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Feng Y, Tang M, Li H, Yao S, Li B. Mouse mesenchymal stem cell-derived exosomal miR-205-5p modulates LPS-induced macrophage polarization and alleviates lung injury by regulating the USP7/FOXM1 axis. Drug Deliv Transl Res 2025:10.1007/s13346-025-01813-z. [PMID: 40000557 DOI: 10.1007/s13346-025-01813-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 02/27/2025]
Abstract
Exosomal microRNAs produced from mesenchymal stem cells (MSCs) are crucial in the management of acute lung injury (ALI). In this work, mMSCs separated from bone marrow were used to extract exosomes (MSC-Exos). MSC-Exos treatment attenuated pathological changes and scores, and edema in ALI mice. Also, MSC-Exos administration modulated the concentrations of inflammatory factors as well as the macrophage polarization both in vivo and in vitro. Upregulation of miR-205-5p in MSC-Exos regulated the macrophage polarization and the contents of inflammatory factors in animal and cell models. MiR-205-5p targeted USP7, and negatively modulated the expression of USP7. USP7 interacted with FOXM1, and reduced the ubiquitination degradation of FOXM1. MSC-derived exosomal miR-205-5p modulated ubiquitination of FOXM1 by targeting USP7. The ameliorative effect of MSC-Exos on the macrophage polarization and the inflammatory factors release was reversed with the overexpression of USP7 in animal and cell models. Collectively, MSC-derived exosomal miR-205-5p regulated lipopolysaccharide (LPS)-induced macrophage polarization and alleviated lung injury by the USP7/FOXM1 axis, which developed a potential target for the treatment of ALI.
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Affiliation(s)
- Yinglu Feng
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Min Tang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Haopeng Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
| | - Bo Li
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology), Ministry of Education, Wuhan, China.
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Ahn J, Kim B, Bello AB, Moon JJ, Arai Y, Lee SH. Regenerative Functions of Regulatory T Cells and Current Strategies Utilizing Mesenchymal Stem Cells in Immunomodulatory Tissue Regeneration. Tissue Eng Regen Med 2025; 22:167-180. [PMID: 39804546 PMCID: PMC11794763 DOI: 10.1007/s13770-024-00690-w] [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: 11/21/2024] [Revised: 12/03/2024] [Accepted: 12/05/2024] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Regulatory T cells (Tregs) are essential for maintaining immune homeostasis and facilitating tissue regeneration by fostering an environment conducive to tissue repair. However, in damaged tissues, excessive inflammatory responses can overwhelm the immunomodulatory capacity of Tregs, compromising their functionality and potentially hindering effective regeneration. Mesenchymal stem cells (MSCs) play a key role in enhancing Treg function. MSCs enhance Treg activity through indirect interactions, such as cytokine secretion, and direct interactions via membrane proteins. METHODS This review examines the regenerative functions of Tregs across various tissues, including bone, cartilage, muscle, and skin, and explores strategies to enhance Treg functionality using MSCs. Advanced techniques, such as the overexpression of relevant genes in MSCs, are highlighted for their potential to further enhance Treg function. Additionally, emerging technologies utilizing extracellular vesicles (EVs) and cell membrane-derived vesicles derived from MSCs offer promising alternatives to circumvent the potential side effects associated with live cell therapies. This review proposes approaches to enhance Treg function and promote tissue regeneration and also outlines future research directions. RESULTS AND CONCLUSION This review elucidates recent technological advancements aimed at enhancing Treg function using MSCs and examines their potential to improve tissue regeneration efficiency.
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Grants
- 2022R1A2C3004850 Ministry of Science and ICT, South Korea
- RS-2024-00405381 Ministry of Science and ICT, South Korea
- RS-2023-00257290 Ministry of Science and ICT, South Korea
- RS-2023-00246418 Ministry of Education
- RS-2023-00275407 Ministry of Education
- 21C0703L1 Ministry of Science and ICT, Ministry of Health & Welfare
- HX23C1734 Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health & Welfare, The Ministry of Food and Drug Safety
- Ministry of Science and ICT, Ministry of Health & Welfare
- Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health & Welfare, The Ministry of Food and Drug Safety
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Affiliation(s)
- Jinsung Ahn
- Department of Biomedical Engineering, Dongguk University, Seoul, South Korea
| | - Bowon Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, South Korea
| | - Alvin Bacero Bello
- Department of Biomedical Engineering, Dongguk University, Seoul, South Korea
| | - James J Moon
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Yoshie Arai
- Department of Biomedical Engineering, Dongguk University, Seoul, South Korea.
| | - Soo-Hong Lee
- Department of Biomedical Engineering, Dongguk University, Seoul, South Korea.
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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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Zhang Y, Fan M, Zhang Y. Revolutionizing bone defect healing: the power of mesenchymal stem cells as seeds. Front Bioeng Biotechnol 2024; 12:1421674. [PMID: 39497791 PMCID: PMC11532096 DOI: 10.3389/fbioe.2024.1421674] [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: 04/22/2024] [Accepted: 10/10/2024] [Indexed: 11/07/2024] Open
Abstract
Bone defects can arise from trauma or pathological factors, resulting in compromised bone integrity and the loss or absence of bone tissue. As we are all aware, repairing bone defects is a core problem in bone tissue engineering. While minor bone defects can self-repair if the periosteum remains intact and normal osteogenesis occurs, significant defects or conditions such as congenital osteogenesis imperfecta present substantial challenges to self-healing. As research on mesenchymal stem cell (MSC) advances, new fields of application have emerged; however, their application in orthopedics remains one of the most established and clinically valuable directions. This review aims to provide a comprehensive overview of the research progress regarding MSCs in the treatment of diverse bone defects. MSCs, as multipotent stem cells, offer significant advantages due to their immunomodulatory properties and ability to undergo osteogenic differentiation. The review will encompass the characteristics of MSCs within the osteogenic microenvironment and summarize the research progress of MSCs in different types of bone defects, ranging from their fundamental characteristics and animal studies to clinical applications.
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Affiliation(s)
- Yueyao Zhang
- Trauma Emergency Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Biomechanics of Hebei Province, Orthopaedic Research Institution of Hebei Province, Shijiazhuang, China
| | - Mengke Fan
- Trauma Emergency Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Biomechanics of Hebei Province, Orthopaedic Research Institution of Hebei Province, Shijiazhuang, China
| | - Yingze Zhang
- Trauma Emergency Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China
- Key Laboratory of Biomechanics of Hebei Province, Orthopaedic Research Institution of Hebei Province, Shijiazhuang, China
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Fu YS, Tsai SW, Tong ZJ, Yeh CC, Chen TH, Chen CF. Wharton's jelly of the umbilical cord serves as a natural biomaterial to promote osteogenesis. Biomater Sci 2024. [PMID: 39415619 DOI: 10.1039/d3bm02137h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Various factors can contribute to bone damage or loss, presenting challenges for bone regeneration. Our study explores the potential clinical applications of two processed forms of Wharton's jelly of the human umbilical cord for treating bone loss. Wharton's jelly from fresh umbilical cords underwent two distinct processes: (1) frozen Wharton's jelly (WJF), preserved with cryoprotective agents, and (2) decellularized Wharton's jelly matrix (WJD), prepared only via lyophilization without cryoprotectants. Both WJD and WJF are rich in collagen, hyaluronan, and polysaccharide proteins. Notably, WJD exhibited a porous structure lacking nuclei from human umbilical cord mesenchymal stem cells, unlike WJF. In direct contact experiments, WJD stimulated osteoblast migration, enhanced osteoblast maturation, and promoted calcium deposition for bone formation when administered to cultured rat osteoblasts. Furthermore, in transwell co-culture experiments, both WJD and WJF increased the rat osteoblast expression of RUNX2 and OPN genes, elevated alkaline phosphatase levels, and enhanced extracellular calcium precipitation, indicating their role in osteoblast maturation and new bone formation. Hyaluronic acid, one of the ingredients from WJD and WJF, was identified as a key component triggering osteogenesis. In vivo experiments involved creating circular bone defects in the calvarias of rats, where WJD and WJF were separately implanted and monitored over five months using micro-computerized tomography. Our results demonstrated that both WJD and WJF enhanced angiogenesis, collagen formation, osteoblast maturation, and bone growth within the bone defects. In summary, WJD and WJF, natural biomaterials with biocompatibility and nontoxicity, act not only as effective scaffolds but also promote osteoblast adhesion and differentiation, and accelerate osteogenesis.
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Affiliation(s)
- Yu-Show Fu
- Department of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
| | - Shang-Wen Tsai
- Division of Joint Reconstruction, Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
- Department of Orthopaedics, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
| | - Zhen-Jie Tong
- Institute of Anatomy and Cell Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
| | - Chang-Ching Yeh
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
- Department of Obstetrics and Gynecology, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
- Department of Nurse-Midwifery and Women Health, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Tien-Hua Chen
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung City, Taiwan
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
- Trauma Center, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
| | - Cheng-Fong Chen
- Division of Joint Reconstruction, Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China.
- Department of Orthopaedics, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China
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Han J, Rindone AN, Elisseeff JH. Immunoengineering Biomaterials for Musculoskeletal Tissue Repair across Lifespan. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2311646. [PMID: 38416061 PMCID: PMC11239302 DOI: 10.1002/adma.202311646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 01/23/2024] [Indexed: 02/29/2024]
Abstract
Musculoskeletal diseases and injuries are among the leading causes of pain and morbidity worldwide. Broad efforts have focused on developing pro-regenerative biomaterials to treat musculoskeletal conditions; however, these approaches have yet to make a significant clinical impact. Recent studies have demonstrated that the immune system is central in orchestrating tissue repair and that targeting pro-regenerative immune responses can improve biomaterial therapeutic outcomes. However, aging is a critical factor negatively affecting musculoskeletal tissue repair and immune function. Hence, understanding how age affects the response to biomaterials is essential for improving musculoskeletal biomaterial therapies. This review focuses on the intersection of the immune system and aging in response to biomaterials for musculoskeletal tissue repair. The article introduces the general impacts of aging on tissue physiology, the immune system, and the response to biomaterials. Then, it explains how the adaptive immune system guides the response to injury and biomaterial implants in cartilage, muscle, and bone and discusses how aging impacts these processes in each tissue type. The review concludes by highlighting future directions for the development and translation of personalized immunomodulatory biomaterials for musculoskeletal tissue repair.
