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Li XL, Zhao YQ, Miao L, An YX, Wu F, Han JY, Han JY, Tay FR, Mu Z, Jiao Y, Wang J. Strategies for promoting neurovascularization in bone regeneration. Mil Med Res 2025; 12:9. [PMID: 40025573 PMCID: PMC11874146 DOI: 10.1186/s40779-025-00596-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 01/26/2025] [Indexed: 03/04/2025] Open
Abstract
Bone tissue relies on the intricate interplay between blood vessels and nerve fibers, both are essential for many physiological and pathological processes of the skeletal system. Blood vessels provide the necessary oxygen and nutrients to nerve and bone tissues, and remove metabolic waste. Concomitantly, nerve fibers precede blood vessels during growth, promote vascularization, and influence bone cells by secreting neurotransmitters to stimulate osteogenesis. Despite the critical roles of both components, current biomaterials generally focus on enhancing intraosseous blood vessel repair, while often neglecting the contribution of nerves. Understanding the distribution and main functions of blood vessels and nerve fibers in bone is crucial for developing effective biomaterials for bone tissue engineering. This review first explores the anatomy of intraosseous blood vessels and nerve fibers, highlighting their vital roles in bone embryonic development, metabolism, and repair. It covers innovative bone regeneration strategies directed at accelerating the intrabony neurovascular system over the past 10 years. The issues covered included material properties (stiffness, surface topography, pore structures, conductivity, and piezoelectricity) and acellular biological factors [neurotrophins, peptides, ribonucleic acids (RNAs), inorganic ions, and exosomes]. Major challenges encountered by neurovascularized materials during their clinical translation have also been highlighted. Furthermore, the review discusses future research directions and potential developments aimed at producing bone repair materials that more accurately mimic the natural healing processes of bone tissue. This review will serve as a valuable reference for researchers and clinicians in developing novel neurovascularized biomaterials and accelerating their translation into clinical practice. By bridging the gap between experimental research and practical application, these advancements have the potential to transform the treatment of bone defects and significantly improve the quality of life for patients with bone-related conditions.
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Affiliation(s)
- Xin-Ling Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Yu-Qing Zhao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Li Miao
- Department of Stomatology, The Seventh Medical Center of PLA General Hospital, Beijing, 100700, China
| | - Yan-Xin An
- Department of General Surgery, The First Affiliated Hospital of Xi'an Medical University, Xi'an, 710077, China
| | - Fan Wu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jin-Yu Han
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jing-Yuan Han
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Franklin R Tay
- Graduate School of Augusta University, Augusta, GA, 30912, USA
| | - Zhao Mu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China.
| | - Yang Jiao
- Department of Stomatology, The Seventh Medical Center of PLA General Hospital, Beijing, 100700, China.
| | - Jing Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China.
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Wang X, Xu L, Wu Z, Lou L, Xia C, Miao H, Dai J, Fei W, Wang J. Exosomes of stem cells: a potential frontier in the treatment of osteoarthritis. PRECISION CLINICAL MEDICINE 2025; 8:pbae032. [PMID: 39781279 PMCID: PMC11705996 DOI: 10.1093/pcmedi/pbae032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/18/2024] [Accepted: 11/25/2024] [Indexed: 01/12/2025] Open
Abstract
The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.
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Affiliation(s)
- Xiaofei Wang
- The Graduate School, Dalian Medical University, Dalian 116044, China
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Lei Xu
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Zhimin Wu
- The Graduate School, Dalian Medical University, Dalian 116044, China
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Linbing Lou
- The Graduate School, Dalian Medical University, Dalian 116044, China
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Cunyi Xia
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Haixiang Miao
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Jihang Dai
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Wenyong Fei
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
| | - Jingcheng Wang
- Department of Orthopedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China
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3
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Fan J, Xie Y, Liu D, Cui R, Zhang W, Shen M, Cao L. Crosstalk Between H-Type Vascular Endothelial Cells and Macrophages: A Potential Regulator of Bone Homeostasis. J Inflamm Res 2025; 18:2743-2765. [PMID: 40026304 PMCID: PMC11871946 DOI: 10.2147/jir.s502604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
The crosstalk between H-type endothelial cells (ECs) and macrophages is critical for maintaining angiogenesis and osteogenesis in bone homeostasis. As core components of type H vessels, ECs respond to various pro-angiogenic signals, forming specialized vascular structures characterized by high expression of platelet-endothelial cell adhesion molecule-1 (CD31) and endothelial mucin (EMCN), thereby facilitating angiogenesis-osteogenesis coupling during bone formation. Macrophages, as key immune cells in the perivascular region, are primarily classified into the classically activated pro-inflammatory M1 phenotype and the selectively activated anti-inflammatory M2 phenotype, thereby performing dual functions in regulating local tissue homeostasis and innate immunity. In recent years, the complex crosstalk between type H vessel ECs and macrophages has garnered significant interest in the context of bone-related diseases. Orderly regulation of angiogenesis and bone immunity provides a new direction for preventing bone metabolic disorders such as osteoporosis and osteoarthritis. However, their interactions in bone homeostasis remain insufficiently understood, with limited clinical data available. This review comprehensively examines the intricate interactions between type H vessel ECs and macrophages with diverse phenotypes, and Insights into the signaling pathways that regulate their crosstalk, focusing on their roles in angiogenesis and osteogenesis. Furthermore, the review discusses recent interventions targeting this crosstalk and the challenges that remain. These insights may offer new perspectives on bone homeostasis and provide a theoretical foundation for developing novel therapeutic strategies.
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Affiliation(s)
- Jiaxuan Fan
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Yaohui Xie
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Desun Liu
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Rui Cui
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Wei Zhang
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Mengying Shen
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
| | - Linzhong Cao
- Clinical College of Traditional Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, People’s Republic of China
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Luo D, Xie W, He X, Zhou X, Ye P, Wang P. Exosomal miR-590-3p derived from bone marrow mesenchymal stem cells promotes osteoblast differentiation and osteogenesis by targeting TGFBR1. In Vitro Cell Dev Biol Anim 2025; 61:46-58. [PMID: 39560913 DOI: 10.1007/s11626-024-00985-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 10/08/2024] [Indexed: 11/20/2024]
Abstract
Bone marrow mesenchymal stem cells (BMSCs) have been verified to be essential factors regulating osteogenic functions, which is mainly attributed to their secretion of extracellular vesicles. Exosomes derived from BMSCs (BMSCs-Exo) contribute to osteoblast functions that are critical for improving bone defect. Our current study aims to investigate the molecular mechanism dominated by BMSCs-Exo that affects osteoblast differentiation and osteogenesis. The first step this study validated that BMSCs co-culture enhanced the differentiation ability of osteoblast and promoted bone mineralization, while these tendencies were abolished after GW4869 treatment. Next, the BMSCs-Exo was isolated and identified by TEM observation, insight detection, and western blot analysis. Furthermore, BMSCs-Exo treatment could efficiently promote the differentiation ability and the bone mineralization of osteoblasts, decrease the mRNA levels of Collagen I and Collagen III, and increase the levels of osteogenic proteins, including alkaline phosphatase (ALP), Turning Bone Morphogenetic Protein 2 (BMP2), Bone sialoprofein (BSP), osteocalcin (OCN), and osterix (OSX). However, the abovementioned effects of BMSCs-Exo could be abolished by miR-590-3p silencing. Mechanistic analysis unmasked the negative regulation of miR-590-3p on its downstream target TGFBR1. Finally, the effects of miR-590-3p/TGFBR1 axis on the differentiation and osteogenesis of osteoblasts were validated by rescue assays. In conclusion, the present study demonstrates that exosomal miR-590-3p secreted by BMSCs can induce osteoblast differentiation and osteogenesis.
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Affiliation(s)
- Dandan Luo
- The Affiliated Hospital of Zunyi Medical University, Huichuan District, Guizhou Province, 149 Dalian Road, Zunyi City, 563000, China
| | - Wantao Xie
- The Affiliated Hospital of Zunyi Medical University, Huichuan District, Guizhou Province, 149 Dalian Road, Zunyi City, 563000, China
| | - Xiaoli He
- The Affiliated Hospital of Zunyi Medical University, Huichuan District, Guizhou Province, 149 Dalian Road, Zunyi City, 563000, China
| | - Xiangui Zhou
- The Affiliated Hospital of Zunyi Medical University, Huichuan District, Guizhou Province, 149 Dalian Road, Zunyi City, 563000, China
| | - Peng Ye
- The Affiliated Hospital of Zunyi Medical University, Huichuan District, Guizhou Province, 149 Dalian Road, Zunyi City, 563000, China
| | - Peng Wang
- The Affiliated Hospital of Zunyi Medical University, Huichuan District, Guizhou Province, 149 Dalian Road, Zunyi City, 563000, China.
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Kong Y, Wang Y, Yang Y, Hou Y, Yu J, Liu M, Xie S, Song Y. Intra-articular injection of exosomes derived from different stem cells in animal models of osteoarthritis: a systematic review and meta- analysis. J Orthop Surg Res 2024; 19:834. [PMID: 39696589 DOI: 10.1186/s13018-024-05227-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 11/01/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND In recent years, the increasing incidence of osteoarthritis (OA) has attracted widespread public attention; however, the available effective treatments are limited. As a result, new therapeutic approaches, including stem cell and exosome therapies, have been proposed and are gradually gaining popularity. Because exosomes are immunocompatible, there is thought to be more potential for their use in clinical settings. This study summarizes the efficacy of exosomes in the treatment of OA. METHODS In total, we conducted a comprehensive search of the PubMed, Web of Science, and Embase databases using medical subject headings terms to identify studies published from their inception until November 2023 that investigated the use of stem cell-derived exosomes in treating OA. We focused on specific outcomes including osteophyte score, chondrocyte count, pain level, qPCR and histological assessments such as the OARSI (Osteoarthritis research society international) score to measure cartilage degeneration. For data extraction, we used GetData Graph Digitizer to retrieve values from graphs, and the meta-analysis was conducted using RevMan 5.3 software. We chose mean difference (MD) as the primary effect measure since all included studies reported the same outcomes. Ultimately, 20 articles met the inclusion criteria and were included in the meta-analysis. RESULTS We evaluated 20 studies comprising a total of 400 subjects. Compared with control groups, the exosome-treated groups showed significantly improved histological outcomes, as measured by the OARSI score (n = 400; MD = -3.54; 95% CI = [-4.30, -2.79]; P < 0.00001; I2 = 98%). This indicates a marked reduction in cartilage degeneration and OA severity in the exosome-treated groups. Notably, exosome therapy was more effective when administered during the early stages of OA. Additionally, a once-weekly dosing schedule yielded better results compared to more frequent administrations. Of the three exosome isolation methods assessed, kit-based extraction demonstrated a trend toward superior therapeutic efficacy. CONCLUSIONS Exosome treatment improved OA compared to placebo treatment.
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Affiliation(s)
- Yajie Kong
- Department of Orthopedics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China
- Hebei Medical University National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
| | - Yuzhong Wang
- Department of Orthopedics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China
- Hebei Key Laboratory of Rare Disease, Shijiazhuang, 050000, Hebei Province, People's Republic of China
| | - Yujia Yang
- Hebei Medical University National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
| | - Yu Hou
- Hebei Medical University National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
| | - Jingjing Yu
- Hebei Medical University National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
| | - Meiling Liu
- Department of Orthopedics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China
- Hebei Medical University National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
| | - Siyi Xie
- Department of Orthopedics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China
- Hebei Medical University National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China
| | - Yongzhou Song
- Department of Orthopedics, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, People's Republic of China.
- Hebei Key Laboratory of Rare Disease, Shijiazhuang, 050000, Hebei Province, People's Republic of China.
- Hebei Medical University National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China.
- Hebei Research Center for Stem Cell Medical Translational Engineering, Hebei Medical University, Shijiazhuang, 050017, Hebei Province, People's Republic of China.
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Shipman WD, Fonseca R, Dominguez M, Bhayani S, Gilligan C, Diwan S, Rosenblum D, Ashina S, Tolba R, Abd-Elsayed A, Kaye AD, Hasoon J, Schatman ME, Deer T, Yong J, Robinson CL. An Update on Emerging Regenerative Medicine Applications: The Use of Extracellular Vesicles and Exosomes for the Management of Chronic Pain. Curr Pain Headache Rep 2024; 28:1289-1297. [PMID: 39495409 DOI: 10.1007/s11916-024-01309-4] [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] [Accepted: 10/18/2024] [Indexed: 11/05/2024]
Abstract
PURPOSE OF REVIEW Chronic pain affects nearly two billion people worldwide, surpassing heart disease, diabetes, and cancer in terms of economic costs. Lower back pain alone is the leading cause of years lived with disability worldwide. Despite limited treatment options, regenerative medicine, particularly extracellular vesicles (EVs) and exosomes, holds early promise for patients who have exhausted other treatment options. EVs, including exosomes, are nano-sized structures released by cells, facilitating cellular communication through bioactive molecule transfer, and offering potential regenerative properties to damaged tissues. Here, we review the potential of EVs and exosomes for the management of chronic pain. RECENT FINDINGS In osteoarthritis, various exosomes, such as those derived from synovial mesenchymal stem cells, human placental cells, dental pulp stem cells, and bone marrow-derived mesenchymal stem cells (MSCs), demonstrate the ability to reduce inflammation, promote tissue repair, and alleviate pain in animal models. In intervertebral disc disease, Wharton's jelly MSC-derived EVs enhance cell viability and reduce inflammation. In addition, various forms of exosomes have been shown to reduce signs of inflammation in neurons and alleviate pain in neuropathic conditions in animal models. Although clinical applications of EVs and exosomes are still in the early clinical stages, they offer immense potential in the future management of chronic pain conditions. Clinical trials are ongoing to explore their therapeutic potential further, and with more research the potential applicability of EVs and exosomes will be fully understood.
