 overexpression on the regulation of the miR-27a-3p/SMG1 axis was investigated. Results In our study, we found overexpression of HPV E6 upregulated the expression of DGCR8 and miR-27a-3p in HNSCC cells. We next confirmed that DGCR8 positively regulated the expression of miR-27a-3p in HNSCC cells. The luciferase reporter gene results verified that miR-27a-3p targeted the 3’UTR of SMG1 mRNA. MiR-27a-3p mimics transfection resulted in a decrease in SMG1 expression and miR-27a-3p inhibitor transfection increased SMG1 expression. Apoptotic activity of HNSCC cells was significantly increased in miR-27a-3p mimics HNSCC cells compared with control HNSCC cells. After treatment with 4 Gy irradiation, UM-SCC47 cells transfected with miR-27a-3p inhibitor or SMG1 overexpressing plasmid formed more colonies than the corresponding control cells. Furthermore, the rescue experiments demonstrated that HPV16 E6 improved the radiosensitivity of HNSCC cells by targeting miR-27a-3p/SMG1. Conclusion Our study demonstrated that HPV16 E6 activated the DGCR8/miR-27a-3p/SMG1 axis to enhance the radiosensitivity. Our findings might provide a novel therapeutic target to improve the response of HNSCC to radiotherapy.
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Song Y, Wang M, Qian Q, Xu J, Zhou Q, Lv S, Miao P. Trace miRNA Assay Based on DNA Nanostructures Formed by Hybridization Chain Reaction and Gold‐Nanoparticle Tags. ChemElectroChem 2021. [DOI: 10.1002/celc.202100466] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Yan Song
- Beihua University Jilin 132013 P. R. China
| | | | - Qin Qian
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences Suzhou 215163 P. R. China
| | - Jun Xu
- Suzhou Blood Center Suzhou 215006 P. R. China
| | | | - Shujie Lv
- Beihua University Jilin 132013 P. R. China
| | - Peng Miao
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences Suzhou 215163 P. R. China
- Ji Hua Laboratory Foshan 528200 P. R. China
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Ponzetti M, Rucci N. Osteoblast Differentiation and Signaling: Established Concepts and Emerging Topics. Int J Mol Sci 2021; 22:ijms22136651. [PMID: 34206294 PMCID: PMC8268587 DOI: 10.3390/ijms22136651] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Osteoblasts, the cells that build up our skeleton, are remarkably versatile and important cells that need tight regulation in all the phases of their differentiation to guarantee proper skeletal development and homeostasis. Although we know many of the key pathways involved in osteoblast differentiation and signaling, it is becoming clearer and clearer that this is just the tip of the iceberg, and we are constantly discovering novel concepts in osteoblast physiology. In this review, we discuss well-established pathways of osteoblastic differentiation, i.e., the classical ones committing mesenchymal stromal cells to osteoblast, and then osteocytes as well as recently emerged players. In particular, we discuss micro (mi)RNAs, long non-coding (lnc)RNAs, circular (circ)RNAs, and extracellular vesicles, focusing on the mechanisms through which osteoblasts are regulated by these factors, and conversely, how they use extracellular vesicles to communicate with the surrounding microenvironment.
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