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Affiliation(s)
- Jin Han
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University; Baltimore, MD 21231, USA
| | - Alexandra N. Rindone
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University; Baltimore, MD 21231, USA
| | - Jennifer H. Elisseeff
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University; Baltimore, MD 21231, USA
- Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine; Baltimore, MD 21231, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University; Baltimore, MD 21231, USA
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Hong J, Luo F, Du X, Xian F, Li X. The immune cells in modulating osteoclast formation and bone metabolism. Int Immunopharmacol 2024; 133:112151. [PMID: 38685175 DOI: 10.1016/j.intimp.2024.112151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 04/10/2024] [Accepted: 04/22/2024] [Indexed: 05/02/2024]
Abstract
Osteoclasts are pivotal in regulating bone metabolism, with immune cells significantly influencing both physiological and pathological processes by modulating osteoclast functions. This is particularly evident in conditions of inflammatory bone resorption, such as rheumatoid arthritis and periodontitis. This review summarizes and comprehensively analyzes the research progress on the regulation of osteoclast formation by immune cells, aiming to unveil the underlying mechanisms and pathways through which diseases, such as rheumatoid arthritis and periodontitis, impact bone metabolism.
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Affiliation(s)
- Jiale Hong
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Fang Luo
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Xingyue Du
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Fa Xian
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China
| | - Xinyi Li
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, PR China.
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8
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Li J, Xia T, Zhao Q, Wang C, Fu L, Zhao Z, Tang Z, Yin C, Wang M, Xia H. Biphasic calcium phosphate recruits Tregs to promote bone regeneration. Acta Biomater 2024; 176:432-444. [PMID: 38185232 DOI: 10.1016/j.actbio.2024.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 12/27/2023] [Accepted: 01/01/2024] [Indexed: 01/09/2024]
Abstract
The use of bone substitute materials is crucial for the healing of large bone defects. Immune response induced by bone substitute materials is essential in bone regeneration. Prior research has mainly concentrated on innate immune cells, such as macrophages. Existing research suggests that T lymphocytes, as adaptive immune cells, play an indispensable role in bone regeneration. However, the mechanisms governing T cell recruitment and specific subsets that are essential for bone regeneration remain unclear. This study demonstrates that CD4+ T cells are indispensable for ectopic osteogenesis by biphasic calcium phosphate (BCP). Subsequently, the recruitment of CD4+ T cells is closely associated with the activation of calcium channels in macrophages by BCP to release chemokines Ccl3 and Ccl17. Finally, these recruited CD4+ T cells are predominantly Tregs, which play a significant role in ectopic osteogenesis by BCP. These findings not only shed light on the immune-regenerative process after bone substitute material implantation but also establish a theoretical basis for developing bone substitute materials for promoting bone tissue regeneration. STATEMENT OF SIGNIFICANCE: Bone substitute material implantation is essential in the healing of large bone defects. Existing research suggests that T lymphocytes are instrumental in bone regeneration. However, the specific mechanisms governing T cell recruitment and specific subsets that are essential for bone regeneration remain unclear. In this study, we demonstrate that activation of calcium channels in macrophages by biphasic calcium phosphate (BCP) causes them to release the chemokines Ccl3 and Ccl17 to recruit CD4+ T cells, predominantly Tregs, which play a crucial role in ectopic osteogenesis by BCP. Our findings provide a theoretical foundation for developing bone substitute material for bone tissue regeneration.
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Affiliation(s)
- Jiaojiao Li
- 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, Wuhan 430079, China
| | - Ting Xia
- 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, Wuhan 430079, China
| | - Qin Zhao
- 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, Wuhan 430079, China
| | - Can 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, Wuhan 430079, China
| | - Liangliang Fu
- 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, Wuhan 430079, China
| | - Zifan Zhao
- Center of Digital Dentistry, Faculty of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & NHC Key Laboratory of Digital Stomatology & Beijing Key Laboratory of Digital Stomatology & Key Laboratory of Digital Stomatology, Chinese Academy of Medical Sciences & NMPA Key Laboratory for Dental Materials, Beijing,100081, China
| | - Ziqiao Tang
- 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, Wuhan 430079, China
| | - Chenghu Yin
- 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, Wuhan 430079, China
| | - Min 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, Wuhan 430079, China.
| | - Haibin Xia
- 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, Wuhan 430079, China.
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Park JS, Kim DY, Hong HS. FGF2/HGF priming facilitates adipose-derived stem cell-mediated bone formation in osteoporotic defects. Heliyon 2024; 10:e24554. [PMID: 38304814 PMCID: PMC10831751 DOI: 10.1016/j.heliyon.2024.e24554] [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: 09/13/2023] [Revised: 12/14/2023] [Accepted: 01/10/2024] [Indexed: 02/03/2024] Open
Abstract
Aims The activity of adipose-derived stem cells (ADSCs) is susceptible to the physiological conditions of the donor. Therefore, employing ADSCs from donors of advanced age or with diseases for cell therapy necessitates a strategy to enhance therapeutic efficacy before transplantation. This study aims to investigate the impact of supplementing Fibroblast Growth Factor 2 (FGF2) and Hepatocyte Growth Factor (HGF) on ADSC-mediated osteogenesis under osteoporotic conditions and to explore the underlying mechanisms of action. Main methods Adipose-derived stem cells (ADSCs) obtained from ovariectomized (OVX) rats were cultured ex vivo. These cells were cultured in an osteogenic medium supplemented with FGF2 and HGF and subsequently autologously transplanted into osteoporotic femur defects using Hydroxyapatite-Tricalcium Phosphate. The assessment of bone formation was conducted four weeks post-transplantation. Key findings Osteoporosis detrimentally affects the viability and osteogenic differentiation potential of ADSCs, often accompanied by a deficiency in FGF2 and HGF signaling. However, priming with FGF2 and HGF facilitated the formation of immature osteoblasts from OVX ADSCs in vitro, promoting the expression of osteoblastogenic proteins, including Runx-2, osterix, and ALP, during the early phase of osteogenesis. Furthermore, FGF2/HGF priming augmented the levels of VEGF and SDF-1α in the microenvironment of OVX ADSCs under osteogenic induction. Importantly, transplantation of OVX ADSCs primed with FGF2/HGF for 6 days significantly enhanced bone formation compared to non-primed cells. The success of bone regeneration was confirmed by the expression of type-1 collagen and osteocalcin in the bone tissue of the deficient area. Significance Our findings corroborate that priming with FGF2/HGF can improve the differentiation potential of ADSCs. This could be applied in autologous stem cell therapy for skeletal disease in the geriatric population.
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Affiliation(s)
- Jeong Seop Park
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, 02447, South Korea
| | - Do Young Kim
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, 02447, South Korea
| | - Hyun Sook Hong
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, 02447, South Korea
- East-West Medical Research Institute, Kyung Hee University, Seoul, 02447, South Korea
- Kyung Hee Institute of Regenerative Medicine (KIRM), Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, 02447, South Korea
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10
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Xu H, Nie X, Deng W, Zhou H, Huang D, Wang Z. Bone marrow mesenchymal stem cells-derived exosomes ameliorate LPS-induced acute lung injury by miR-223-regulated alveolar macrophage M2 polarization. J Biochem Mol Toxicol 2024; 38:e23568. [PMID: 37899695 DOI: 10.1002/jbt.23568] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/15/2023] [Accepted: 10/12/2023] [Indexed: 10/31/2023]
Abstract
Numerous studies have shown that the M2 polarization of alveolar macrophages (AM) plays a protective role in acute lung injury (ALI). Mesenchymal stem cells (MSCs) secreted exosomes have been reported to be involved in inflammatory diseases by the effects of polarized M1/M2 macrophage populations. However, whether bone marrow mesenchymal stem cells (BMMSCs) derived exosomes could protect from ALI and its mechanisms are still unclear. Here, we explored the role of exosomes from BMMSC in rat AM polarization and the lipopolysaccharide- (LPS-) induced ALI rat model. Furthermore, the levels of exosomal miR-223 in BMMSCs were measured by RT-qPCR. Additionally, miR-223 mimics and its inhibitors were used to verify the vital role of miR-223 of BMMSCs-derived exosomes in the polarization of M2 macrophages. The results showed that BMMSCs-derived exosomes were taken up by the AM. Exosomes derived from BMMSCs promoted M2 polarization of AM in vitro. BMMSCs exosomes effectively mitigated pathological injuries, lung edema, and the inflammation of rats from LPS-induced ALI, accompanied by an increase of M2 polarization of AM in lung tissue. Interestingly, we also found that miR-223 was enriched in BMMSCs-derived exosomes, and overexpression of miR-223 in BMMSCs-derived exosomes promoted M2 polarization of AM while depressing miR-223 showed opposite effects in AM. The present study demonstrated that BMMSCs-derived exosomes triggered alveolar M2 polarization to improve inflammation by transferring miR-223, which may provide new therapeutic strategies in ALI.