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Affiliation(s)
- William D Shipman
- Department of Dermatology, Yale University School of Medicine, 333 Cedar Street, LMP 5040, Box 208059, New Haven, CT, 06520, USA.
- Skin & Beauty Center, Pasadena, CA, USA.
| | - Raquel Fonseca
- Department of Neurology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Moises Dominguez
- Department of Neurology, Weill Cornell Medicine, New York, NY, USA
| | - Sadiq Bhayani
- Pain Management Department in the Anesthesiology Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
| | | | - Sudhir Diwan
- Manhattan Spine and Pain Medicine, Lenox Hill Hospital, New York, NY, USA
| | - David Rosenblum
- Department of Anesthesiology, Division of Pain Medicine, Maimonides Medical Center, New York, NY, USA
| | - Sait Ashina
- Department of Anesthesiology, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Reda Tolba
- Pain Management Department in the Anesthesiology Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE
| | - Alaa Abd-Elsayed
- Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, USA
| | - Jamal Hasoon
- Department of Anesthesia and Pain Medicine, UTHealth McGovern Medical School, Houston, TX, USA
| | - Michael E Schatman
- Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, New York, NY, USA
- Department of Population Health-Division of Medical Ethics, NYU Grossman School of Medicine, New York, NY, USA
| | - Timothy Deer
- The Spine and Nerve Center of the Virginias, Charleston, WV, USA
| | - Jason Yong
- Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Christopher L Robinson
- Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
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Huang Y, Zuo F, Wu J, Wu S. TNF-α Regulated Bidirectional Interaction Between Bone Marrow Mesenchymal Stem Cells and Articular Chondrocytes. Cartilage 2024:19476035241297693. [PMID: 39567501 PMCID: PMC11580114 DOI: 10.1177/19476035241297693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/10/2024] [Accepted: 10/17/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Articular chondrocytes (ACs) secrete a variety of extracellular matrix components to maintain the functions of articular cartilage. Degeneration of ACs leads to the degeneration of articular cartilage and consequently to osteoarthritis. The secretion of bone marrow mesenchymal stem cells (BMSCs) is capable of protecting ACs from degeneration, and thus BMSCs are widely applied to treat osteoarthritis. OBJECTIVE This study aims to explore whether BMSCs and ACs will affect the functions of each other through their secretions in the context of osteoarthritis. DESIGN BMSCs and ACs isolated from rabbits were identified using flow cytometry and immunocytochemistry. Conditioned medium of BMSCs and ACs treated with 0, 5, 10, 20, and 40 ng/ml of tumor necrosis factor-alpha (TNF-α) were collected and used to treat ACs and BMSCs, respectively. The viabilities of ACs and BMSCs treated with condition medium were assessed using a Cell Count Kit-8 (CCK-8) kit. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and enzyme-linked immunosorbent assay (ELISA) methods were employed to evaluate the relative expression levels of genes and proteins, as well as the cytokine concentrations in the supernatant. RESULTS Immunofluorescence and flow cytometry results indicated that the purity of isolated cells exceeded 95%. CCK-8 analysis showed that 6 hours of treatment with a conditioned medium did not affect the viability of BMSCs and ACs. However, treatment for 12 hours or longer significantly increased the viability of BMSCs (p < 0.05) and significantly decreased the viability of ACs (p < 0.01). RT-qPCR results demonstrated that the relative expression levels of Runx2 (1.15-3.91), Alp (1.06-2.84), TNF (BMSCs: 0.94-2.54; ACs: 1.03-2.64), IL6 (BMSCs: 0.98-2.78; ACs: 0.96-3.71), IL17A (BMSCs: 1.08-5.91; ACs: 0.90-4.20), and IL10 (BMSCs: 0.93-2.82; ACs: 0.89-2.25) genes in conditioned medium-treated BMSCs and ACs were dose-dependently elevated (p < 0.001) by TNF-α treatment. Immunoblotting analysis revealed that the expression levels of RUNX2 (0.53-0.86) and ALP (0.49-0.85) proteins were also dose-dependently elevated (p < 0.001) by TNF-α treatment. ELISA results showed similar TNF-α dose-dependent increases (p < 0.001) in the supernatant concentrations of pro-inflammatory cytokines TNF-α (BMSCs: 36.90 ± 0.75 to 199.38 pg/ml; ACs: 29.76 to 293.99 pg/ml), interleukin (IL)-6 (BMSCs: 4.96-48.24 pg/ml; ACs: 6.12-38.15 pg/ml), IL-17 (BMSCs: 3.06-28.99 pg/ml; ACs: 3.08-28.51 pg/ml), as well as the anti-inflammatory cytokine IL-10 (BMSCs: 6.34-65.02 pg/ml; ACs: 5.30-34.85 pg/ml). CONCLUSION Together, these results indicate a TNF-α-regulated bidirectional interaction between BMSCs and ACs, deepening our understanding of the pathogenesis of osteoarthritis and aiding in its prevention and treatment.
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Affiliation(s)
- Yu Huang
- Department of Science and Education, Sichuan Taikang Hospital, Chengdu, China
| | - Fengqiong Zuo
- School of Basic Medicine and Forensic Sciences, Sichuan University, Chengdu, China
| | - Jue Wu
- Department of Science and Education, Sichuan Taikang Hospital, Chengdu, China
| | - Shaoping Wu
- Department of Science and Education, Sichuan Taikang Hospital, Chengdu, China
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José Alcaraz M. Control of articular degeneration by extracellular vesicles from stem/stromal cells as a potential strategy for the treatment of osteoarthritis. Biochem Pharmacol 2024; 228:116226. [PMID: 38663683 DOI: 10.1016/j.bcp.2024.116226] [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: 01/19/2024] [Revised: 04/05/2024] [Accepted: 04/18/2024] [Indexed: 05/18/2024]
Abstract
Osteoarthritis (OA) is a degenerative joint condition that contributes to years lived with disability. Current therapeutic approaches are limited as there are no disease-modifying interventions able to delay or inhibit the progression of disease. In recent years there has been an increasing interest in the immunomodulatory and regenerative properties of mesenchymal stem/stromal cells (MSCs) to develop new OA therapies. Extracellular vesicles (EVs) mediate many of the biological effects of these cells and may represent an alternative avoiding the limitations of cell-based therapy. There is also a growing interest in EV modifications to enhance their efficacy and applications. Recent preclinical studies have provided strong evidence supporting the potential of MSC EVs for the development of OA treatments. Thus, MSC EVs may regulate chondrocyte functions to avoid cartilage destruction, inhibit abnormal subchondral bone metabolism and synovial tissue alterations, and control pain behavior. EV actions may be mediated by the transfer of their cargo to target cells, with an important role for proteins and non-coding RNAs modulating signaling pathways relevant for OA progression. Nevertheless, additional investigations are needed concerning EV optimization, and standardization of preparation procedures. More research is also required for a better knowledge of possible effects on different OA phenotypes, pharmacokinetics, mechanism of action, long-term effects and safety profile. Furthermore, MSC EVs have a high potential as vehicles for drug delivery or as adjuvant therapy to potentiate or complement the effects of other approaches.
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Affiliation(s)
- María José Alcaraz
- Department of Pharmacology, University of Valencia, Av. Vicent A. Estellés s/n, 46100 Burjasot, Valencia, Spain.
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Wu J, Wu J, Liu Z, Gong Y, Feng D, Xiang W, Fang S, Chen R, Wu Y, Huang S, Zhou Y, Liu N, Xu H, Zhou S, Liu B, Ni Z. Mesenchymal stem cell-derived extracellular vesicles in joint diseases: Therapeutic effects and underlying mechanisms. J Orthop Translat 2024; 48:53-69. [PMID: 39170747 PMCID: PMC11338158 DOI: 10.1016/j.jot.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/09/2024] [Accepted: 07/08/2024] [Indexed: 08/23/2024] Open
Abstract
Joint diseases greatly impact the daily lives and occupational functioning of patients globally. However, conventional treatments for joint diseases have several limitations, such as unsatisfatory efficacy and side effects, necessitating the exploration of more efficacious therapeutic strategies. Mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have demonstrated high therapeutic efficacyin tissue repair and regeneration, with low immunogenicity and tumorigenicity. Recent studies have reported that EVs-based therapy has considerable therapeutic effects against joint diseases, including osteoarthritis, tendon and ligament injuries, femoral head osteonecrosis, and rheumatoid arthritis. Herein, we review the therapeutic potential of various types of MSC-EVs in the aforementioned joint diseases, summarise the mechanisms underlying specific biological effects of MSC-EVs, and discuss future prospects for basic research on MSC-EV-based therapeutic modalities and their clinical translation. In general, this review provides an in-depth understanding of the therapeutic effects of MSC-EVs in joint diseases, as well as the underlying mechanisms, which may be beneficial to the clinical translation of MSC-EV-based treatment. The translational potential of this article: MSC-EV-based cell-free therapy can effectively promote regeneration and tissue repair. When used to treat joint diseases, MSC-EVs have demonstrated desirable therapeutic effects in preclinical research. This review may supplement further research on MSC-EV-based treatment of joint diseases and its clinical translation.
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Affiliation(s)
- Jinhui Wu
- Department of Joint Surgery and Sport Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, China
| | - Jiangyi Wu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, China
| | - Zheng Liu
- Department of Joint Surgery and Sport Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, China
| | - Yunquan Gong
- Department of Rehabilitation Medicine, Daping Hospital, Army Medical University, Chongqing, 400022, China
| | - Daibo Feng
- Department of Rehabilitation Medicine, Daping Hospital, Army Medical University, Chongqing, 400022, China
| | - Wei Xiang
- Department of Rehabilitation Medicine, Daping Hospital, Army Medical University, Chongqing, 400022, China
| | - Shunzheng Fang
- Department of Rehabilitation Medicine, Daping Hospital, Army Medical University, Chongqing, 400022, China
| | - Ran Chen
- War Trauma Medical Center, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center, Daping Hospital, Army Medical University, Chongqing, 40038, China
| | - Yaran Wu
- Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Gantaoyan Street, Shapinba District, Chongqing, 400038, China
| | - Shu Huang
- Department of Joint Surgery and Sport Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, China
| | - Yizhao Zhou
- Department of Joint Surgery and Sport Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, China
| | - Ningning Liu
- Department of Laboratory Medicine, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, 450003, China
| | - Hao Xu
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zhengzhou University Zhengzhou, 450003, China
| | - Siru Zhou
- War Trauma Medical Center, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center, Daping Hospital, Army Medical University, Chongqing, 40038, China
| | - Baorong Liu
- Department of Joint Surgery and Sport Medicine, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, 410000, China
| | - Zhenhong Ni
- Department of Rehabilitation Medicine, Daping Hospital, Army Medical University, Chongqing, 400022, China
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10
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Vadhan A, Gupta T, Hsu WL. Mesenchymal Stem Cell-Derived Exosomes as a Treatment Option for Osteoarthritis. Int J Mol Sci 2024; 25:9149. [PMID: 39273098 PMCID: PMC11395657 DOI: 10.3390/ijms25179149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Osteoarthritis (OA) is a leading cause of pain and disability worldwide in elderly people. There is a critical need to develop novel therapeutic strategies that can effectively manage pain and disability to improve the quality of life for older people. Mesenchymal stem cells (MSCs) have emerged as a promising cell-based therapy for age-related disorders due to their multilineage differentiation and strong paracrine effects. Notably, MSC-derived exosomes (MSC-Exos) have gained significant attention because they can recapitulate MSCs into therapeutic benefits without causing any associated risks compared with direct cell transplantation. These exosomes help in the transport of bioactive molecules such as proteins, lipids, and nucleic acids, which can influence various cellular processes related to tissue repair, regeneration, and immune regulation. In this review, we have provided an overview of MSC-Exos as a considerable treatment option for osteoarthritis. This review will go over the underlying mechanisms by which MSC-Exos may alleviate the pathological hallmarks of OA, such as cartilage degradation, synovial inflammation, and subchondral bone changes. Furthermore, we have summarized the current preclinical evidence and highlighted promising results from in vitro and in vivo studies, as well as progress in clinical trials using MSC-Exos to treat OA.