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Affiliation(s)
- Hui Xu
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Xiangbi Nie
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Wu Deng
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Han Zhou
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Dan Huang
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
| | - Zenggeng Wang
- Department of Emergency, Jiangxi Provincial People's Hospital (The First Affiliated Hospital of Nanchang Medical College), Nanchang, China
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11
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Xu W, Yang Y, Li N, Hua J. Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair. Int J Mol Sci 2023; 24:14484. [PMID: 37833933 PMCID: PMC10572976 DOI: 10.3390/ijms241914484] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing.
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Affiliation(s)
| | | | - Na Li
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
| | - Jinlian Hua
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
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12
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Namjoynik A, Islam MA, Islam M. Evaluating the efficacy of human dental pulp stem cells and scaffold combination for bone regeneration in animal models: a systematic review and meta-analysis. Stem Cell Res Ther 2023; 14:132. [PMID: 37189187 DOI: 10.1186/s13287-023-03357-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 04/27/2023] [Indexed: 05/17/2023] Open
Abstract
INTRODUCTION Human adult dental pulp stem cells (hDPSC) and stem cells from human exfoliated deciduous teeth (SHED) hold promise in bone regeneration for their easy accessibility, high proliferation rate, self-renewal and osteogenic differentiation capacity. Various organic and inorganic scaffold materials were pre-seeded with human dental pulp stem cells in animals, with promising outcomes in new bone formation. Nevertheless, the clinical trial for bone regeneration using dental pulp stem cells is still in its infancy. Thus, the aim of this systematic review and meta-analysis is to synthesise the evidence of the efficacy of human dental pulp stem cells and the scaffold combination for bone regeneration in animal bone defect models. METHODOLOGY This study was registered in PROSPERO (CRD2021274976), and PRISMA guideline was followed to include the relevant full-text papers using exclusion and inclusion criteria. Data were extracted for the systematic review. Quality assessment and the risk of bias were also carried out using the CAMARADES tool. Quantitative bone regeneration data of the experimental (scaffold + hDPSC/SHED) and the control (scaffold-only) groups were also extracted for meta-analysis. RESULTS Forty-nine papers were included for systematic review and only 27 of them were qualified for meta-analysis. 90% of the included papers were assessed as medium to low risk. In the meta-analysis, qualified studies were grouped by the unit of bone regeneration measurement. Overall, bone regeneration was significantly higher (p < 0.0001) in experimental group (scaffold + hDPSC/SHED) compared to the control group (scaffold-only) (SMD: 1.863, 95% CI 1.121-2.605). However, the effect is almost entirely driven by the % new bone formation group (SMD: 3.929, 95% CI 2.612-5.246) while % BV/TV (SMD: 2.693, 95% CI - 0.001-5.388) shows a marginal effect. Dogs and hydroxyapatite-containing scaffolds have the highest capacity in % new bone formation in response to human DPSC/SHED. The funnel plot exhibits no apparent asymmetry representing a lack of remarkable publication bias. Sensitivity analysis also indicated that the results generated in this meta-analysis are robust and reliable. CONCLUSION This is the first synthesised evidence showing that human DPSCs/SHED and scaffold combination enhanced bone regeneration highly significantly compared to the cell-free scaffold irrespective of scaffold type and animal species used. So, dental pulp stem cells could be a promising tool for treating various bone diseases, and more clinical trials need to be conducted to evaluate the effectiveness of dental pulp stem cell-based therapies.
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Affiliation(s)
- Amin Namjoynik
- School of Dentistry, University of Dundee, Dundee, DD1 4HR, Scotland, UK
| | - Md Asiful Islam
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TT, UK
| | - Mohammad Islam
- School of Dentistry, University of Dundee, Dundee, DD1 4HR, Scotland, UK.
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13
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Bowles-Welch AC, Jimenez AC, Stevens HY, Frey Rubio DA, Kippner LE, Yeago C, Roy K. Mesenchymal stromal cells for bone trauma, defects, and disease: Considerations for manufacturing, clinical translation, and effective treatments. Bone Rep 2023. [DOI: 10.1016/j.bonr.2023.101656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
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14
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Kang IH, Baliga UK, Chatterjee S, Chakraborty P, Choi S, Buchweitz N, Li H, Wu Y, Yao H, Mehrotra S, Mehrotra M. Quantitative increase in T regulatory cells enhances bone remodeling in osteogenesis imperfecta. iScience 2022; 25:104818. [PMID: 36034228 PMCID: PMC9400089 DOI: 10.1016/j.isci.2022.104818] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 06/07/2022] [Accepted: 07/19/2022] [Indexed: 02/03/2023] Open
Abstract
Osteogenesis imperfecta (OI) is characterized by repeated bone fractures. Recent studies have shown that T lymphocytes and regulatory T cells (Tregs) regulate the functions of osteoclasts and osteoblasts, thus playing a role in bone turnover. We demonstrate an activated effector phenotype and higher secretion of pro-inflammatory cytokines, IFN-γ, and TNF-α in OI peripheral T cells as compared with wild-type (WT). Suppressive Tregs (spleen and thymus) were qualitatively similar, whereas there was a quantitative decrease in OI versus WT. Restoring Treg numbers by systemic transplantation in OI mice resulted in reduced T cell activation and effector cytokine secretion that correlated with significant improvements in tibial trabecular and cortical bone parameters and stiffness of femur, along with increased osteoblast mineralization and decreased osteoclast numbers. Therefore, Tregs can dampen the pro-inflammatory environment and enhance bone remodeling in OI mice. Thus, this study will be helpful in developing future autologous immunotherapy-based treatment modalities for OI.
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Affiliation(s)
- In-Hong Kang
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Uday K. Baliga
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Shilpak Chatterjee
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Paramita Chakraborty
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Seungho Choi
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Nathan Buchweitz
- Department of Orthopedics, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
- Clemson-MUSC Joint Bioengineering Program, South Carolina, USA
| | - Hong Li
- Depatment of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Yongren Wu
- Department of Orthopedics, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
- Clemson-MUSC Joint Bioengineering Program, South Carolina, USA
| | - Hai Yao
- Department of Orthopedics, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Bioengineering, Clemson University, Clemson, SC 29634, USA
- Clemson-MUSC Joint Bioengineering Program, South Carolina, USA
- Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Meenal Mehrotra
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Oral Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA
- Center for Oral Health Research, Medical University of South Carolina, Charleston, SC 29425, USA
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15
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Su N, Villicana C, Yang F. Immunomodulatory strategies for bone regeneration: A review from the perspective of disease types. Biomaterials 2022; 286:121604. [PMID: 35667249 PMCID: PMC9881498 DOI: 10.1016/j.biomaterials.2022.121604] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/19/2022] [Accepted: 05/24/2022] [Indexed: 02/08/2023]
Abstract
Tissue engineering strategies for treating bone loss to date have largely focused on targeting stem cells or vascularization. Immune cells, including macrophages and T cells, can also indirectly enhance bone healing via cytokine secretion to interact with other bone niche cells. Bone niche cues and local immune environment vary depending on anatomical location, size of defects and disease types. As such, it is critical to evaluate the role of the immune system in the context of specific bone niche and different disease types. This review focuses on immunomodulation research for bone applications using biomaterials and cell-based strategies, with a unique perspective from different disease types. We first reviewed applications for prolonging orthopaedic implant lifetime and enhancing fracture healing, two clinical challenges where immunomodulatory strategies were initially developed for orthopedic applications. We then reviewed recent research progress in harnessing immunomodulatory strategies for regenerating critical-sized, long bone or cranial bone defects, and treating osteolytic bone diseases. Remaining gaps in knowledge, future directions and opportunities were also discussed.
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Affiliation(s)
- Ni Su
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Cassandra Villicana
- Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Fan Yang
- Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.,Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, 94305, USA.,: Corresponding Author Fan Yang, Ph D, Department of Orthopaedic Surgery and Bioengineering, Stanford University School of Medicine, 240 Pasteur Dr, Palo Alto, CA 94304, Biomedical Innovation Building, 1st floor, Room 1200, , Phone: (650) 646-8558
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16
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Yang Y, Chu C, Xiao W, Liu L, Man Y, Lin J, Qu Y. Strategies for advanced particulate bone substitutes regulating the osteo-immune microenvironment. Biomed Mater 2022; 17. [PMID: 35168224 DOI: 10.1088/1748-605x/ac5572] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 02/15/2022] [Indexed: 02/05/2023]
Abstract
The usage of bone substitute granule materials has improved the clinical results of alveolar bone deficiencies treatment and thus broadened applications in implant dentistry. However, because of the complicated mechanisms controlling the foreign body response, no perfect solution can avoid the fibrotic encapsulation of materials till now, which may impair the results of bone regeneration, even cause the implant materials rejection. Recently, the concept of 'osteoimmunology' has been stressed. The outcomes of bone regeneration are proved to be related to the bio-physicochemical properties of biomaterials, which allow them to regulate the biological behaviours of both innate and adaptive immune cells. With the development of single cell transcriptome, the truly heterogeneity of osteo-immune cells has been clarifying, which is helpful to overcome the limitations of traditional M1/M2 macrophage nomenclature and drive the advancements of particulate biomaterials applications. This review aims at introducing the mechanisms of optimal osseointegration regulated by immune systems and provides feasible strategies for the design of next generation 'osteoimmune-smart' particulate bone substitute materials in dental clinic.
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Affiliation(s)
- Yang Yang
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Chenyu Chu
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Wenlan Xiao
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Li Liu
- State Key Laboratory of Biotherapy and Laboratory, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yi Man
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Jie Lin
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yili Qu
- Department of Oral Implantology & Department of Prosthodontics & State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People's Republic of China
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17
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Chen R, Hao Z, Wang Y, Zhu H, Hu Y, Chen T, Zhang P, Li J. Mesenchymal Stem Cell-Immune Cell Interaction and Related Modulations for Bone Tissue Engineering. Stem Cells Int 2022; 2022:7153584. [PMID: 35154331 PMCID: PMC8825274 DOI: 10.1155/2022/7153584] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Critical bone defects and related delayed union and nonunion are still worldwide problems to be solved. Bone tissue engineering is mainly aimed at achieving satisfactory bone reconstruction. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells that can differentiate into bone cells and can be used as one of the key pillars of bone tissue engineering. In recent decades, immune responses play an important role in bone regeneration. Innate immune responses provide a suitable inflammatory microenvironment for bone regeneration and initiate bone regeneration in the early stage of fracture repair. Adaptive immune responses maintain bone regeneration and bone remodeling. MSCs and immune cells regulate each other. All kinds of immune cells and secreted cytokines can regulate the migration, proliferation, and osteogenic differentiation of MSCs, which have a strong immunomodulatory ability to these immune cells. This review mainly introduces the interaction between MSCs and immune cells on bone regeneration and its potential mechanism, and discusses the practical application in bone tissue engineering by modulating this kind of cell-to-cell crosstalk. Thus, an in-depth understanding of these principles of bone immunology can provide a new way for bone tissue engineering.
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Affiliation(s)
- Renxin Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Zhuowen Hao
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yi Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Hongzhen Zhu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Yingkun Hu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Tianhong Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Peng Zhang
- Department of Orthopedics, Suzhou Science and Technology Town Hospital, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou 215153, China
| | - Jingfeng Li
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
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18
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Ohori-Morita Y, Niibe K, Limraksasin P, Nattasit P, Miao X, Yamada M, Mabuchi Y, Matsuzaki Y, Egusa H. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:434-449. [PMID: 35267026 PMCID: PMC9052431 DOI: 10.1093/stcltm/szab030] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 12/02/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
- Yumi Ohori-Morita
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Kunimichi Niibe
- Corresponding authors: Kunimichi Niibe, DDS, PhD, Associate Professor, Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai-city, Miyagi 980-8575, Japan. Tel: +81-22-717-8363; Fax: +81-22-717-8367;
| | - Phoonsuk Limraksasin
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Praphawi Nattasit
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Xinchao Miao
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Masahiro Yamada
- Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
| | - Yo Mabuchi
- Department of Biochemistry and Biophysics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yumi Matsuzaki
- Department of Life Science, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Hiroshi Egusa
- Hiroshi Egusa, DDS, PhD, Director, Center for Advanced Stem Cell and Regenerative Research, Professor and Chair, Division of Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai-city 980-8575, Japan. Tel: +81-22-717-8363; Fax: +81-22-717-8367;
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19
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Zhao H, Wang X, Zhang W, Wang L, Zhu C, Huang Y, Chen R, Chen X, Wang M, Pan G, Shi Q, Zhou X. Bioclickable Mussel-Derived Peptides With Immunoregulation for Osseointegration of PEEK. Front Bioeng Biotechnol 2021; 9:780609. [PMID: 34900969 PMCID: PMC8652040 DOI: 10.3389/fbioe.2021.780609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 10/25/2021] [Indexed: 02/01/2023] Open
Abstract
Polyether ether ketone (PEEK)–based biomaterials have been widely used in the field of spine and joint surgery. However, lack of biological activity limits their further clinical application. In this study, we synthesized a bioclickable mussel-derived peptide Azide-DOPA4 as a PEEK surface coating modifier and further combined bone morphogenetic protein 2 functional peptides (BMP2p) with a dibenzylcyclooctyne (DBCO) motif through bio-orthogonal reactions to obtain DOPA4@BMP2p-PEEK. As expected, more BMP2p can be conjugated on PEEK after Azide-DOPA4 coating. The surface roughness and hydrophilicity of DOPA4@BMP2p-PEEK were obviously increased. Then, we optimized the osteogenic capacity of PEEK substrates. In vitro, compared with the BMP2p-coating PEEK material, DOPA4@BMP2p-PEEK showed significantly higher osteogenic induction capability of rat bone marrow mesenchymal stem cells. In vivo, we constructed a rat calvarial bone defect model and implanted PEEK materials with a differently modified surface. Micro-computed tomography scanning displayed that the DOPA4@BMP2p-PEEK implant group had significantly higher new bone volume and bone mineral density than the BMP2p-PEEK group. Histological staining of hard tissue further confirmed that the DOPA4@BMP2p-PEEK group revealed a better osseointegrative effect than the BMP2p-PEEK group. More importantly, we also found that DOPA4@BMP2p coating has a synergistic effect with induced Foxp3+ regulatory T (iTreg) cells to promote osteogenesis. In summary, with an easy-to-perform, two-step surface bioengineering approach, the DOPA4@BMP2p-PEEK material reported here displayed excellent biocompatibility and osteogenic functions. It will, moreover, offer insights to engineering surfaces of orthopedic implants.
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Affiliation(s)
- Huan Zhao
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China
| | - Xiaokang Wang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China.,Department of Orthopaedics, The Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong University, Nantong, China
| | - Wen Zhang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China
| | - Lin Wang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China
| | - Can Zhu
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China
| | - Yingkang Huang
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China
| | - Rongrong Chen
- Department of Pediatrics, The Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong University, Nantong, China
| | - Xu Chen
- Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University, Zhenjiang, China
| | - Miao Wang
- Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University, Zhenjiang, China
| | - Guoqing Pan
- Institute for Advanced Materials, School of Materials Science and Engineering, Jiangsu University, Zhenjiang, China
| | - Qin Shi
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China
| | - Xichao Zhou
- Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Orthopaedic Institute of Soochow University, Suzhou, China
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20
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Hsiao HY, Nien CY, Hong HH, Cheng MH, Yen TH. Application of dental stem cells in three-dimensional tissue regeneration. World J Stem Cells 2021; 13:1610-1624. [PMID: 34909114 PMCID: PMC8641025 DOI: 10.4252/wjsc.v13.i11.1610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/06/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023] Open
Abstract
Dental stem cells can differentiate into different types of cells. Dental pulp stem cells, stem cells from human exfoliated deciduous teeth, periodontal ligament stem cells, stem cells from apical papilla, and dental follicle progenitor cells are five different types of dental stem cells that have been identified during different stages of tooth development. The availability of dental stem cells from discarded or removed teeth makes them promising candidates for tissue engineering. In recent years, three-dimensional (3D) tissue scaffolds have been used to reconstruct and restore different anatomical defects. With rapid advances in 3D tissue engineering, dental stem cells have been used in the regeneration of 3D engineered tissue. This review presents an overview of different types of dental stem cells used in 3D tissue regeneration, which are currently the most common type of stem cells used to treat human tissue conditions.
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Affiliation(s)
- Hui-Yi Hsiao
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
| | - Chung-Yi Nien
- Department of Life Sciences, National Central University, Zhongli, Taoyuan 320, Taiwan
| | - Hsiang-Hsi Hong
- Department of Periodontics, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
| | - Ming-Huei Cheng
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- Division of Reconstructive Microsurgery, Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Linkou Branch, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Tzung-Hai Yen
- Center for Tissue Engineering, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- Department of Nephrology, Clinical Poison Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan 333, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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Ehnert S, Relja B, Schmidt-Bleek K, Fischer V, Ignatius A, Linnemann C, Rinderknecht H, Huber-Lang M, Kalbitz M, Histing T, Nussler AK. Effects of immune cells on mesenchymal stem cells during fracture healing. World J Stem Cells 2021; 13:1667-1695. [PMID: 34909117 PMCID: PMC8641016 DOI: 10.4252/wjsc.v13.i11.1667] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
In vertebrates, bone is considered an osteoimmune system which encompasses functions of a locomotive organ, a mineral reservoir, a hormonal organ, a stem cell pool and a cradle for immune cells. This osteoimmune system is based on cooperatively acting bone and immune cells, cohabitating within the bone marrow. They are highly interdependent, a fact that is confounded by shared progenitors, mediators, and signaling pathways. Successful fracture healing requires the participation of all the precursors, immune and bone cells found in the osteoimmune system. Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing. In this review, first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely. The separate paragraphs focus on the specific cell types, starting with the cells of the innate immune response followed by cells of the adaptive immune response, and the complement system as mediator between them. Finally, a brief overview on the challenges of preclinical testing of immune-based therapeutic strategies to support fracture healing will be given.
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Affiliation(s)
- Sabrina Ehnert
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg 39120, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute and Berlin Institute of Health Center of Regenerative Therapies, Charité - University Medicine Berlin, Berlin 13353, Germany
| | - Verena Fischer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Caren Linnemann
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Helen Rinderknecht
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma-Immunology (ITI), University Hospital Ulm, Ulm 89091, Germany
| | - Miriam Kalbitz
- Department of Trauma and Orthopedic Surgery, University Hospital Erlangen Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany
| | - Tina Histing
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Andreas K Nussler
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
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22
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Zhang B, Su Y, Zhou J, Zheng Y, Zhu D. Toward a Better Regeneration through Implant-Mediated Immunomodulation: Harnessing the Immune Responses. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100446. [PMID: 34117732 PMCID: PMC8373114 DOI: 10.1002/advs.202100446] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/08/2021] [Indexed: 05/06/2023]
Abstract
Tissue repair/regeneration, after implantation or injury, involves comprehensive physiological processes wherein immune responses play a crucial role to enable tissue restoration, amidst the immune cells early-stage response to tissue damages. These cells break down extracellular matrix, clear debris, and secret cytokines to orchestrate regeneration. However, the immune response can also lead to abnormal tissue healing or scar formation if not well directed. This review first introduces the general immune response post injury, with focus on the major immune cells including neutrophils, macrophages, and T cells. Next, a variety of implant-mediated immunomodulation strategies to regulate immune response through physical, chemical, and biological cues are discussed. At last, various scaffold-facilitated regenerations of different tissue types, such as, bone, cartilage, blood vessel, and nerve system, by harnessing the immunomodulation are presented. Therefore, the most recent data in biomaterials and immunomodulation is presented here in a bid to shape expert perspectives, inspire researchers to go in new directions, and drive development of future strategies focusing on targeted, sequential, and dynamic immunomodulation elicited by implants.