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Affiliation(s)
- Anupama Vadhan
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin 632007, Taiwan;
| | - Tanvi Gupta
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan;
| | - Wen-Li Hsu
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin 632007, Taiwan;
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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11
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Karoichan A, Boucenna S, Tabrizian M. Therapeutics of the future: Navigating the pitfalls of extracellular vesicles research from an osteoarthritis perspective. J Extracell Vesicles 2024; 13:e12435. [PMID: 38943211 PMCID: PMC11213691 DOI: 10.1002/jev2.12435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/12/2024] [Accepted: 03/22/2024] [Indexed: 07/01/2024] Open
Abstract
Extracellular vesicles have gained wide momentum as potential therapeutics for osteoarthritis, a highly prevalent chronic disease that still lacks an approved treatment. The membrane-bound vesicles are secreted by all cells carrying different cargos that can serve as both disease biomarkers and disease modifiers. Nonetheless, despite a significant peak in research regarding EVs as OA therapeutics, clinical implementation seems distant. In addition to scalability and standardization challenges, researchers often omit to focus on and consider the proper tropism of the vesicles, the practicality and relevance of their source, their low native therapeutic efficacy, and whether they address the disease as a whole. These considerations are necessary to better understand EVs in a clinical light and have been comprehensively discussed and ultimately summarized in this review into a conceptualized framework termed the nanodiamond concept. Future perspectives are also discussed, and alternatives are presented to address some of the challenges and concerns.
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Affiliation(s)
- Antoine Karoichan
- Faculty of Dental Medicine and Oral Health SciencesMcGill UniversityMontrealQuebecCanada
| | - Sarah Boucenna
- Faculty of Dental Medicine and Oral Health SciencesMcGill UniversityMontrealQuebecCanada
| | - Maryam Tabrizian
- Faculty of Dental Medicine and Oral Health SciencesMcGill UniversityMontrealQuebecCanada
- Department of Biomedical EngineeringMcGill UniversityMontrealQuebecCanada
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12
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Shimomura K, Wong KL, Saseendar S, Muthu S, Concaro S, Fernandes TL, Mahmood A. Exploring the potential of mesenchymal stem/stromal cell-derived extracellular vesicles as cell-free therapy for osteoarthritis: a narrative review. JOURNAL OF CARTILAGE & JOINT PRESERVATION 2024; 4:100184. [DOI: 10.1016/j.jcjp.2024.100184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
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13
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Wang Y, Wen J, Lu T, Han W, Jiao K, Li H. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Bone-Related Diseases: Intercellular Communication Messengers and Therapeutic Engineering Protagonists. Int J Nanomedicine 2024; 19:3233-3257. [PMID: 38601346 PMCID: PMC11005933 DOI: 10.2147/ijn.s441467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/23/2024] [Indexed: 04/12/2024] Open
Abstract
Extracellular vesicles (EVs) can deliver various bioactive molecules among cells, making them promising diagnostic and therapeutic alternatives in diseases. Mesenchymal stem cell-derived EVs (MSC-EVs) have shown therapeutic potential similar to MSCs but with drawbacks such as lower yield, reduced biological activities, off-target effects, and shorter half-lives. Improving strategies utilizing biotechniques to pretreat MSCs and enhance the properties of released EVs, as well as modifying MSC-EVs to enhance targeting abilities and achieve controlled release, shows potential for overcoming application limitations and enhancing therapeutic effects in treating bone-related diseases. This review focuses on recent advances in functionalizing MSC-EVs to treat bone-related diseases. Firstly, we underscore the significance of MSC-EVs in facilitating crosstalk between cells within the skeletal environment. Secondly, we highlight strategies of functional-modified EVs for treating bone-related diseases. We explore the pretreatment of stem cells using various biotechniques to enhance the properties of resulting EVs, as well as diverse approaches to modify MSC-EVs for targeted delivery and controlled release. Finally, we address the challenges and opportunities for further research on MSC-EVs in bone-related diseases.
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Affiliation(s)
- Yanyi Wang
- Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China
- Medical School of Nanjing University, Nanjing, People’s Republic of China
| | - Juan Wen
- Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China
- Medical School of Nanjing University, Nanjing, People’s Republic of China
- Centre for Orofacial Regeneration, Reconstruction and Rehabilitation (COR3), School of Dentistry, The University of Queensland, Brisbane, Queensland, 4006, Australia
| | - Tong Lu
- Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China
- Medical School of Nanjing University, Nanjing, People’s Republic of China
| | - Wei Han
- Medical School of Nanjing University, Nanjing, People’s Republic of China
- Department of Oral and Maxillofacial Surgery, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China
| | - Kai Jiao
- Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China
| | - Huang Li
- Department of Orthodontics, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Research Institute of Stomatology, Nanjing University, Nanjing, People’s Republic of China
- Medical School of Nanjing University, Nanjing, People’s Republic of China
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Xiong Z, Hu Y, Jiang M, Liu B, Jin W, Chen H, Yang L, Han X. Hypoxic bone marrow mesenchymal stem cell exosomes promote angiogenesis and enhance endometrial injury repair through the miR-424-5p-mediated DLL4/Notch signaling pathway. PeerJ 2024; 12:e16953. [PMID: 38406291 PMCID: PMC10894593 DOI: 10.7717/peerj.16953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 01/25/2024] [Indexed: 02/27/2024] Open
Abstract
Background Currently, bone marrow mesenchymal stem cells (BMSCs) have been reported to promote endometrial regeneration in rat models of mechanically injury-induced uterine adhesions (IUAs), but the therapeutic effects and mechanisms of hypoxic BMSC-derived exosomes on IUAs have not been elucidated. Objective To investigate the potential mechanism by which the BMSCS-derived exosomal miR-424-5p regulates IUA angiogenesis through the DLL4/Notch signaling pathway under hypoxic conditions and promotes endometrial injury repair. Methods The morphology of the exosomes was observed via transmission electron microscopy, and the expression of exosome markers (CD9, CD63, CD81, and HSP70) was detected via flow cytometry and Western blotting. The expression of angiogenesis-related genes (Ang1, Flk1, Vash1, and TSP1) was detected via RT‒qPCR, and the expression of DLL4/Notch signaling pathway-related proteins (DLL4, Notch1, and Notch2) was detected via Western blotting. Cell proliferation was detected by a CCK-8 assay, and angiogenesis was assessed via an angiogenesis assay. The expression of CD3 was detected by immunofluorescence. The endometrial lesions of IUA rats were observed via HE staining, and the expression of CD3 and VEGFA was detected via immunohistochemistry. Results Compared with those in exosomes from normoxic conditions, miR-424-5p was more highly expressed in the exosomes from hypoxic BMSCs. Compared with those in normoxic BMSC-derived exosomes, the proliferation and angiogenesis of HUVECs were significantly enhanced after treatment with hypoxic BMSC-derived exosomes, and these effects were weakened after inhibition of miR-424-5p. miR-424-5p can target and negatively regulate the expression of DLL4, promote the expression of the proangiogenic genes Ang1 and Flk1, and inhibit the expression of the antiangiogenic genes Vash1 and TSP1. The effect of miR-424-5p can be reversed by overexpression of DLL4. In IUA rats, treatment with hypoxic BMSC exosomes and the miR-424-5p mimic promoted angiogenesis and improved endometrial damage. Conclusion The hypoxic BMSC-derived exosomal miR-424-5p promoted angiogenesis and improved endometrial injury repair by regulating the DLL4/Notch signaling pathway, which provides a new idea for the treatment of IUAs.
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Affiliation(s)
- Zhenghua Xiong
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Department of Gynecology, Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan, China
| | - Yong Hu
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Min Jiang
- Department of Gynecology, Women and Children’s Hospital Affiliated to Qingdao University, Qingdao, Shandong, China
| | - Beibei Liu
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Wenjiao Jin
- Department of Gynecology, Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan, China
| | - Huiqin Chen
- Department of Gynecology, Chuxiong Hospital of Traditional Chinese Medicine, Chuxiong, Yunnan, China
| | - Linjuan Yang
- Department of Gynecology and Obstetrics, Baoshan Hospital of Traditional Chinese Medicine, Baoshan, Yunnan, China
| | - Xuesong Han
- Department of Gynecology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Department of Gynecology, Yan’an Hospital Affiliated to Kunming Medical University/Yan’an Hospital of Kunming City, Kunming, Yunnan, China
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15
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Mustonen AM, Palviainen M, Säisänen L, Karttunen L, Tollis S, Esrafilian A, Reijonen J, Julkunen P, Siljander PRM, Kröger H, Mäki J, Arokoski J, Nieminen P. Tetraspanin profiles of serum extracellular vesicles reflect functional limitations and pain perception in knee osteoarthritis. Arthritis Res Ther 2024; 26:33. [PMID: 38254142 PMCID: PMC10801950 DOI: 10.1186/s13075-023-03234-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Emerging evidence suggests that extracellular vesicles (EVs) can play roles in inflammatory processes and joint degradation in primary osteoarthritis (OA), a common age-associated joint disease. EV subpopulations express tetraspanins and platelet markers that may reflect OA pathogenesis. The present study investigated the associations between these EV surface markers and articular cartilage degradation, subjectively and objectively assessed pain, and functional limitations in primary knee OA (KOA). METHODS Serum EVs were determined by high-sensitivity flow cytometry (large CD61+ EVs) and single particle interferometric reflectance imaging sensor (small CD41+, CD63+, CD81+, and CD9+ EVs) from end-stage KOA patients and controls (n = 8 per group). Knee pain and physical functions were assessed with several health- and pain-related questionnaires, established measurements of physical medicine, and neuromuscular examination. The obtained data were analyzed using supervised and unsupervised univariate and multivariate models. RESULTS With the combined dataset of cartilage thickness, knee function, pain, sensation, and EV molecular signatures, we identified highly correlated groups of variables and found several EV markers that were statistically significant predictors of pain, physical limitations, and other aspects of well-being for KOA patients, for instance CD41+/CD63+/CD9+ small EVs associated with the range of motion of the knee, physical performance, and pain sensitivity. CONCLUSIONS Particular serum EV subpopulations showed clear associations with KOA pain and functional limitations, suggesting that their implications in OA pathophysiology warrant further study.
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Affiliation(s)
- Anne-Mari Mustonen
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
- Department of Environmental and Biological Sciences, Faculty of Science, Forestry and Technology, University of Eastern Finland, Joensuu, Finland.
| | - Mari Palviainen
- EV core and EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences University of Helsinki, Helsinki, Finland
| | - Laura Säisänen
- Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland
- Department of Technical Physics, Faculty of Science, Forestry and Technology, University of Eastern Finland, Kuopio, Finland
| | - Lauri Karttunen
- Department of Physical and Rehabilitation Medicine, Central Finland Hospital Nova, Jyväskylä, Finland
| | - Sylvain Tollis
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
| | - Amir Esrafilian
- Department of Technical Physics, Faculty of Science, Forestry and Technology, University of Eastern Finland, Kuopio, Finland
| | - Jusa Reijonen
- Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland
- Department of Technical Physics, Faculty of Science, Forestry and Technology, University of Eastern Finland, Kuopio, Finland
| | - Petro Julkunen
- Department of Clinical Neurophysiology, Kuopio University Hospital, Kuopio, Finland
- Department of Technical Physics, Faculty of Science, Forestry and Technology, University of Eastern Finland, Kuopio, Finland
| | - Pia R-M Siljander
- EV core and EV group, Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences University of Helsinki, Helsinki, Finland
| | - Heikki Kröger
- Department of Orthopaedics, Traumatology and Hand Surgery, Kuopio University Hospital, Kuopio, Finland
- Kuopio Musculoskeletal Research Unit, University of Eastern Finland, Kuopio, Finland
| | - Jussi Mäki
- Department of Rehabilitation, Kuopio University Hospital, Kuopio, Finland
| | - Jari Arokoski
- Department of Physical and Rehabilitation Medicine, Helsinki University Hospital, Helsinki, Finland and University of Helsinki, Helsinki, Finland
| | - Petteri Nieminen
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
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16
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Wilson JE, Today BA, Salazar M, Kuo J, Ransom JT, Lightner AL, Chen G, Wong A. Safety of bone marrow derived mesenchymal stem cell extracellular vesicle injection for lumbar facet joint pain. Regen Med 2024; 19:19-26. [PMID: 38327218 DOI: 10.2217/rme-2023-0110] [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] [Indexed: 02/09/2024] Open
Abstract
Aim: A 3-month pilot study to evaluate the safety of injecting a bone marrow-derived mesenchymal stem cell extracellular vesicle advanced investigational product (IP) into the lumbar facet joint space as a treatment for chronic low back pain. Methods: 20 healthy adults were treated with IP injections (0.5 ml/joint) and evaluated by three functional assessments 1, 3, 7, 14, 30, 60 and 90 days later. Results: No adverse effects or complications occurred across the 3-month follow-up. There were no reports of worsening pain. After 3 months group average scores improved significantly (p < 0.0001) in the Severity Index (65.04%), Interference Index (72.09%) and Oswestry Disability Index (58.43%) assessments. Conclusion: IP injections were safe and associated with significant functional improvements.