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Affiliation(s)
- Ben Zhang
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew York11794USA
| | - Yingchao Su
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew York11794USA
| | - Juncen Zhou
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew York11794USA
| | - Yufeng Zheng
- Department of Materials Science and EngineeringCollege of EngineeringPeking UniversityBeijing100871China
| | - Donghui Zhu
- Department of Biomedical EngineeringStony Brook UniversityStony BrookNew York11794USA
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23
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Fu J, Wang Y, Jiang Y, Du J, Xu J, Liu Y. Systemic therapy of MSCs in bone regeneration: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:377. [PMID: 34215342 PMCID: PMC8254211 DOI: 10.1186/s13287-021-02456-w] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 06/12/2021] [Indexed: 12/30/2022] Open
Abstract
Objectives Over the past decades, many studies focused on mesenchymal stem cells (MSCs) therapy for bone regeneration. Due to the efficiency of topical application has been widely dicussed and systemic application was also a feasible way for new bone formation, the aim of this study was to systematically review systemic therapy of MSCs for bone regeneration in pre-clinical studies. Methods The article search was conducted in PubMed and Embase databases. Original research articles that assessed potential effect of systemic application of MSCs for bone regeneration in vivo were selected and evaluated in this review, according to eligibility criteria. The efficacy of MSC systemic treatment was analyzed by random effects meta-analysis, and the outcomes were expressed in standard mean difference (SMD) and its 95% confidence interval. Subgroup analyses were conducted on animal species and gender, MSCs types, frequency and time of injection, and bone diseases. Results Twenty-three articles were selected in this review, of which 21 were included in meta-analysis. The results showed that systemic therapy increased bone mineral density (SMD 3.02 [1.84, 4.20]), bone volume to tissue volume ratio (2.10 [1.16, 3.03]), and the percentage of new bone area (7.03 [2.10, 11.96]). Bone loss caused by systemic disease tended to produce a better response to systemic treatment (p=0.05 in BMD, p=0.03 in BV/TV). Conclusion This study concluded that systemic therapy of MSCs promotes bone regeneration in preclinical experiments. These results provided important information for the systemic application of MSCs as a potential application of bone formation in further animal experiments. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02456-w.
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Affiliation(s)
- Jingfei Fu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yanxue Wang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yiyang Jiang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Junji Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China.
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China.
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24
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Shen P, Chen Y, Luo S, Fan Z, Wang J, Chang J, Deng J. Applications of biomaterials for immunosuppression in tissue repair and regeneration. Acta Biomater 2021; 126:31-44. [PMID: 33722787 DOI: 10.1016/j.actbio.2021.03.019] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/24/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022]
Abstract
The immune system plays an essential role in tissue repair and regeneration. Regardless of innate or adaptive immune responses, immunosuppressive strategies such as macrophage polarization and regulatory T (Treg) cell induction can be used to modulate the immune system to promote tissue repair and regeneration. Biomaterials can improve the production of anti-inflammatory macrophages and Treg cells by providing physiochemical cues or delivering therapeutics such as cytokines, small molecules, microRNA, growth factors, or stem cells in the damaged tissues. Herein, we present an overview of immunosuppressive modulation by biomaterials in tissue regeneration and highlight the mechanisms of macrophage polarization and Treg cell induction. Overall, we foresee that future biomaterials for regenerative strategies will entail more interactions between biomaterials and the immune cells, and more mechanisms of immunosuppression related to T cell subsets remain to be discovered and applied to develop novel biomaterials for tissue repair and regeneration. STATEMENT OF SIGNIFICANCE: Immunosuppression plays a key role in tissue repair and regeneration, and biomaterials can interact with the immune system through their biological properties and by providing physiochemical cues. Here, we summarize the studies on biomaterials that have been used for immunosuppression to facilitate tissue regeneration. In the first part of this review, we demonstrate the crucial role of macrophage polarization and induction of T regulatory (Treg) cells in immunosuppression. In the second part, distinct approaches used by biomaterials to induce immunosuppression are introduced, which show excellent performance in terms of promoting tissue regeneration.
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Affiliation(s)
- Peng Shen
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Yanxin Chen
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Shuai Luo
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Zhiyuan Fan
- Department of Materials Science and Engineering, Drexel University, Philadelphia, PA 19104, USA
| | - Jilong Wang
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China
| | - Jiang Chang
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China; State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, China.
| | - Junjie Deng
- Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
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25
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Zhang FQ, Jiang JL, Zhang JT, Niu H, Fu XQ, Zeng LL. Current status and future prospects of stem cell therapy in Alzheimer's disease. Neural Regen Res 2020; 15:242-250. [PMID: 31552889 PMCID: PMC6905342 DOI: 10.4103/1673-5374.265544] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 03/18/2019] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease is a common progressive neurodegenerative disorder, pathologically characterized by the presence of β-amyloid plaques and neurofibrillary tangles. Current treatment approaches using drugs only alleviate the symptoms without curing the disease, which is a serious issue and influences the quality of life of the patients and their caregivers. In recent years, stem cell technology has provided new insights into the treatment of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Currently, the main sources of stem cells include neural stem cells, embryonic stem cells, mesenchymal stem cells, and induced pluripotent stem cells. In this review, we discuss the pathophysiology and general treatment of Alzheimer's disease, and the current state of stem cell transplantation in the treatment of Alzheimer's disease. We also assess future challenges in the clinical application and drug development of stem cell transplantation as a treatment for Alzheimer's disease.
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Affiliation(s)
- Fu-Qiang Zhang
- Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Jin-Lan Jiang
- Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, Jilin Province, China
| | - Jing-Tian Zhang
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Han Niu
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Xue-Qi Fu
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
| | - Lin-Lin Zeng
- School of Life Sciences, Jilin University, Changchun, Jilin Province, China
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26
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Kiernan CH, Asmawidjaja PS, Fahy N, Witte-Bouma J, Wolvius EB, Brama PAJ, Lubberts E, Farrell E. Allogeneic Chondrogenic Mesenchymal Stromal Cells Alter Helper T Cell Subsets in CD4+ Memory T Cells. Tissue Eng Part A 2020; 26:490-502. [PMID: 31797740 DOI: 10.1089/ten.tea.2019.0177] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Implantation of chondrogenically differentiated mesenchymal stromal cells (MSCs) leads to bone formation in vivo through the process of endochondral ossification. The use of allogeneic MSCs for this purpose may be a promising new approach to replace the current gold standard of bone regeneration. However, the success of using allogeneic cells depends on the interaction between the implanted cells and the host's endogenous immune cells. Th17 T cells and other CD4 helper T cell subtypes have been shown to negatively impact chondrogenesis, however, it is unclear how the interaction between these cells affects bone regeneration mediated by these cells. The aim of the current work was to assess the effect of chondrogenic MSC pellets on Th1, Th2, Th17, and regulatory T cells in vitro. Human MSCs were nonchondrogenic (-TGFβ3) and chondrogenically (+TGFβ3) differentiated for 7 or 21 days. Memory T cells (sorted from the CD4 population of peripheral blood mononuclear cells [PBMCs]), as well as total PBMCs were cocultured with allogeneic nonchondrogenic and chondrogenic MSC pellets for 3 days. Seven-day differentiated allogeneic nonchondrogenic and chondrogenic MSC pellets that were cocultured with memory T cells resulted in a significant increase in Th2 and a decrease in Th1 T cells. Furthermore, the co-culture of 21-day differentiated nonchondrogenic and chondrogenic MSC pellets with memory T cells resulted in a significant increase in Th2 and Th17 T cells, as well as a decrease in Th1 and regulatory T cells. Interleukin (IL)-6 was identified as a predominant cytokine involved in this interaction between allogeneic chondrogenically differentiated MSC pellets and memory CD4 T cells, with high levels of IL-6 being secreted in the supernatants of this cocultured condition. The findings of this study highlight the potential of chondrogenically differentiated MSC pellets to alter the ratio of Th1 and Th2 as well as Th17 and regulatory T cell subsets. Additional analysis investigating bone formation by chondrogenically differentiated MSCs in an allogeneic setting may identify a novel role of these T cell subsets in bone regeneration processes mediated by chondrogenically differentiated MSCs. Impact statement Allogeneic mesenchymal stromal cells (MSCs) have the potential to be an off-the-shelf treatment for bone repair. However, the lack of knowledge of the immune cells involved in this process has hampered the progression to the clinic. The current study has shown that allogeneic chondrogenic MSCs have the potential to skew the ratio of specific helper CD4 T cell subsets in vitro. This has now provided insight for future in vivo experiments to investigate the role of these T cell subsets in the early stages of bone regeneration mediated by allogeneic chondrogenic MSCs.
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Affiliation(s)
- Caoimhe H Kiernan
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Patrick S Asmawidjaja
- Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Niamh Fahy
- Department of Orthopaedics, and Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Janneke Witte-Bouma
- Department of Orthopaedics, and Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Eppo B Wolvius
- Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Pieter A J Brama
- School of Veterinary Medicine, Veterinary Science Center, University College Dublin, Dublin, Ireland
| | - Erik Lubberts
- Department of Rheumatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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27
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Medhat D, Rodríguez CI, Infante A. Immunomodulatory Effects of MSCs in Bone Healing. Int J Mol Sci 2019; 20:ijms20215467. [PMID: 31684035 PMCID: PMC6862454 DOI: 10.3390/ijms20215467] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are capable of differentiating into multilineage cells, thus making them a significant prospect as a cell source for regenerative therapy; however, the differentiation capacity of MSCs into osteoblasts seems to not be the main mechanism responsible for the benefits associated with human mesenchymal stem cells hMSCs when used in cell therapy approaches. The process of bone fracture restoration starts with an instant inflammatory reaction, as the innate immune system responds with cytokines that enhance and activate many cell types, including MSCs, at the site of the injury. In this review, we address the influence of MSCs on the immune system in fracture repair and osteogenesis. This paradigm offers a means of distinguishing target bone diseases to be treated with MSC therapy to enhance bone repair by targeting the crosstalk between MSCs and the immune system.
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Affiliation(s)
- Dalia Medhat
- Medical Biochemistry Department, National Research Centre, Dokki, Giza 12622, Egypt.
| | - Clara I Rodríguez
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Bizkaia, Spain.
| | - Arantza Infante
- Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Plaza de Cruces S/N, 48903 Barakaldo, Bizkaia, Spain.
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28
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Hydrogen Sulfide in Bone Tissue Regeneration and Repair: State of the Art and New Perspectives. Int J Mol Sci 2019; 20:ijms20205231. [PMID: 31652532 PMCID: PMC6834365 DOI: 10.3390/ijms20205231] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 12/12/2022] Open
Abstract
The importance of hydrogen sulfide (H2S) in the regulation of multiple physiological functions has been clearly recognized in the over 20 years since it was first identified as a novel gasotransmitter. In bone tissue H2S exerts a cytoprotective effect and promotes bone formation. Just recently, the scientific community has begun to appreciate its role as a therapeutic agent in bone pathologies. Pharmacological administration of H2S achieved encouraging results in preclinical studies in the treatment of systemic bone diseases, such as osteoporosis; however, a local delivery of H2S at sites of bone damage may provide additional opportunities of treatment. Here, we highlight how H2S stimulates multiple signaling pathways involved in various stages of the processes of bone repair. Moreover, we discuss how material science and chemistry have recently developed biomaterials and H2S-donors with improved features, laying the ground for the development of H2S-releasing devices for bone regenerative medicine. This review is intended to give a state-of-the-art description of the pro-regenerative properties of H2S, with a focus on bone tissue, and to discuss the potential of H2S-releasing scaffolds as a support for bone repair.
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29
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Liu XM, Liu Y, Yu S, Jiang LM, Song B, Chen X. Potential immunomodulatory effects of stem cells from the apical papilla on Treg conversion in tissue regeneration for regenerative endodontic treatment. Int Endod J 2019; 52:1758-1767. [DOI: 10.1111/iej.13197] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 07/31/2019] [Indexed: 02/07/2023]
Affiliation(s)
- X. M. Liu
- Department of Paediatric Dentistry School of Stomatology China Medical University ShenyangChina
- Liaoning Province Key Laboratory of Oral Disease ShenyangChina
- State Key Laboratory of Military Stomatology Xi'an China
| | - Y. Liu
- Department of Paediatric Dentistry School of Stomatology China Medical University ShenyangChina
- Liaoning Province Key Laboratory of Oral Disease ShenyangChina
- State Key Laboratory of Military Stomatology Xi'an China
| | - S. Yu
- Department of Paediatric Dentistry School of Stomatology China Medical University ShenyangChina
- Liaoning Province Key Laboratory of Oral Disease ShenyangChina
| | - L. M. Jiang
- Department of Paediatric Dentistry School of Stomatology China Medical University ShenyangChina
- Liaoning Province Key Laboratory of Oral Disease ShenyangChina
| | - B. Song
- School of Dentistry Cardiff University Cardiff UK
| | - X. Chen
- Department of Paediatric Dentistry School of Stomatology China Medical University ShenyangChina
- Liaoning Province Key Laboratory of Oral Disease ShenyangChina
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30
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Stem cell-based bone and dental regeneration: a view of microenvironmental modulation. Int J Oral Sci 2019; 11:23. [PMID: 31423011 PMCID: PMC6802669 DOI: 10.1038/s41368-019-0060-3] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/28/2019] [Accepted: 06/12/2019] [Indexed: 02/06/2023] Open
Abstract
In modern medicine, bone and dental loss and defects are common and widespread morbidities, for which regenerative therapy has shown great promise. Mesenchymal stem cells, obtained from various sources and playing an essential role in organ development and postnatal repair, have exhibited enormous potential for regenerating bone and dental tissue. Currently, mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering. Nevertheless, the efficacy of MSC-based regeneration is not always fulfilled, especially in diseased microenvironments. Specifically, the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs, both as donors and recipients. Accordingly, approaches targeting a diseased microenvironment have been established, including improving the diseased niche to restore endogenous MSCs, enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies. Moreover, the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy. In this review, we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment, emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.
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31
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D'Alessio FR, Kurzhagen JT, Rabb H. Reparative T lymphocytes in organ injury. J Clin Invest 2019; 129:2608-2618. [PMID: 31259743 DOI: 10.1172/jci124614] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Acute organ injuries such as acute cerebrovascular accidents, myocardial infarction, acute kidney injury, acute lung injury, and others are among the leading causes of death worldwide. Dysregulated or insufficient organ repair mechanisms limit restoration of homeostasis and contribute to chronic organ failure. Studies reveal that both humans and mice harness potent non-stem cells that are capable of directly or indirectly promoting tissue repair. Specific populations of T lymphocytes have emerged as important reparative cells with context-specific actions. These T cells can resolve inflammation and secrete reparative cytokines and growth factors as well as interact with other immune and stromal cells to promote the complex and active process of tissue repair. This Review focuses on the major populations of T lymphocytes known to mediate tissue repair, their reparative mechanisms, and the diseases in which they have been implicated. Elucidating and harnessing the mechanisms that promote the reparative functions of these T cells could greatly improve organ dysfunction after acute injury.
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Affiliation(s)
| | - Johanna T Kurzhagen
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hamid Rabb
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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32
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Wang J, Jiang H, Qiu Y, Wang Y, Sun G, Zhao J. Effector memory regulatory T cells were most effective at suppressing RANKL but their frequency was downregulated in tibial fracture patients with delayed union. Immunol Lett 2019; 209:21-27. [PMID: 30946855 DOI: 10.1016/j.imlet.2019.03.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 03/17/2019] [Accepted: 03/30/2019] [Indexed: 12/12/2022]
Abstract
Delayed union and nonunion occur in a minor subject of bone fractures, presenting ongoing challenges to treatment. RANKL, which promotes the differentiation of bone-resorbing osteoclasts, is thought to negatively impact bone healing. In this study, we recruited patients with isolated closed tibial fracture, who were later categorized into normal healing and delayed healing groups based on their healing progression. The regulatory T cell (Treg) compartment was then investigated in each patient. Based on CD45RA and CD62L expression, we distinguished circulating Treg cells into CD45RA+CD62L+ naive (N), CD45RA-CD62L+ central memory (CM), and CD45RA-CD62L- effector memory (EM) subsets. Compared to normal patients, delayed patients presented significantly lower EM Treg proportion and significantly higher N Treg proportion. Among the N, EM, and CM Treg cells, the EM Treg cells were the most potent at suppressing RANKL expression in T conventional (Tconv) cells. This functionality of EM Treg cells was present in both normal healing patients and delayed healing patients, and was dependent on IL-10, as neutralization of IL-10 resulted in significantly elevated RANKL expression. EM Treg cells presented the highest IL-10 and TGF-β expression directly ex vivo, as well as after anti-CD3/anti-CD28/IL-2 stimulation. CM Treg cells did not present high expression of inhibitory cytokines ex vivo, but was capable of upregulating cytokine expression upon stimulation. N Treg cells, on the other hand, presented limited capacity to upregulate inhibitory cytokines. In summary, our study identified that, while the EM Treg cells were the most effective at suppressing RANKL, they in delayed union patients were present at lower frequencies with functional impairment, resulting in decreased RANKL suppression. Hence, bone-resorbing osteoclast formation may be favored in these patients thus suggesting a possible mechanism for delayed bone healing.
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Affiliation(s)
- Jun Wang
- Department of Orthopedics, Jinling School of Clinical Medicine, Nanjing Medical University, Jinling Hospital, Nanjing, 210002, Jiangsu Province, China
| | - Hui Jiang
- Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu Province, China
| | - Yang Qiu
- Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu Province, China
| | - Yicun Wang
- Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu Province, China
| | - Guojing Sun
- Department of Orthopedics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, Jiangsu Province, China.
| | - Jianning Zhao
- Department of Orthopedics, Jinling School of Clinical Medicine, Nanjing Medical University, Jinling Hospital, Nanjing, 210002, Jiangsu Province, China.
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Bone Morphogenetic Protein 6 Inhibits the Immunomodulatory Property of BMMSCs via Id1 in Sjögren's Syndrome. Stem Cells Int 2018; 2018:9837035. [PMID: 30174696 PMCID: PMC6098892 DOI: 10.1155/2018/9837035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 06/19/2018] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) treatment has emerged as a promising approach for treating Sjögren's syndrome (SS). Impaired immunoregulatory activities of bone marrow mesenchymal stem cells (BMMSCs) are found in both SS patients and animal models, and the underlying mechanism is poorly understood. Increased expression of BMP6 is reported to be related to SS. The aim herein was to determine the effects of BMP6 on BMMSCs function. BMMSCs were isolated from SS patients and NOD mice and showed a high level of BMP6 expression. The effects of BMP6 on BMMSCs function were investigated using in vitro BMMSCs differentiation and in vitro and in vivo T cell proliferation and polarization assays. BMP6 increased osteogenic differentiation of BMMSCs and inhibited the immunomodulatory properties of BMMSCs. BMP6 enhanced T cell proliferation and Th1/Th17 differentiation in a T cell-BMMSC coculture system. Mechanistically, BMP6 downregulated PGE2 and upregulated IFN-gamma via Id1 (inhibitor of DNA-binding protein 1). Neutralizing BMP6 and knockdown of Id1 could restore the BMMSCs immunosuppressive function both in vitro and in vivo. The present results suggest a novel role of Id1 in BMP-mediated MSCs function, which may contribute to a better understanding of the mechanism of action of MSCs in treating autoimmune diseases.