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Affiliation(s)
- James E Wilson
- Interventional Pain Specialists, 28604 Ravine Circle, Covert, MI 49043, USA
| | - Bobbie A Today
- Interventional Pain Specialists, 28604 Ravine Circle, Covert, MI 49043, USA
| | - Maria Salazar
- Interventional Pain Specialists, 28604 Ravine Circle, Covert, MI 49043, USA
| | | | - John T Ransom
- Direct Biologics, 5301 Southwest Parkway, Building 1, Suite 415, Austin, TX 78735, USA
| | - Amy L Lightner
- Direct Biologics, 5301 Southwest Parkway, Building 1, Suite 415, Austin, TX 78735, USA
| | - Grace Chen
- Hudson Medical Group, 160 7th Ave S, NY 10014, USA
| | - Anita Wong
- Hudson Medical Group, 160 7th Ave S, NY 10014, USA
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17
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Ren K, Vickers R, Murillo J, Ruparel NB. Revolutionizing orofacial pain management: the promising potential of stem cell therapy. FRONTIERS IN PAIN RESEARCH 2023; 4:1239633. [PMID: 38028430 PMCID: PMC10679438 DOI: 10.3389/fpain.2023.1239633] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 09/22/2023] [Indexed: 12/01/2023] Open
Abstract
Orofacial pain remains a significant health issue in the United States. Pain originating from the orofacial region can be composed of a complex array of unique target tissue that contributes to the varying success of pain management. Long-term use of analgesic drugs includes adverse effects such as physical dependence, gastrointestinal bleeding, and incomplete efficacy. The use of mesenchymal stem cells for their pain relieving properties has garnered increased attention. In addition to the preclinical and clinical results showing stem cell analgesia in non-orofacial pain, studies have also shown promising results for orofacial pain treatment. Here we discuss the outcomes of mesenchymal stem cell treatment for pain and compare the properties of stem cells from different tissues of origin. We also discuss the mechanism underlying these analgesic/anti-nociceptive properties, including the role of immune cells and the endogenous opioid system. Lastly, advancements in the methods and procedures to treat patients experiencing orofacial pain with mesenchymal stem cells are also discussed.
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Affiliation(s)
- Ke Ren
- Department of Pain and Neural Sciences, University of Maryland, Baltimore, MD, United States
| | - Russel Vickers
- Clinical Stem Cells Pty Ltd., Sydney, NSW, Australia
- Oral Health Center, School of Dentistry, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, QLD, Australia
- Institute for Glycomics, Griffith University Queensland, Southport, QLD, Australia
| | - Josue Murillo
- Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Nikita B. Ruparel
- Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
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18
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Li Z, Bi R, Zhu S. The Dual Role of Small Extracellular Vesicles in Joint Osteoarthritis: Their Global and Non-Coding Regulatory RNA Molecule-Based Pathogenic and Therapeutic Effects. Biomolecules 2023; 13:1606. [PMID: 38002288 PMCID: PMC10669328 DOI: 10.3390/biom13111606] [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: 09/13/2023] [Revised: 10/20/2023] [Accepted: 10/24/2023] [Indexed: 11/26/2023] Open
Abstract
OA is the most common joint disease that affects approximately 7% of the global population. Current treatment methods mainly relieve its symptoms with limited repairing effect on joint destructions, which ultimately contributes to the high morbidity rate of OA. Stem cell treatment is a potential regenerative medical therapy for joint repair in OA, but the uncertainty in differentiation direction and immunogenicity limits its clinical usage. Small extracellular vesicles (sEVs), the by-products secreted by stem cells, show similar efficacy levels but have safer regenerative repair effect without potential adverse outcomes, and have recently drawn attention from the broader research community. A series of research works and reviews have been performed in the last decade, providing references for the application of various exogenous therapeutic sEVs for treating OA. However, the clinical potential of target intervention involving endogenous pathogenic sEVs in the treatment of OA is still under-explored and under-discussed. In this review, and for the first time, we emphasize the dual role of sEVs in OA and explain the effects of sEVs on various joint tissues from both the pathogenic and therapeutic aspects. Our aim is to provide a reference for future research in the field.
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Affiliation(s)
- Zhi Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China;
| | - Ruiye Bi
- Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Songsong Zhu
- Department of Orthognathic and TMJ Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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19
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Huang S, Liu Y, Wang C, Xiang W, Wang N, Peng L, Jiang X, Zhang X, Fu Z. Strategies for Cartilage Repair in Osteoarthritis Based on Diverse Mesenchymal Stem Cells-Derived Extracellular Vesicles. Orthop Surg 2023; 15:2749-2765. [PMID: 37620876 PMCID: PMC10622303 DOI: 10.1111/os.13848] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 08/26/2023] Open
Abstract
Osteoarthritis (OA) causes disability and significant economic and social burden. Cartilage injury is one of the main pathological features of OA, and is often manifested by excessive chondrocyte death, inflammatory response, abnormal bone metabolism, imbalance of extracellular matrix (ECM) metabolism, and abnormal vascular or nerve growth. Regrettably, due to the avascular nature of cartilage, its capacity to repair is notably limited. Mesenchymal stem cells-derived extracellular vesicles (MSCs-EVs) play a pivotal role in intercellular communication, presenting promising potential not only as early diagnostic biomarkers in OA but also as efficacious therapeutic strategy. MSCs-EVs were confirmed to play a therapeutic role in the pathological process of cartilage injury mentioned above. This paper comprehensively provides the functions and mechanisms of MSCs-EVs in cartilage repair.
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Affiliation(s)
- Shanjun Huang
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Yujiao Liu
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Chenglong Wang
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Wei Xiang
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Nianwu Wang
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Li Peng
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Xuanang Jiang
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Xiaomin Zhang
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
| | - Zhijiang Fu
- Orthopedics DepartmentThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouChina
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Zhao J, Sun Y, Sheng X, Xu J, Dai G, He R, Jin Y, Liu Z, Xie Y, Wu T, Cao Y, Hu J, Duan C. Hypoxia-treated adipose mesenchymal stem cell-derived exosomes attenuate lumbar facet joint osteoarthritis. Mol Med 2023; 29:120. [PMID: 37670256 PMCID: PMC10478461 DOI: 10.1186/s10020-023-00709-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/26/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND Lumbar facet joint osteoarthritis (LFJ OA) is a common disease, and there is still a lack of effective disease-modifying therapies. Our aim was to determine the therapeutic effect of hypoxia-treated adipose mesenchymal stem cell (ADSC)-derived exosomes (Hypo-ADSC-Exos) on the protective effect against LFJ OA. METHODS The protective effect of Hypo-ADSC-Exos against LFJ OA was examined in lumbar spinal instability (LSI)-induced LFJ OA models. Spinal pain behavioural assessments and CGRP (Calcitonin Gene-Related Peptide positive) immunofluorescence were evaluated. Cartilage degradation and subchondral bone remodelling were assessed by histological methods, immunohistochemistry, synchrotron radiation-Fourier transform infrared spectroscopy (SR-FTIR), and 3D X-ray microscope scanning. RESULTS Hypoxia enhanced the protective effect of ADSC-Exos on LFJ OA. Specifically, tail vein injection of Hypo-ADSC-Exos protected articular cartilage from degradation, as demonstrated by lower FJ OA scores of articular cartilage and less proteoglycan loss in lumbar facet joint (LFJ) cartilage than in the ADSC-Exo group, and these parameters were significantly improved compared to those in the PBS group. In addition, the levels and distribution of collagen and proteoglycan in LFJ cartilage were increased in the Hypo-ADSC-Exo group compared to the ADSC-Exo or PBS group by SR-FTIR. Furthermore, Hypo-ADSC-Exos normalized uncoupled bone remodelling and aberrant H-type vessel formation in subchondral bone and effectively reduced symptomatic spinal pain caused by LFJ OA in mice compared with those in the ADSC-Exo or PBS group. CONCLUSIONS Our results show that hypoxia is an effective method to improve the therapeutic effect of ADSC-Exos on ameliorating spinal pain and LFJ OA progression.
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Affiliation(s)
- Jinyun Zhao
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yi Sun
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Xiaolong Sheng
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaqi Xu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guoyu Dai
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Rundong He
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yuxin Jin
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhide Liu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yong Xie
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Tianding Wu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China
- Hunan Engineering Research Center of Sports and Health, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yong Cao
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China.
- Hunan Engineering Research Center of Sports and Health, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jianzhong Hu
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China.
- Hunan Engineering Research Center of Sports and Health, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Chunyue Duan
- Department of Spine Surgery and Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, 410008, China.
- Hunan Engineering Research Center of Sports and Health, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Zhang Y, Feng S, Cheng X, Lou K, Liu X, Zhuo M, Chen L, Ye J. The potential value of exosomes as adjuvants for novel biologic local anesthetics. Front Pharmacol 2023; 14:1112743. [PMID: 36778004 PMCID: PMC9909291 DOI: 10.3389/fphar.2023.1112743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/13/2023] [Indexed: 01/27/2023] Open
Abstract
The side effects of anesthetic drugs are a key preoperative concern for anesthesiologists. Anesthetic drugs used for general anesthesia and regional blocks are associated with a potential risk of systemic toxicity. This prompted the use of anesthetic adjuvants to ameliorate these side effects and improve clinical outcomes. However, the adverse effects of anesthetic adjuvants, such as neurotoxicity and gastrointestinal reactions, have raised concerns about their clinical use. Therefore, the development of relatively safe anesthetic adjuvants with fewer side effects is an important area for future anesthetic drug research. Exosomes, which contain multiple vesicles with genetic information, can be released by living cells with regenerative and specific effects. Exosomes released by specific cell types have been found to have similar effects as many local anesthetic adjuvants. Due to their biological activity, carrier efficacy, and ability to repair damaged tissues, exosomes may have a better efficacy and safety profile than the currently used anesthetic adjuvants. In this article, we summarize the contemporary literature about local anesthetic adjuvants and highlight their potential side effects, while discussing the potential of exosomes as novel local anesthetic adjuvant drugs.
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Affiliation(s)
- Yunmeng Zhang
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shangzhi Feng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xin Cheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Kecheng Lou
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xin Liu
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Ming Zhuo
- Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Li Chen
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,*Correspondence: Li Chen, ; Junming Ye,
| | - Junming Ye
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,*Correspondence: Li Chen, ; Junming Ye,
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Exosomes treating osteoarthritis: hope with challenge. Heliyon 2023; 9:e13152. [PMID: 36711315 PMCID: PMC9880404 DOI: 10.1016/j.heliyon.2023.e13152] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/23/2023] Open
Abstract
Osteoarthritis (OA) has been proven as the second primary cause of pain and disability in the elderly population, impact patients both physically and mentally, as well as imposing a heavy burden on the global healthcare system. Current treatment methods, whether conservative or surgical, that aim at relieving symptoms can not delay or reverse the degenerative process in the structure. Scientists and clinicians are facing a revolution in OA treatment strategies. The emergence of exosomes brings hope for OA treatment based on pathology, which is attributed to its full potential in protecting chondrocytes from excessive death, alleviating inflammation, maintaining cartilage matrix metabolism, and regulating angiogenesis and subchondral bone remodeling. Therefore, we summarized the recent studies of exosomes in OA, aiming to comprehensively understand the functions and mechanisms of exosomes in OA treatment, which may provide direction and theoretical support for formulating therapeutic strategies in the future.
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23
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Du R, Xu G, Bai X, Li Z. Facet Joint Syndrome: Pathophysiology, Diagnosis, and Treatment. J Pain Res 2022; 15:3689-3710. [PMID: 36474960 PMCID: PMC9719706 DOI: 10.2147/jpr.s389602] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/17/2022] [Indexed: 11/16/2023] Open
Abstract
Facet joint osteoarthritis (OA) is the most frequent form of facet joint syndrome. Medical history, referred pain patterns, physical examination, and diagnostic imaging studies (standard radiographs, magnetic resonance imaging, computed tomography and single-photon emission computed tomography) may suggest but not confirm lumbar facet joint (LFJ) syndrome as a source of low back pain (LBP). However, the diagnosis and treatment of facet joint syndrome is still controversial and needs further study. It is widely acknowledged that block with local anesthetic is perhaps the most effective method to establish a diagnosis of pain from LFJ. Particularly, there are different rates of success among different populations selected for diagnostic block with various positive criteria. Currently, in addition to conservative treatments for pain such as painkillers, functional exercises, and massage, there are many other methods, including block, denervation of the nerves that innervate the joints by radiofrequency, freezing or endoscopy, and injections. Due to the limited duration of pain relief from neurolysis of medial branch, many scholars have recently turned their targets to dorsal roots and LFJ capsules. Therefore, we reviewed the latest research progress of facet joint syndrome from diagnosis to treatment.
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Affiliation(s)
- Ruihuan Du
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Gang Xu
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian, People’s Republic of China
| | - Xujue Bai
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
| | - Zhonghai Li
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
- Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Dalian, People’s Republic of China
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Hu J, Shi ZS, Liu XZ, Cai HT, Yang AF, Sun DM, Xu LL, Yang Y, Li ZH. Exosomes Derived from Runx2-Overexpressing BMSCs Enhance Cartilage Tissue Regeneration and Prevent Osteoarthritis of the Knee in a Rabbit Model. Stem Cells Int 2022; 2022:6865041. [PMID: 39282499 PMCID: PMC11401735 DOI: 10.1155/2022/6865041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 10/18/2022] [Accepted: 11/08/2022] [Indexed: 09/19/2024] Open
Abstract
Objectives Osteoarthritis is the leading disease of joints worldwide. Osteoarthritis may be treated by exosomes derived from Runx2-overexpressed bone marrow mesenchymal stem cells (R-BMSCs-Exos). R-BMSCs-Exos would promote the proliferation, migration, and phenotypic maintenance of articular chondrocytes. Methods BMSCs were transfected with and without Runx2. Exosomes derived from BMSCs and R-BMSCs (BMSCs-Exos and R-BMSCs-Exos) were isolated and identified. Proliferation, migration, and phenotypic maintenance were determined in vitro and compared between groups. The mechanism for activation of Yes-associated protein (YAP) was investigated using small interfering RNA (siRNA). The exosomes' preventive role was determined in vivo using Masson trichrome and immunohistochemical staining. Results R-BMSCs-Exos enhance the proliferation, migration, and phenotypic maintenance of articular chondrocytes based on the YAP being activated. R-BMSCs-Exos prevent knee osteoarthritis as studied in vivo through a rabbit model. Conclusions Findings emphasize the efficacy of R-BMSCs-Exos in preventing osteoarthritis. Potential source of exosomes is sorted out for the advantages and shortcomings. The exosomes are then modified based on the molecular mechanisms to address their limitations. Such exosomes derived from modified cells have the role in future therapeutics.
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Affiliation(s)
- Jing Hu
- Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430015, China
| | - Zheng-Shuai Shi
- Huanggang Hospital of TCM Affiliated to Hubei University of Chinese Medicine, Huanggang 438000, China
| | - Xiang-Zhong Liu
- Department of Orthopedics, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430060, China
| | - Han-Tao Cai
- Hubei University of Chinese Medicine, Wuhan 430061, China
| | - Ao-Fei Yang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, China
| | - Da-Ming Sun
- Wuhan Sports University, Wuhan 430079, China
| | | | - Yi Yang
- Wuhan Sports University, Wuhan 430079, China
| | - Zhang-Hua Li
- Department of Orthopedics, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430060, China
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25
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Ye C, Zhang Y, Su Z, Wu S, Li Y, Yi J, Lai W, Chen J, Zheng Y. hMSC exosomes as a novel treatment for female sensitive skin: An in vivo study. Front Bioeng Biotechnol 2022; 10:1053679. [PMID: 36338115 PMCID: PMC9633936 DOI: 10.3389/fbioe.2022.1053679] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 10/13/2022] [Indexed: 11/29/2022] Open
Abstract
Background: Recent studies have reported that the incidence of sensitive skin is increasing. Skin sensitivity and skin barrier functions were related to many skin diseases including atopic dermatitis, psoriasis, rosacea, and so on. Mesenchymal stem cell (MSC)-derived exosomes (hMSC) might be considered as a new effective therapeutic scheme. Aims: This study aims to investigate the safety and efficacy of hMSC exosomes as a novel topical treatment for sensitive skin. Patients/Methods: Exosomes were extracted from primary hMSC via ultracentrifugation method. The morphology of hMSC exosomes was studied via transmission electron microscope. Expression of exosome specific surface marker was detected via Western blot. 22 subjects (female, aged 18–55) diagnosed with sensitive skin were enrolled. Follow-up was conducted before, 7-day, 14-day, and 28-day after hMSC exosomes use. Transepidermal water loss (TEWL), surface hydration, sebum secretion, and L*a*b* value were simultaneously tested at the same time point in an environment-controlled room. Results: Under transmission electron microscopy, the extracted hMSC exosomes were circular or elliptical with intact membrane structure, and their diameters ranged mainly from 40 to 80 nm. Western blot showed that the expression of markers CD63, CD9, and Tsg101 was positive. Brownian motion based nanoparticle trajectory analysis (NTA) showed that the main peak of particle size distribution occurred around 96 nm, the average particle size was 122 nm, and the main peak accounted for 96.7%. All this conformed to the biological characteristics of exosomes standardized by the International Society for Extracellular Vesicles. In the clinical trial, scores of objective symptoms including roughness, scales, erythema, and subjective symptoms including tension, burning, or itching, were improved after 7-, 14-, and 28- day using hMSC-exosomes. TEWL, hydration, sebum, pH, and a* values were tended to return to the level of healthy skin. Conclusion: The hMSC-exosomes, with the advantages of biocompatibility and biodegradability, could improve clinical symptoms and eruptions in sensitive skin patients, and might be as an MSC cell-free novel therapy in sensitive skin-related disease treatment.
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Affiliation(s)
- Congxiu Ye
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yunqing Zhang
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhen Su
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shuxia Wu
- AIE Bioscience (Guangdong) Co., LTD., Torch Development Zone, Zhongshan, Guangdong, China
| | - Yuxia Li
- AIE Bioscience (Guangdong) Co., LTD., Torch Development Zone, Zhongshan, Guangdong, China
| | - Jinling Yi
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wei Lai
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- *Correspondence: Wei Lai, ; Jian Chen, ; Yue Zheng,
| | - Jian Chen
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- *Correspondence: Wei Lai, ; Jian Chen, ; Yue Zheng,
| | - Yue Zheng
- Department of Dermato-venereology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- *Correspondence: Wei Lai, ; Jian Chen, ; Yue Zheng,
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Yin H, Li M, Tian G, Ma Y, Ning C, Yan Z, Wu J, Ge Q, Sui X, Liu S, Zheng J, Guo W, Guo Q. The role of extracellular vesicles in osteoarthritis treatment via microenvironment regulation. Biomater Res 2022; 26:52. [PMID: 36199125 PMCID: PMC9532820 DOI: 10.1186/s40824-022-00300-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 09/18/2022] [Indexed: 11/10/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease that is common among the middle-aged and older populations, causes patients to experience recurrent pain in their joints and negatively affects their quality of life. Currently, therapeutic options for patients with OA consist of medications to alleviate pain and treat the symptoms; however, due to typically poor outcomes, patients with advanced OA are unlikely to avoid joint replacement. In recent years, several studies have linked disrupted homeostasis of the joint cavity microenvironment to the development of OA. Recently, extracellular vesicles (EVs) have received increasing attention in the field of OA. EVs are natural nano-microcarrier materials with unique biological activity that are produced by cells through paracrine action. They are composed of lipid bilayers that contain physiologically active molecules, such as nucleic acids and proteins. Moreover, EVs may participate in local and distal intercellular and intracellular communication. EVs have also recently been shown to influence OA development by regulating biochemical factors in the OA microenvironmental. In this article, we first describe the microenvironment of OA. Then, we provide an overview of EVs, summarize the main types used for the treatment of OA, and describe their mechanisms. Next, we review clinical studies using EVs for OA treatment. Finally, the specific mechanism underlying the application of miRNA-enriched EVs in OA therapy is described.
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Affiliation(s)
- Han Yin
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Muzhe Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
- Department of Orthopedics, The First Affiliated Hospital of University of South China, Hengyang, 421000, China
| | - Guangzhao Tian
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yang Ma
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Chao Ning
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Zineng Yan
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Jiang Wu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Qian Ge
- Huaiyin People's Hospital of Huai'an, Huai'an, 223001, China
| | - Xiang Sui
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Shuyun Liu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China.
| | - Jinxuan Zheng
- Department of Orthodontics, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, No.56 Linyuan Xi Road, Yuexiu District, Guangzhou, Guangdong, 510055, People's Republic of China.
| | - Weimin Guo
- Department of Orthopaedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-Sen University, No.58 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, Guangdong, China.
| | - Quanyi Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China.
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Jeyaraman M, Muthu S, Shehabaz S, Jeyaraman N, Rajendran RL, Hong CM, Nallakumarasamy A, Packkyarathinam RP, Sharma S, Ranjan R, Khanna M, Ahn BC, Gangadaran P. Current understanding of MSC-derived exosomes in the management of knee osteoarthritis. Exp Cell Res 2022; 418:113274. [PMID: 35810774 DOI: 10.1016/j.yexcr.2022.113274] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/29/2022] [Accepted: 07/02/2022] [Indexed: 02/08/2023]
Abstract
Mesenchymal stem cell-derived exosomes (MSC-Exos) have been utilized as medicinal agents or as delivery vehicles in cartilage injuries and cartilage-based diseases. Given the ongoing emergence of evidence on the effector mechanisms and methods of the utility of the MSC-Exos in knee osteoarthritis, a comprehensive review of the current evidence is the need of the hour. Hence, in this article, we review the current understanding of the role of MSC-Exos in the management of knee osteoarthritis in view of their classification, characterization, biogenesis, mechanism of action, pathways involved in their therapeutic action, in-vitro evidence on cartilage regeneration, in-vivo evidence in OA knee models and recent advances in using MSC-Exos to better streamline future research from bench to bedside for OA knee.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, Faculty of Medicine - Sri Lalithambigai Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai, 600095, Tamil Nadu, India; Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, 201310, Uttar Pradesh, India; Indian Stem Cell Study Group (ISCSG) Association, Lucknow, 226010, Uttar Pradesh, India
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, 201310, Uttar Pradesh, India; Indian Stem Cell Study Group (ISCSG) Association, Lucknow, 226010, Uttar Pradesh, India; Department of Orthopaedics, Government Medical College and Hospital, Dindigul, 624304, Tamil Nadu, India
| | - Syed Shehabaz
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, 226010, Uttar Pradesh, India; Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow, 226010, Uttar Pradesh, India
| | - Naveen Jeyaraman
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, 226010, Uttar Pradesh, India; Orthopaedic Rheumatology, Dr. RML National Law University, Lucknow, 226010, Uttar Pradesh, India; Joint Replacement, Department of Orthopaedics, Atlas Hospitals, Tiruchirappalli, 620002, Tamil Nadu, India.
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
| | - Chae Moon Hong
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
| | - Arulkumar Nallakumarasamy
- Department of Orthopaedics, All India Institute of Medical Sciences, Bhubaneswar, 751019, Odissa, India
| | | | - Shilpa Sharma
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, 226010, Uttar Pradesh, India; Department of Paediatric Surgery, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rajni Ranjan
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, 201310, Uttar Pradesh, India
| | - Manish Khanna
- Indian Stem Cell Study Group (ISCSG) Association, Lucknow, 226010, Uttar Pradesh, India; Department of Orthopaedics, Prasad Institute of Medical Sciences, Lucknow, 226401, Uttar Pradesh, India
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea; BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea; BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, Department of Biomedical Sciences, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
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Dong B, Liu X, Li J, Wang B, Yin J, Zhang H, Liu W. Berberine encapsulated in exosomes derived from platelet-rich plasma promotes chondrogenic differentiation of the Bone Marrow Mesenchymal Stem Cells via the Wnt/β-catenin pathway. Biol Pharm Bull 2022; 45:1444-1451. [PMID: 35858798 DOI: 10.1248/bpb.b22-00206] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cartilage regenerative medicine, wherein the stem cells from adults exert a crucial role, has high potential in the treatment of defective articular cartilage. Recently, Bone marrow mesenchymal stem cells (BMSCs) are being increasingly recognized as an alternative source of adult stem cells, which are capable of differentiating into several cell types (e.g., adipocytes, chondrocytes, and osteoblasts). However, their proliferative properties and tendency to dedifferentiate restrict their use in clinical settings. Recently, a possible bioactive material PRP-exos (exosomes derived from platelet-rich plasma), has emerged, which can effectively facilitate the differentiation and proliferation of cells. Recent studies have reported that berberine (Ber), known to have anti-inflammatory properties, plays a role in osteogenesis. Since biological molecules are used in combinations, we attempted to assess the effect of Exos-Ber (PRP-exos in combination with Ber) on the chondrogenic differentiation of BMSCs in vitro. In this study, Exos-Ber was observed to promote the proliferation of BMSCs and cause their chondrogenic differentiation in vitro. Additionally, Exos-Ber could promote the migration of BMSCs and increase the protein expression of the chondrogenic genes (Collagen II, SOX9, Aggrecan). After treatment with Exos-Ber, significant induction of β-catenin expression was observed, which could be repressed successfully by adding β-catenin inhibitor XAV-939. Interestingly, the repression of the Wnt/β-catenin axis also resulted in reduced gene expression levels of Collagen II, SOX9, and Aggrecan. These observations indicated that Exos-Ber facilitated the differentiation of chondrogenic BMSCs by modulating the Wnt/β-catenin axis, which offers innovative insights into the reconstruction of cartilage.