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Li J, Tan J, Martino MM, Lui KO. Regulatory T-Cells: Potential Regulator of Tissue Repair and Regeneration. Front Immunol 2018; 9:585. [PMID: 29662491 PMCID: PMC5890151 DOI: 10.3389/fimmu.2018.00585] [Citation(s) in RCA: 212] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 03/08/2018] [Indexed: 12/22/2022] Open
Abstract
The identification of stem cells and growth factors as well as the development of biomaterials hold great promise for regenerative medicine applications. However, the therapeutic efficacy of regenerative therapies can be greatly influenced by the host immune system, which plays a pivotal role during tissue repair and regeneration. Therefore, understanding how the immune system modulates tissue healing is critical to design efficient regenerative strategies. While the innate immune system is well known to be involved in the tissue healing process, the adaptive immune system has recently emerged as a key player. T-cells, in particular, regulatory T-cells (Treg), have been shown to promote repair and regeneration of various organ systems. In this review, we discuss the mechanisms by which Treg participate in the repair and regeneration of skeletal and heart muscle, skin, lung, bone, and the central nervous system.
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Affiliation(s)
- Jiatao Li
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong.,Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Jean Tan
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Mikaël M Martino
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Kathy O Lui
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong.,Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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Sui BD, Hu CH, Liu AQ, Zheng CX, Xuan K, Jin Y. Stem cell-based bone regeneration in diseased microenvironments: Challenges and solutions. Biomaterials 2017; 196:18-30. [PMID: 29122279 DOI: 10.1016/j.biomaterials.2017.10.046] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/21/2017] [Accepted: 10/28/2017] [Indexed: 12/17/2022]
Abstract
Restoration of extensive bone loss and defects remain as an unfulfilled challenge in modern medicine. Given the critical contributions to bone homeostasis and diseases, mesenchymal stem cells (MSCs) have shown great promise to jumpstart and facilitate bone healing, with immense regenerative potential in both pharmacology-based endogenous MSC rescue/mobilization in skeletal diseases and emerging application of MSC transplantation in bone tissue engineering and cytotherapy. However, efficacy of MSC-based bone regeneration was not always achieved; particularly, fulfillment of MSC-mediated bone healing in diseased microenvironments of host comorbidities remains as a major challenge. Indeed, impacts of diseased microenvironments on MSC function rely not only on the dynamic regulation of resident MSCs by surrounding niche to convoy pathological signals of bone, but also on the profound interplay between transplanted MSCs and recipient components that mediates and modulates therapeutic effects on skeletal conditions. Accordingly, novel solutions have recently been developed, including improving resistance of MSCs to diseased microenvironments, recreating beneficial microenvironments to guarantee MSC-based regeneration, and usage of subcellular vesicles of MSCs in cell-free therapies. In this review, we summarize state-of-the-art knowledge regarding applications and challenges of MSC-mediated bone healing, further offering principles and effective strategies to optimize MSC-based bone regeneration in aging and diseases.
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Affiliation(s)
- Bing-Dong Sui
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Cheng-Hu Hu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi 710032, China
| | - An-Qi Liu
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Chen-Xi Zheng
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Kun Xuan
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
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Du J, Mei S, Guo L, Su Y, Wang H, Liu Y, Zhao Z, Wang S, Liu Y. Platelet‐rich fibrin/aspirin complex promotes alveolar bone regeneration in periodontal defect in rats. J Periodontal Res 2017; 53:47-56. [PMID: 28862325 DOI: 10.1111/jre.12485] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/16/2017] [Indexed: 12/24/2022]
Affiliation(s)
- J. Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
| | - S. Mei
- Department of Pharmacy Beijing Tiantan Hospital Capital Medical University Beijing China
| | - L. Guo
- Department of Orthodontics School of Stomatology Capital Medical University Beijing China
| | - Y. Su
- Department of Stomatology Beijing Tiantan Hospital Capital Medical University Beijing China
| | - H. Wang
- Department of Stomatology Beijing Tiantan Hospital Capital Medical University Beijing China
| | - Y. Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
| | - Z. Zhao
- Department of Pharmacy Beijing Tiantan Hospital Capital Medical University Beijing China
| | - S. Wang
- Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy and Tooth Regeneration School of Stomatology Capital Medical University Beijing China
| | - Y. Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing China
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Mescher AL, Neff AW, King MW. Inflammation and immunity in organ regeneration. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2017; 66:98-110. [PMID: 26891614 DOI: 10.1016/j.dci.2016.02.015] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/19/2016] [Accepted: 02/09/2016] [Indexed: 06/05/2023]
Abstract
The ability of vertebrates to regenerate amputated appendages is increasingly well-understood at the cellular level. Cells mediating an innate immune response and inflammation in the injured tissues are a prominent feature of the limb prior to formation of a regeneration blastema, with macrophage activity necessary for blastema growth and successful development of the new limb. Studies involving either anti-inflammatory or pro-inflammatory agents suggest that the local inflammation produced by injury and its timely resolution are both important for regeneration, with blastema patterning inhibited in the presence of unresolved inflammation. Various experiments with Xenopus larvae at stages where regenerative competence is declining show improved digit formation after treatment with certain immunosuppressive, anti-inflammatory, or antioxidant agents. Similar work with the larval Xenopus tail has implicated adaptive immunity with regenerative competence and suggests a requirement for regulatory T cells in regeneration, which also occurs in many systems of tissue regeneration. Recent analyses of the human nail organ indicate a capacity for local immune tolerance, suggesting roles for adaptive immunity in the capacity for mammalian appendage regeneration. New information and better understanding regarding the neuroendocrine-immune axis in the response to stressors, including amputation, suggest additional approaches useful for investigating effects of the immune system during repair and regeneration.
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Affiliation(s)
- Anthony L Mescher
- Center for Developmental and Regenerative Biology; Indiana University School of Medicine - Bloomington, USA.
| | - Anton W Neff
- Center for Developmental and Regenerative Biology; Indiana University School of Medicine - Bloomington, USA.
| | - Michael W King
- Center for Developmental and Regenerative Biology; Indiana University School of Medicine - Terre Haute, USA.
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Abstract
Unlike many other postnatal tissues, bone can regenerate and repair itself; nevertheless, this capacity can be overcome. Traditionally, surgical reconstructive strategies have implemented autologous, allogeneic, and prosthetic materials. Autologous bone--the best option--is limited in supply and also mandates an additional surgical procedure. In regenerative tissue engineering, there are myriad issues to consider in the creation of a functional, implantable replacement tissue. Importantly, there must exist an easily accessible, abundant cell source with the capacity to express the phenotype of the desired tissue, and a biocompatible scaffold to deliver the cells to the damaged region. A literature review was performed using PubMed; peer-reviewed publications were screened for relevance in order to identify key advances in stem and progenitor cell contribution to the field of bone tissue engineering. In this review, we briefly introduce various adult stem cells implemented in bone tissue engineering such as mesenchymal stem cells (including bone marrow- and adipose-derived stem cells), endothelial progenitor cells, and induced pluripotent stem cells. We then discuss numerous advances associated with their application and subsequently focus on technological advances in the field, before addressing key regenerative strategies currently used in clinical practice. Stem and progenitor cell implementation in bone tissue engineering strategies have the ability to make a major impact on regenerative medicine and reduce patient morbidity. As the field of regenerative medicine endeavors to harness the body's own cells for treatment, scientific innovation has led to great advances in stem cell-based therapies in the past decade.
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Zhou Y, van den Beucken JJJP. Special Collection: Cell-Based Therapy for Bone Regeneration. Tissue Eng Part A 2016; 22:1127-1128. [PMID: 27393469 DOI: 10.1089/ten.tea.2016.0249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Yinghong Zhou
- 1 The Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT) , Brisbane, Australia .,2 Australia-China Center for Tissue Engineering and Regenerative Medicine (ACCTERM) , Brisbane, Australia
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Premise and promise of mesenchymal stem cell-based therapies in clinical vascularized composite allotransplantation. Curr Opin Organ Transplant 2016; 20:608-14. [PMID: 26536421 DOI: 10.1097/mot.0000000000000247] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Over the past decade, clinical vascularized composite allotransplantation (VCA) has enabled functional and quality of life restoration in a wide range of indications secondary to devastating tissue loss. However, the spectre of toxicity and long-term complications of chronic immunosuppression has curtailed the momentum of VCA. This study summarizes the literature evidence behind successful mesenchymal stem cell (MSC)-based cell therapies highlighting their multipronged immunomodulatory, restorative and regenerative characteristics with special emphasis towards VCA applications. RECENT FINDINGS Experimental and clinical studies in solid organs and VCA have confirmed that MSCs facilitate immunosuppression-free allograft survival or tolerance, stimulate peripheral nerve regeneration, attenuate ischaemia-reperfusion injury, and improve tissue healing after surgery. It has been hypothesized that MSC-induced long-term operational tolerance in experimental VCA is mediated by induction of mixed donor-specific chimerism and regulatory T-cell mechanisms. All these characteristics of MSCs could thus help expand the scope and clinical feasibility of VCA. SUMMARY Cellular therapies, especially those focusing on MSCs, are emerging in solid organ transplantation including VCA. Although some clinical trials have begun to assess the effects of MSCs in solid organ transplantation, much scientific domain remains uncharted, especially for VCA.