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Affiliation(s)
- Bingjiang Dong
- Department of Orthopaedics, The Affiliated Jiangning Hospital with Nanjing Medical University
| | - Xinhui Liu
- Department of Orthopaedics, The Affiliated Jiangning Hospital with Nanjing Medical University
| | - Jiwei Li
- Department of Clinical Laboratory, The Affiliated Jiangning Hospital with Nanjing Medical University
| | - Bin Wang
- Department of Orthopaedics, The Affiliated Jiangning Hospital with Nanjing Medical University
| | - Jian Yin
- Department of Orthopaedics, The Affiliated Jiangning Hospital with Nanjing Medical University
| | - Hailong Zhang
- Department of Orthopaedics, The Affiliated Jiangning Hospital with Nanjing Medical University
| | - Wei Liu
- Department of Orthopaedics, The Affiliated Jiangning Hospital with Nanjing Medical University
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Connection between Mesenchymal Stem Cells Therapy and Osteoclasts in Osteoarthritis. Int J Mol Sci 2022; 23:ijms23094693. [PMID: 35563083 PMCID: PMC9102843 DOI: 10.3390/ijms23094693] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 04/21/2022] [Accepted: 04/22/2022] [Indexed: 12/12/2022] Open
Abstract
The use of mesenchymal stem cells constitutes a promising therapeutic approach, as it has shown beneficial effects in different pathologies. Numerous in vitro, pre-clinical, and, to a lesser extent, clinical trials have been published for osteoarthritis. Osteoarthritis is a type of arthritis that affects diarthritic joints in which the most common and studied effect is cartilage degradation. Nowadays, it is known that osteoarthritis is a disease with a very powerful inflammatory component that affects the subchondral bone and the rest of the tissues that make up the joint. This inflammatory component may induce the differentiation of osteoclasts, the bone-resorbing cells. Subchondral bone degradation has been suggested as a key process in the pathogenesis of osteoarthritis. However, very few published studies directly focus on the activity of mesenchymal stem cells on osteoclasts, contrary to what happens with other cell types of the joint, such as chondrocytes, synoviocytes, and osteoblasts. In this review, we try to gather the published bibliography in relation to the effects of mesenchymal stem cells on osteoclastogenesis. Although we find promising results, we point out the need for further studies that can support mesenchymal stem cells as a therapeutic tool for osteoclasts and their consequences on the osteoarthritic joint.
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30
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Exosomes: A promising therapeutic strategy for intervertebral disc degeneration. Exp Gerontol 2022; 163:111806. [DOI: 10.1016/j.exger.2022.111806] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/25/2022] [Accepted: 04/06/2022] [Indexed: 11/23/2022]
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31
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Zhang Y, Tu B, Sha Q, Qian J. Bone marrow mesenchymal stem cells-derived exosomes suppress miRNA-5189-3p to increase fibroblast-like synoviocyte apoptosis via the BATF2/JAK2/STAT3 signaling pathway. Bioengineered 2022; 13:6767-6780. [PMID: 35246006 PMCID: PMC8973596 DOI: 10.1080/21655979.2022.2045844] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Ankylosing spondylitis (AS) is characterized by inflammation of the sacroiliac joint and the attachment point of the spine. Herein, we aimed to investigate the effect of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on apoptosis of fibroblast-like synoviocytes (FLSs) and explored its molecular mechanism. Exosomes were isolated from BMSCs and verified by transmission electron microscope and nanoparticle tracking analysis. FLSs were isolated and co-incubated with BMSC exosomes. Cell apoptosis was assessed using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis and flow cytometry. The results showed that BMSC exosomes increased apoptosis of FLSs. MiR-5189-3p was downregulated, while basic leucine zipper transcription factor ATF-like 2 (BATF2) was upregulated in FLSs by treatment of BMSC exosomes. As a direct target of miR-5189-3p, BATF2 inactivates the JAK2/STAT3 pathway. MiR-5189-3p suppressed apoptosis of FLSs and BATF2 exerted an opposite effect. In conclusion, BMSCs-derived exosomes suppress miR-5189-3p to facilitate the apoptosis of FLSs via the BATF2/JAK2/STAT3 signaling pathway, which facilitates the understanding of the therapeutic effect of BMSCs on AS and the underlying molecular mechanism.
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Affiliation(s)
- Yiqun Zhang
- Department of Spine Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Bizhi Tu
- Department of Spine Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qi Sha
- Department of Spine Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jun Qian
- Department of Spine Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Morgan M, Thai J, Nazemian V, Song R, Ivanusic JJ. Changes to the activity and sensitivity of nerves innervating subchondral bone contribute to pain in late-stage osteoarthritis. Pain 2022; 163:390-402. [PMID: 34108432 PMCID: PMC8756348 DOI: 10.1097/j.pain.0000000000002355] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/20/2021] [Accepted: 05/07/2021] [Indexed: 11/30/2022]
Abstract
ABSTRACT Although it is clear that osteoarthritis (OA) pain involves activation and/or sensitization of nociceptors that innervate knee joint articular tissues, much less is known about the role of the innervation of surrounding bone. In this study, we used monoiodoacetate (MIA)-induced OA in male rats to test the idea that pain in OA is driven by differential contributions from nerves that innervate knee joint articular tissues vs the surrounding bone. The time-course of pain behavior was assayed using the advanced dynamic weight-bearing device, and histopathology was examined using haematoxylin and eosin histology. Extracellular electrophysiological recordings of knee joint and bone afferent neurons were made early (day 3) and late (day 28) in the pathogenesis of MIA-induced OA. We observed significant changes in the function of knee joint afferent neurons, but not bone afferent neurons, at day 3 when there was histological evidence of inflammation in the joint capsule, but no damage to the articular cartilage or subchondral bone. Changes in the function of bone afferent neurons were only observed at day 28, when there was histological evidence of damage to the articular cartilage and subchondral bone. Our findings suggest that pain early in MIA-induced OA involves activation and sensitization of nerves that innervate the joint capsule but not the underlying subchondral bone, and that pain in late MIA-induced OA involves the additional recruitment of nerves that innervate the subchondral bone. Thus, nerves that innervate bone should be considered important targets for development of mechanism-based therapies to treat pain in late OA.
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Affiliation(s)
- Michael Morgan
- Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia
| | - Jenny Thai
- Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia
| | - Vida Nazemian
- Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia
| | - Richard Song
- Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia
| | - Jason J. Ivanusic
- Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia
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Amsar RM, Wijaya CH, Ana ID, Hidajah AC, Notobroto HB, Kencana Wungu TD, Barlian A. Extracellular vesicles: a promising cell-free therapy for cartilage repair. Future Sci OA 2022; 8:FSO774. [PMID: 35070356 PMCID: PMC8765097 DOI: 10.2144/fsoa-2021-0096] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 11/12/2021] [Indexed: 11/23/2022] Open
Abstract
Few effective therapies for cartilage repair have been found as cartilage has a low regenerative capacity. Extracellular vesicles (EVs), including exosomes, are produced by cells and contain bioactive components such as nucleic acids, proteins, lipids and other metabolites that have potential for treating cartilage injuries. Challenges like the difficulty in standardizing targeted therapy have prevented EVs from being used frequently as a treatment option. In this review we present current studies, mechanisms and delivery strategies of EVs. Additionally, we describe the challenges and future directions of EVs as therapeutic agents for cartilage repair. Repairing cartilage damage is challenging due to the tissue’s low regenerative capacity. Extracellular vesicles (EVs) contain bioactive components that may be able to treat cartilage injuries. However, EV-based therapy is not widely used. This review summarizes the current state of knowledge regarding the use of EVs for cartilage repair, including the mechanisms, delivery strategies, challenges and future directions.
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Affiliation(s)
- Rizka Musdalifah Amsar
- School of Life Science & Technology, Institut Teknologi Bandung, Bandung, West Java, 40132, Indonesia
| | - Christofora Hanny Wijaya
- Department of Food Science & Technology, Bogor Agricultural University, West Java, 16680, Indonesia
| | - Ika Dewi Ana
- Department of Dental Biomedical Sciences, Faculty of Dentistry, Gadjah Mada University, Yogyakarta, 55281, Indonesia
| | - Atik Choirul Hidajah
- Department of Epidemiology Faculty of Public Health, Airlangga University, East Java, 60115, Indonesia
| | - Hari Basuki Notobroto
- Department of Biostatics & Population Faculty of Public Health, Airlangga University, East Java, 60115, Indonesia
| | - Triati Dewi Kencana Wungu
- Nuclear Physics & Biophysics Research Group, Department of Physics, Faculty of Mathematics & Natural Sciences, Institut Teknologi Bandung, West Java, 40132, Indonesia
- Research Center for Nanoscience & Nanotechnology, Institut Teknologi Bandung, West Java, 40132, Indonesia
| | - Anggraini Barlian
- School of Life Science & Technology, Institut Teknologi Bandung, Bandung, West Java, 40132, Indonesia
- Research Center for Nanoscience & Nanotechnology, Institut Teknologi Bandung, West Java, 40132, Indonesia
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Jelodari S, Ebrahimi Sadrabadi A, Zarei F, Jahangir S, Azami M, Sheykhhasan M, Hosseini S. New Insights into Cartilage Tissue Engineering: Improvement of Tissue-Scaffold Integration to Enhance Cartilage Regeneration. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7638245. [PMID: 35118158 PMCID: PMC8807044 DOI: 10.1155/2022/7638245] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/20/2021] [Accepted: 12/29/2021] [Indexed: 02/05/2023]
Abstract
Distinctive characteristics of articular cartilage such as avascularity and low chondrocyte conversion rate present numerous challenges for orthopedists. Tissue engineering is a novel approach that ameliorates the regeneration process by exploiting the potential of cells, biodegradable materials, and growth factors. However, problems exist with the use of tissue-engineered construct, the most important of which is scaffold-cartilage integration. Recently, many attempts have been made to address this challenge via manipulation of cellular, material, and biomolecular composition of engineered tissue. Hence, in this review, we highlight strategies that facilitate cartilage-scaffold integration. Recent advances in where efficient integration between a scaffold and native cartilage could be achieved are emphasized, in addition to the positive aspects and remaining problems that will drive future research.
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Affiliation(s)
- Sahar Jelodari
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amin Ebrahimi Sadrabadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fatemeh Zarei
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | | | - Mahmoud Azami
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Sheykhhasan
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Samaneh Hosseini
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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35
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Yin B, Ni J, Witherel CE, Yang M, Burdick JA, Wen C, Wong SHD. Harnessing Tissue-derived Extracellular Vesicles for Osteoarthritis Theranostics. Theranostics 2022; 12:207-231. [PMID: 34987642 PMCID: PMC8690930 DOI: 10.7150/thno.62708] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a prevalent chronic whole-joint disease characterized by low-grade systemic inflammation, degeneration of joint-related tissues such as articular cartilage, and alteration of bone structures that can eventually lead to disability. Emerging evidence has indicated that synovium or articular cartilage-secreted extracellular vesicles (EVs) contribute to OA pathogenesis and physiology, including transporting and enhancing the production of inflammatory mediators and cartilage degrading proteinases. Bioactive components of EVs are known to play a role in OA include microRNA, long non-coding RNA, and proteins. Thus, OA tissues-derived EVs can be used in combination with advanced nanomaterial-based biosensors for the diagnostic assessment of OA progression. Alternatively, mesenchymal stem cell- or platelet-rich plasma-derived EVs (MSC-EVs or PRP-EVs) have high therapeutic value for treating OA, such as suppressing the inflammatory immune microenvironment, which is often enriched by pro-inflammatory immune cells and cytokines that reduce chondrocytes apoptosis. Moreover, those EVs can be modified or incorporated into biomaterials for enhanced targeting and prolonged retention to treat OA effectively. In this review, we explore recently reported OA-related pathological biomarkers from OA joint tissue-derived EVs and discuss the possibility of current biosensors for detecting EVs and EV-related OA biomarkers. We summarize the applications of MSC-EVs and PRP-EVs and discuss their limitations for cartilage regeneration and alleviating OA symptoms. Additionally, we identify advanced therapeutic strategies, including engineered EVs and applying biomaterials to increase the efficacy of EV-based OA therapies. Finally, we provide our perspective on the future of EV-related diagnosis and therapeutic potential for OA treatment.
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Affiliation(s)
- Bohan Yin
- Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hong Kong, 999077, China
| | - Junguo Ni
- Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hong Kong, 999077, China
| | | | - Mo Yang
- Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hong Kong, 999077, China
| | - Jason A. Burdick
- Department of Bioengineering, University of Pennsylvania, PA 16802, USA.,✉ Corresponding authors: Jason A. Burdick: . Chunyi Wen: . Siu Hong Dexter Wong:
| | - Chunyi Wen
- Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hong Kong, 999077, China.,Research Institute of Smart Ageing, the Hong Kong Polytechnic University, Hong Kong, 999077, China.,✉ Corresponding authors: Jason A. Burdick: . Chunyi Wen: . Siu Hong Dexter Wong:
| | - Siu Hong Dexter Wong
- Department of Biomedical Engineering, the Hong Kong Polytechnic University, Hong Kong, 999077, China.,✉ Corresponding authors: Jason A. Burdick: . Chunyi Wen: . Siu Hong Dexter Wong:
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36
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Jeyaraman M, Muthu S, Gulati A, Jeyaraman N, G.S P, Jain R. Mesenchymal Stem Cell-Derived Exosomes: A Potential Therapeutic Avenue in Knee Osteoarthritis. Cartilage 2021; 13:1572S-1585S. [PMID: 33016114 PMCID: PMC8808857 DOI: 10.1177/1947603520962567] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Knee osteoarthritis is the leading cause of functional disability in adults. The goals of knee osteoarthritis management are directed toward symptomatic pain relief along with the attainment of the functional quality of life. The treatment strategy ranges from conservative to surgical management with reparative and restorative techniques. The emergence of cell-based therapies has paved the way for the usage of mesenchymal stem cells (MSCs) in cartilage disorders. Currently, global researchers are keen on their research on nanomedicine and targeted drug delivery. MSC-derived exosomes act as a directed therapy to halt the disease progression and to provide a pain-free range of movements with increased quality of cartilage on regeneration. International Society for Extracellular Vesicles and the European Network on Microvesicles and Exosomes in Health and Disease have formed guidelines to foster the use of the growing therapeutic potential of exosomal therapy in osteoarthritis. Although regenerative therapies with MSC are being seen to hold a future in the management of osteoarthritis, extracellular vesicle-based technology holds the key to unlock the potential toward knee preservation and regeneration. The intricate composition and uncertain functioning of exosomes are inquisitive facets warranting further exploration.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopedics, School of
Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh,
India
| | - Sathish Muthu
- Government Hospital, Velayuthampalayam,
Karur, Tamil Nadu, India
| | - Arun Gulati
- Kalpana Chawla Government Medical
College, Karnal, Haryana, India
| | | | - Prajwal G.S
- JJM Medical College, Davangere,
Karnataka, India
| | - Rashmi Jain
- School of Medical Sciences and Research,
Sharda University, Greater Noida, Uttar Pradesh, India
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37
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Liu Y, Zhang S, Xue Z, Zhou X, Tong L, Liao J, Pan H, Zhou S. Bone mesenchymal stem cells-derived miR-223-3p-containing exosomes ameliorate lipopolysaccharide-induced acute uterine injury via interacting with endothelial progenitor cells. Bioengineered 2021; 12:10654-10665. [PMID: 34738867 PMCID: PMC8810142 DOI: 10.1080/21655979.2021.2001185] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022] Open
Abstract
Bone mesenchymal stem cells (BMSCs) have been used for the treatment of acute uterine injury (AUI)-induced intrauterine adhesion (IUA) via interacting with the endothelial progenitor cells (EPCs), and BMSCs-derived exosomes (BMSCs-exo) may be the key regulators for this process. However, the underlying mechanisms have not been studied. Based on the existed literatures, lipopolysaccharide (LPS) was used to induce AUI in mice models and EPCs to mimic the realistic pathogenesis of IUA in vivo and in vitro. Our data suggested that LPS induced apoptotic and pyroptotic cell death in mice uterine horn tissues and EPCs, and the clinical data supported that increased levels of pro-inflammatory cytokines IL-18 and IL-1β were also observed in IUA patients' serum samples, and silencing of NLRP3 rescued cell viability in LPS-treated EPCs. Next, the LPS-treated EPCs were respectively co-cultured with BMSCs in the Transwell system and BMSCs-exo, and the results hinted that both BMSCs and BMSCs-exo reversed the promoting effects of LPS treatment-induced cell death in EPCs. Then, we screened out miR-223-3p, as the upstream regulator for NLRP3, was enriched in BMSCs-exo, and BMSCs-exo inactivated NLRP3-mediated cell pyroptosis in EPCs via delivering miR-223-3p. Interestingly, upregulation of miR-223-3p attenuated LPS-induced cell death in EPCs. Collectively, we concluded that BMSCs-exo upregulated miR-223-3p to degrade NLRP3 in EPCs, which further reversed the cytotoxic effects of LPS treatment on EPCs to ameliorate LPS-induced AUI.
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Affiliation(s)
- Yana Liu
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetric and Gynecologic and Pediatric Disease and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichaun, China
| | - Shihong Zhang
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetric and Gynecologic and Pediatric Disease and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichaun, China
| | - Zhiwei Xue
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetric and Gynecologic and Pediatric Disease and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichaun, China
| | - Xiaoxia Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetric and Gynecologic and Pediatric Disease and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichaun, China
| | - Lin Tong
- Department of Obstetrics and Gynecology, Minerva Hospital for Women and Children, Chengdu, Sichuan, China
| | - Jiachen Liao
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetric and Gynecologic and Pediatric Disease and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichaun, China
| | - Huan Pan
- Department of Obstetrics and Gynecology, Chengdu Second People’s Hospital, Chengdu, Sichuan, China
| | - Shu Zhou
- Department of Obstetrics and Gynecology, Key Laboratory of Obstetric and Gynecologic and Pediatric Disease and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichaun, China
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Zhou YK, Patel HH, Roth DM. Extracellular Vesicles: A New Paradigm for Cellular Communication in Perioperative Medicine, Critical Care, and Pain Management. Anesth Analg 2021; 133:1162-1179. [PMID: 34304233 PMCID: PMC8542619 DOI: 10.1213/ane.0000000000005655] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Extracellular vesicles (EVs) play critical roles in many health and disease states, including ischemia, inflammation, and pain, which are major concerns in the perioperative period and in critically ill patients. EVs are functionally active, nanometer-sized, membrane-bound vesicles actively secreted by all cells. Cell signaling is essential to physiological and pathological processes, and EVs have recently emerged as key players in intercellular communication. Recent studies in EV biology have improved our mechanistic knowledge of the pathophysiological processes in perioperative and critical care patients. Studies also show promise in using EVs in novel diagnostic and therapeutic clinical applications. This review considers the current advances and gaps in knowledge of EVs in the areas of ischemia, inflammation, pain, and in organ systems that are most relevant to anesthesiology, perioperative medicine, critical care, and pain management. We expect the reader will better understand the relationship between EVs and perioperative and critical care pathophysiological states and their potential use as novel diagnostic and therapeutic modalities.
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Affiliation(s)
- Yingqiu K. Zhou
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
| | - Hemal H. Patel
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
| | - David M. Roth
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA and Department of Anesthesiology, UCSD School of Medicine, San Diego, CA, USA
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Nguyen TH, Duong CM, Nguyen XH, Than UTT. Mesenchymal Stem Cell-Derived Extracellular Vesicles for Osteoarthritis Treatment: Extracellular Matrix Protection, Chondrocyte and Osteocyte Physiology, Pain and Inflammation Management. Cells 2021; 10:2887. [PMID: 34831109 PMCID: PMC8616200 DOI: 10.3390/cells10112887] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/22/2021] [Accepted: 10/24/2021] [Indexed: 12/11/2022] Open
Abstract
Osteoarthritis (OA) is a common degenerative disease that can lead to persistent pain and motion restriction. In the last decade, stem cells, particularly mesenchymal stem cells (MSCs), have been explored as a potential alternative OA therapy due to their regenerative capacity. Furthermore, it has been shown that trophic factors enveloped in extracellular vesicles (EVs), including exosomes, are a crucial aspect of MSC-based treatment for OA. Evidently, EVs derived from different MSC sources might rescue the OA phenotype by targeting many biological processes associated with cartilage extracellular matrix (ECM) degradation and exerting protective effects on different joint cell types. Despite this advancement, different studies employing EV treatment for OA have revealed reverse outcomes depending on the EV cargo, cell source, and pathological condition. Hence, in this review, we aim to summarize and discuss the possible effects of MSC-derived EVs based on recent findings at different stages of OA development, including effects on cartilage ECM, chondrocyte biology, osteocytes and bone homeostasis, inflammation, and pain management. Additionally, we discuss further strategies and technical advances for manipulating EVs to specifically target OA to bring the therapy closer to clinical use.
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Affiliation(s)
- Thu Huyen Nguyen
- Department of Bioscience, University of Milan, 20133 Milan, Italy;
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi 100000, Vietnam; (C.M.D.); (X.-H.N.)
| | - Chau Minh Duong
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi 100000, Vietnam; (C.M.D.); (X.-H.N.)
- Department of Biology, Clark University, Worcester, MA 01610, USA
| | - Xuan-Hung Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi 100000, Vietnam; (C.M.D.); (X.-H.N.)
- Vinmec Research Institute of Applied Sciences and Regenerative Medicine, Vinmec Healthcare System, Hanoi 100000, Vietnam
- College of Health Sciences, VinUniversity, Hanoi 100000, Vietnam
| | - Uyen Thi Trang Than
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi 100000, Vietnam; (C.M.D.); (X.-H.N.)
- Vinmec Research Institute of Applied Sciences and Regenerative Medicine, Vinmec Healthcare System, Hanoi 100000, Vietnam
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40
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Liu Z, Wang B, Guo Q. MiR-26b-5p-modified hUB-MSCs derived exosomes attenuate early brain injury during subarachnoid hemorrhage via MAT2A-mediated the p38 MAPK/STAT3 signaling pathway. Brain Res Bull 2021; 175:107-115. [PMID: 34284075 DOI: 10.1016/j.brainresbull.2021.07.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/25/2021] [Accepted: 07/15/2021] [Indexed: 01/03/2023]
Abstract
Early brain injury (EBI) is a major cause of adverse outcomes following subarachnoid hemorrhage (SAH). There is evidence that mesenchymal stem cells (MSCs) - derived exosomes are involved in the repair of SAH. Exosomes were extracted from human umbilical cord mesenchymal stem cells (hubMSCs) and identified. OxyHb treated PC12 cells were transfected with exosomes alone or together with miR-26b-5p inhibitor. Hub-MSCs derived exosomes promote cell proliferation, inhibit apoptosis and reduce inflammatory mediator expression. Transfection of miR-26b-5p inhibitor abolished the promoting effect of exosomes on the proliferation of PC12 cells, as well as the inhibitory effect on cell apoptosis. In addition, methionine adenosyltransferase II alpha (MAT2A) was one target gene of miR-26b-5p. OxyHb treated PC12 cells were transfected with exosomes alone or together with pcDNA-MAT2A and observed that the promoting effect of exosomes on PC12 cell proliferation was abolished by pcDNA-MAT2A, which was the same as the effect of miR-26b-5p inhibitor. OxyHb treated PC cells incubated with exosomes were transfected with miR-26b-5p inhibitor alone or together with si-MAT2A, respectively, and it was observed that exosomes decreased the phosphorylation levels of p38 MAPK and STAT3 proteins, inhibited cell apoptosis and inflammatory mediator expression, and miR-26b-5p inhibitor abrogated the effects of exosomes, while transfection of si-MAT2A reversed the effects of miR-26b-5p inhibitor. Moreover, injection of miR-26b-5p inhibitor resulted in increased MAT2A and pathway protein expression, increased inflammatory mediators, and aggravated neurological symptoms in the brain tissues of SAH rats.
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Affiliation(s)
- Zunwei Liu
- Department of Renal Transplantation, Nephropathy Hospital, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Bo Wang
- Center for Brain Science, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Qihang Guo
- Department of Renal Transplantation, Nephropathy Hospital, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
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41
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Li Z, Huang Z, Bai L. Cell Interplay in Osteoarthritis. Front Cell Dev Biol 2021; 9:720477. [PMID: 34414194 PMCID: PMC8369508 DOI: 10.3389/fcell.2021.720477] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/14/2021] [Indexed: 01/15/2023] Open
Abstract
Osteoarthritis (OA) is a common chronic disease and a significant health concern that needs to be urgently solved. OA affects the cartilage and entire joint tissues, including the subchondral bone, synovium, and infrapatellar fat pads. The physiological and pathological changes in these tissues affect the occurrence and development of OA. Understanding complex crosstalk among different joint tissues and their roles in OA initiation and progression is critical in elucidating the pathogenic mechanism of OA. In this review, we begin with an overview of the role of chondrocytes, synovial cells (synovial fibroblasts and macrophages), mast cells, osteoblasts, osteoclasts, various stem cells, and engineered cells (induced pluripotent stem cells) in OA pathogenesis. Then, we discuss the various mechanisms by which these cells communicate, including paracrine signaling, local microenvironment, co-culture, extracellular vesicles (exosomes), and cell tissue engineering. We particularly focus on the therapeutic potential and clinical applications of stem cell-derived extracellular vesicles, which serve as modulators of cell-to-cell communication, in the field of regenerative medicine, such as cartilage repair. Finally, the challenges and limitations related to exosome-based treatment for OA are discussed. This article provides a comprehensive summary of key cells that might be targets of future therapies for OA.