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Yu Y, Wu RX, Gao LN, Xia Y, Tang HN, Chen FM. Stromal cell-derived factor-1-directed bone marrow mesenchymal stem cell migration in response to inflammatory and/or hypoxic stimuli. Cell Adh Migr 2016; 10:342-59. [PMID: 26745021 DOI: 10.1080/19336918.2016.1139287] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Directing cell trafficking toward a target site of interest is critical for advancing stem cell therapy in clinical theranostic applications. In this study, we investigated the effects of inflammatory and/or hypoxic stimuli on the migration of bone marrow mesenchymal stem cells (BMMSCs) during in vitro culture and after in vivo implantation. Using tablet scratch experiments and observations from a transwell system, we found that both inflammatory and hypoxic stimuli significantly enhanced cell migration. However, the combination of inflammatory and hypoxic stimuli did not result in a synergistic effect. The presence of stromal cell-derived factor-1 (SDF-1) significantly enhanced cell migration irrespective of the incubation conditions, and these positive effects could be blocked by treatment with AMD3100. Based on a time course experiment, we found that preconditioning cells with either inflammatory or hypoxic stimuli for 24 h or with both stimuli for 12 h led to high levels of chemokine receptor type 4 (CXCR4) expression. In vivo studies further demonstrated that pretreatment of BMMSCs with inflammatory and/or hypoxic stimuli resulted in an increased number of systemically injected cells migrating toward skin injuries, and local SDF-1 administration significantly increased cell migration. These findings suggest that in vitro control of either inflammatory or hypoxic stimuli has significant potential to enhance SDF-1-directed BMMSC migration via the upregulation of CXCR4 expression. Although combining the stimuli did not necessarily lead to a synergistic effect, the potential to reduce the dose and time required for cell preconditioning indicates that combinations of various strategies warrant further exploration.
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Affiliation(s)
- Yang Yu
- a State Key Laboratory of Military Stomatology, Department of Periodontology, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China.,b Shaanxi Key Laboratory of Stomatology, Biomaterials Unit, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China
| | - Rui-Xin Wu
- a State Key Laboratory of Military Stomatology, Department of Periodontology, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China.,b Shaanxi Key Laboratory of Stomatology, Biomaterials Unit, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China
| | - Li-Na Gao
- a State Key Laboratory of Military Stomatology, Department of Periodontology, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China.,b Shaanxi Key Laboratory of Stomatology, Biomaterials Unit, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China
| | - Yu Xia
- a State Key Laboratory of Military Stomatology, Department of Periodontology, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China.,b Shaanxi Key Laboratory of Stomatology, Biomaterials Unit, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China
| | - Hao-Ning Tang
- a State Key Laboratory of Military Stomatology, Department of Periodontology, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China.,b Shaanxi Key Laboratory of Stomatology, Biomaterials Unit, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China
| | - Fa-Ming Chen
- a State Key Laboratory of Military Stomatology, Department of Periodontology, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China.,b Shaanxi Key Laboratory of Stomatology, Biomaterials Unit, School of Stomatology, Fourth Military Medical University , Xi'an , P. R., China
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Chen S, Ye X, Yu X, Xu Q, Pan K, Lu S, Yang P. Co-culture with periodontal ligament stem cells enhanced osteoblastic differentiation of MC3T3-E1 cells and osteoclastic differentiation of RAW264.7 cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:14596-14607. [PMID: 26823783 PMCID: PMC4713569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Accepted: 10/19/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVES Periodontal ligament stem cells (PDLSCs) are characterized by having multipotential differentiation and immunoregulatory properties, which are the main mechanisms of PDLSCs-mediated periodontal regeneration. Periodontal or bone regeneration requires coordination of osteoblast and osteoclast, however, very little is known about the interactions between PDLSCs and osteoblast-like cells or osteoclast precursors. In this study, the indirect co-culture approach was introduced to preliminarily elucidate the effects of PDLSCs on differentiation of osteoblast-like cells and osteoclast precursors in vitro. MATERIALS AND METHODS Human PDLSCs were obtained from premolars extracted and their stemness was identified in terms of their colony-forming ability, proliferative capacity, cell surface epitopes and multi-lineage differentiation potentials. A noncontact co-culture system of PDLSCs and preosteoblastic cell line MC3T3-E1 or osteoclast precursor cell line RAW264.7 was established, and osteoblastic differentiation of MC3T3-E1 and osteoclastic differentiation of RAW264.7 were evaluated. RESULTS PDLSCs exhibited features of mesenchymal stem cells. Further investigation through indirect co-culture system showed that PDLSCs enhanced ALP activity, expressions of ALP, Runx2, BSP, OPN mRNA and BSP, OPN proteins and mineralization matrix deposition in MC3T3-E1. Meanwhile, they improved maturation of osteoclasts and expressions of TRAP, CSTK, TRAF6 mRNA and TRAP, TRAF6 proteins in RAW264.7. CONCLUSIONS PDLSCs stimulates osteoblastic differentiation of osteoblast precursors and osteoclastic differentiation of osteoclast precursors, at least partially, in a paracrine fasion.
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Affiliation(s)
- Shulan Chen
- School of Stomatology, Shandong UniversityJinan 250012, Shandong, China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong UniversityJinan 250012, Shandong, China
- Department of Stomatology, Qingdao Municipal HospitalQingdao 266011, Shandong, China
| | - Xin Ye
- School of Stomatology, Shandong UniversityJinan 250012, Shandong, China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong UniversityJinan 250012, Shandong, China
| | - Xinbo Yu
- Department of Periodontology, Affiliated Hospital of Qingdao UniversityQingdao 266011, Shandong, China
| | - Quanchen Xu
- Department of Periodontology, Affiliated Hospital of Qingdao UniversityQingdao 266011, Shandong, China
| | - Keqing Pan
- Department of Periodontology, Affiliated Hospital of Qingdao UniversityQingdao 266011, Shandong, China
| | - Shulai Lu
- Department of Stomatology, Qingdao Municipal HospitalQingdao 266011, Shandong, China
| | - Pishan Yang
- School of Stomatology, Shandong UniversityJinan 250012, Shandong, China
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong UniversityJinan 250012, Shandong, China
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Mesenchymal Stem/Stromal Cells Derived from Induced Pluripotent Stem Cells Support CD34(pos) Hematopoietic Stem Cell Propagation and Suppress Inflammatory Reaction. Stem Cells Int 2015; 2015:843058. [PMID: 26185499 PMCID: PMC4491576 DOI: 10.1155/2015/843058] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 05/14/2015] [Accepted: 05/25/2015] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a promising cell source for research and therapeutic applications, but their restricted ex vivo propagation capabilities limit putative applications. Substantial self-renewing of stem cells can be achieved by reprogramming cells into induced pluripotent stem cells (iPSCs) that can be easily expanded as undifferentiated cells even in mass culture. Here, we investigated a differentiation protocol enabling the generation and selection of human iPSC-derived MSCs exhibiting relevant surface marker expression profiles (CD105 and CD73) and functional characteristics. We generated such iPSC-MSCs from fibroblasts and bone marrow MSCs utilizing two different reprogramming constructs. All such iPSC-MSCs exhibited the characteristics of normal bone marrow-derived (BM) MSCs. In direct comparison to BM-MSCs our iPSC-MSCs exhibited a similar surface marker expression profile but shorter doubling times without reaching senescence within 20 passages. Considering functional capabilities, iPSC-MSCs provided supportive feeder layer for CD34+ hematopoietic stem cells' self-renewal and colony forming capacities. Furthermore, iPSC-MSCs gained immunomodulatory function to suppress CD4+ cell proliferation, reduce proinflammatory cytokines in mixed lymphocyte reaction, and increase regulatory CD4+/CD69+/CD25+ T-lymphocyte population. In conclusion, we generated fully functional MSCs from various iPSC lines irrespective of their starting cell source or reprogramming factor composition and we suggest that such iPSC-MSCs allow repetitive cell applications for advanced therapeutic approaches.
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Tang J, Wu T, Xiong J, Su Y, Zhang C, Wang S, Tang Z, Liu Y. Porphyromonas gingivalis lipopolysaccharides regulate functions of bone marrow mesenchymal stem cells. Cell Prolif 2015; 48:239-48. [PMID: 25676907 DOI: 10.1111/cpr.12173] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 11/11/2014] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES Periodontitis is one of the most widespread inflammatory diseases; it causes tooth loss and is also associated with a variety of systemic diseases. Mesenchymal stem cells (MSCs) have been used to treat periodontitis. However, it is unknown whether bacterial toxins in the periodontal environment affect MSC-mediated periodontal regeneration. Porphyromonas gingivalis lipopolysaccharides (Pg-LPS) are key toxins for development of periodontitis. The purpose of the present study was to investigate effects of P. gingivalis LPS on biological properties of MSCs. MATERIALS AND METHODS Mesenchymal stem cells from bone marrow (BMMSCs) were treated with different concentrations of P. gingivalis LPS (0.1-10 μg/ml), then its effects were evaluated on biological properties of BMMSCs including proliferation, apoptosis, osteogenic differentiation and capacities to inhibit activated T cells. RESULTS Low concentration of P. gingivalis LPS (0.1 μg/ml) accelerated MSC proliferation, osteogenic differentiation and capacities to inhibit activated T cells via up-regulation of nitric oxide. However, high concentration of P. gingivalis LPS (10 μg/ml) reduced MSC proliferation, osteogenic differentiation and capacities to inhibit activated T cells. CONCLUSIONS Mesenchymal stem cells were functionally different following exposure to P. gingivalis LPS at the investigated concentrations. These findings suggest that MSC-mediated periodontal regeneration may be regulated by P. gingivalis LPS.
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Affiliation(s)
- J Tang
- Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Oral and Maxillofacial Surgery, Xiangya Stomatological Hospital, Central South University, Changsha, Hunan, 410008, China; Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, 100050, China
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