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Affiliation(s)
- Zihao Li
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ziyu Huang
- Foreign Languages College, Shanghai Normal University, Shanghai, China
| | - Lunhao Bai
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
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42
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Lin J, Wang L, Lin J, Liu Q. The Role of Extracellular Vesicles in the Pathogenesis, Diagnosis, and Treatment of Osteoarthritis. Molecules 2021; 26:4987. [PMID: 34443573 PMCID: PMC8398019 DOI: 10.3390/molecules26164987] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 08/10/2021] [Accepted: 08/14/2021] [Indexed: 02/08/2023] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease that affects the entire joint and has been a tremendous burden on the health care system worldwide. Although cell therapy has made significant progress in the treatment of OA and cartilage regeneration, there are still a series of problems. Recently, more and more evidence shows that extracellular vesicles (EVs) play an important role in the progression and treatment of OA. Here, we discuss that EVs from different cell sources not only participate in OA progression, but can also be used as effective tools for the diagnosis and treatment of OA. In addition, cell pretreatment strategies and EV tissue engineering play an increasingly prominent role in the field of OA treatment. This article will systematically review the latest developments in these areas. As stated above, it may provide new insights for improving OA and cartilage regeneration.
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Affiliation(s)
- Jianjing Lin
- Arthritis Clinical and Research Center, Peking University People’s Hospital, No. 11 Xizhimen South Street, Beijing 100044, China; (J.L.); (J.L.)
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Li Wang
- Department of Biomedical Engineering, College of Engineering, Peking University, Beijing 100871, China;
| | - Jianhao Lin
- Arthritis Clinical and Research Center, Peking University People’s Hospital, No. 11 Xizhimen South Street, Beijing 100044, China; (J.L.); (J.L.)
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Qiang Liu
- Arthritis Clinical and Research Center, Peking University People’s Hospital, No. 11 Xizhimen South Street, Beijing 100044, China; (J.L.); (J.L.)
- Arthritis Institute, Peking University, Beijing 100044, China
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43
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Qiao K, Chen Q, Cao Y, Li J, Xu G, Liu J, Cui X, Tian K, Zhang W. Diagnostic and Therapeutic Role of Extracellular Vesicles in Articular Cartilage Lesions and Degenerative Joint Diseases. Front Bioeng Biotechnol 2021; 9:698614. [PMID: 34422779 PMCID: PMC8371972 DOI: 10.3389/fbioe.2021.698614] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/28/2021] [Indexed: 01/15/2023] Open
Abstract
Two leading contributors to the global disability are cartilage lesions and degenerative joint diseases, which are characterized by the progressive cartilage destruction. Current clinical treatments often fail due to variable outcomes and an unsatisfactory long-term repair. Cell-based therapies were once considered as an effective solution because of their anti-inflammatory and immunosuppression characteristics as well as their differentiation capacity to regenerate the damaged tissue. However, stem cell-based therapies have inherent limitations, such as a high tumorigenicity risk, a low retention, and an engraftment rate, as well as strict regulatory requirements, which result in an underwhelming therapeutic effect. Therefore, the non-stem cell-based therapy has gained its popularity in recent years. Extracellular vesicles (EVs), in particular, like the paracrine factors secreted by stem cells, have been proven to play a role in mediating the biological functions of target cells, and can achieve the therapeutic effect similar to stem cells in cartilage tissue engineering. Therefore, a comprehensive review of the therapeutic role of EVs in cartilage lesions and degenerative joint diseases can be discussed both in terms of time and favorability. In this review, we summarized the physiological environment of a joint and its pathological alteration after trauma and consequent changes in EVs, which are lacking in the current literature studies. In addition, we covered the potential working mechanism of EVs in the repair of the cartilage and the joint and also discussed the potential therapeutic applications of EVs in future clinical use.
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Affiliation(s)
- Kai Qiao
- First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Qi Chen
- First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yiguo Cao
- First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Jie Li
- First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Gang Xu
- First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Jiaqing Liu
- Qingdao University of Science and Technology, Qingdao, China
| | - Xiaolin Cui
- First Affiliated Hospital, Dalian Medical University, Dalian, China
- Department of Orthopaedic Surgery and Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
| | - Kang Tian
- First Affiliated Hospital, Dalian Medical University, Dalian, China
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Weiguo Zhang
- First Affiliated Hospital, Dalian Medical University, Dalian, China
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44
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Cata JP, Uhelski ML, Gorur A, Dougherty PM. Nociception and Pain: New Roles for Exosomes. Neuroscientist 2021; 28:349-363. [PMID: 34166130 DOI: 10.1177/10738584211027105] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The interchange of information from one cell to another relies on the release of hundreds of different molecules including small peptides, amino acids, nucleotides, RNA, steroids, retinoids, or fatty acid metabolites. Many of them are released to the extracellular matrix as free molecules and others can be part of the cargo of cellular vesicles. Small extracellular vesicles (30-150 nm), also known as exosomes, are a known mechanism of cell-to-cell communication in the nervous system. Exosomes participate in the pathogenesis of several neurological conditions including Alzheimer's and Parkinson's disease. However, exciting emerging evidence demonstrates that exosomes also regulate mechanisms of the sensory process including nociception. The goal of this review is to summarize the literature on exosome biogenesis, methods of small vesicle isolation and purification, and their role in nociception. We also provide insights on the potential applications of exosomes as pain biomarkers or as novel therapeutics.
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Affiliation(s)
- Juan P Cata
- Department of Anesthesiology and Perioperative Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.,Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA
| | - Megan L Uhelski
- Department of Pain Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA
| | - Aysegul Gorur
- Department of Anesthesiology and Perioperative Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA.,Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA
| | - Patrick M Dougherty
- Department of Pain Medicine, The University of Texas-MD Anderson Cancer Center, Houston, TX, USA
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Huang Y, Zhang X, Zhan J, Yan Z, Chen D, Xue X, Pan X. Bone marrow mesenchymal stem cell-derived exosomal miR-206 promotes osteoblast proliferation and differentiation in osteoarthritis by reducing Elf3. J Cell Mol Med 2021; 25:7734-7745. [PMID: 34160894 PMCID: PMC8358849 DOI: 10.1111/jcmm.16654] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/28/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) serve as gene silencers involved in essential cell functions. The role of miR‐206 and E74‐like factor 3 (Elf3) has been identified in osteoarthritis (OA), while the effect of exosomal miR‐206 from bone marrow mesenchymal stem cells (BMSCs) in OA remains largely unknown. Thus, we aim to explore the role of exosomal miR‐206 from BMSCs in OA with the involvement of Elf3. BMSCs and BMSC‐derived exosomes (BMSC‐exos) were obtained and identified. OA mouse models were constructed by anterior cruciate ligament transection and then treated with BMSC‐exos or BMSC‐exos containing miR‐206 mimic/inhibitor. The expression of miR‐206, Elf3, inflammatory factors, osteocalcin (OCN) and bone morphogenetic protein 2 (BMP2) in mouse femoral tissues was assessed. The pathological changes in mouse femur tissues were observed. The mouse osteoblasts were identified and treated with untransfected or transfected BMSC‐exos, and then, the expression of miR‐206, Elf3, OCN and BMP2 was determined. The alkaline phosphatase (ALP) activity, calcium deposition level, OCN secretion, proliferation, apoptosis and cell cycle arrest in osteoblasts were measured. MiR‐206 was down‐regulated while Elf3 was up‐regulated in OA animal and cellular models. Exosomal miR‐206 ameliorated inflammation and increased expression of OCN and BMP2 in mouse femoral tissues. Moreover, exosomal miR‐206 promoted ALP activity, calcium deposition level, OCN secretion and proliferation and inhibited apoptosis in OA osteoblasts. Overexpressed Elf3 reversed miR‐206 up‐regulation‐induced effects on OA osteoblasts. BMSC‐derived exosomal miR‐206 promotes proliferation and differentiation of osteoblasts in OA by reducing Elf3. Our research may provide novel targets for OA treatment.
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Affiliation(s)
- Yijiang Huang
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China
| | - Xiumeng Zhang
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China
| | - Jingdi Zhan
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China
| | - Zijiang Yan
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China
| | - Daosen Chen
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China
| | - Xinghe Xue
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China
| | - Xiaoyun Pan
- Department of Orthopaedic, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China
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46
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Zhang B, Tian X, Qu Z, Liu J, Yang L, Zhang W. Efficacy of extracellular vesicles from mesenchymal stem cells on osteoarthritis in animal models: a systematic review and meta-analysis. Nanomedicine (Lond) 2021; 16:1297-1310. [PMID: 34044578 DOI: 10.2217/nnm-2021-0047] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background: Some studies have reported results from the use of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) to treat osteoarthritis (OA). Objective: To evaluate the efficacy of MSC-EVs as a treatment for OA. Data sources: Databases were searched using the terms 'mesenchymal stem cells', 'osteoarthritis' and 'extracellular vesicles.' Study eligibility criteria: Studies performed in animal models utilizing MSC-EVs to treat OA that described the macroscopic evaluation or histological evaluation were included. Study appraisal: The quality of the studies was examined using the CAMARADES quality checklist. Results: MSC-EVs were superior to the placebo in the macroscopic evaluation and histological evaluation. MSC-EVs were more effective in the early stage of OA and once a week was better than multiple times a week. Limitations: The included studies were highly heterogeneous. Conclusion: MSC-EVs may improve the results of macroscopic and histological evaluations of OA.
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Affiliation(s)
- Bocheng Zhang
- Department of Orthopaedics, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116000, China.,Graduate School, Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Xiaoyuan Tian
- Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116000, China.,Graduate School, Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Zhenan Qu
- Orthopedics IV, Affiliated Zhongshan Hospital of Dalian University, Liaoning, 116000, China
| | - Jiaming Liu
- Graduate School, Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Liang Yang
- Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Weiguo Zhang
- Department of Orthopaedics, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116000, China.,Graduate School, Dalian Medical University, Dalian, Liaoning, 116000, China
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47
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Miao C, Zhou W, Wang X, Fang J. The Research Progress of Exosomes in Osteoarthritis, With Particular Emphasis on the Mediating Roles of miRNAs and lncRNAs. Front Pharmacol 2021; 12:685623. [PMID: 34093208 PMCID: PMC8176107 DOI: 10.3389/fphar.2021.685623] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/10/2021] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a kind of degenerative disease, which is caused by many factors such as aging, obesity, strain, trauma, congenital joint abnormalities, joint deformities. Exosomes are mainly derived from the invagination of intracellular lysosomes, which are released into the extracellular matrix after fusion of the outer membrane of multi vesicles with the cell membrane. Exosomes mediate intercellular communication and regulate the biological activity of receptor cells by carrying non-coding RNA, long noncoding RNAs (lncRNAs), microRNAs (miRNAs), proteins and lipids. Evidences show that exosomes are involved in the pathogenesis of OA. In view of the important roles of exosomes in OA, this paper systematically reviewed the roles of exosomes in the pathogenesis of OA, including the roles of exosomes in OA diagnosis, the regulatory mechanisms of exosomes in the pathogenesis, and the intervention roles of exosomes in the treatment of OA. Reviewing the roles of exosomes in OA will help to clarify the pathogenesis of OA and explore new diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Chenggui Miao
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.,Department of Pharmacy, School of Life and Health Sciences, Anhui University of Science and Technology, Fengyang, China.,Institute of Prevention and Treatment of Rheumatoid Arthritis of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Wanwan Zhou
- Department of Pharmacology, School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Xiao Wang
- Department of Clinical Nursing, School of Nursing, Anhui University of Chinese Medicine, Hefei, China
| | - Jihong Fang
- Department of Nursing, Anhui Provincial Children's Hospital, Affiliated to Anhui Medical University, Hefei, China.,Department of Orthopedics, Anhui Provincial Children's Hospital, Affiliated to Anhui Medical University, Hefei, China
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48
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Mustonen AM, Nieminen P. Extracellular Vesicles and Their Potential Significance in the Pathogenesis and Treatment of Osteoarthritis. Pharmaceuticals (Basel) 2021; 14:ph14040315. [PMID: 33915903 PMCID: PMC8065796 DOI: 10.3390/ph14040315] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/18/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is a chronic joint disease characterized by inflammation, gradual destruction of articular cartilage, joint pain, and functional limitations that eventually lead to disability. Join tissues, including synovium and articular cartilage, release extracellular vesicles (EVs) that have been proposed to sustain joint homeostasis as well as to contribute to OA pathogenesis. EVs transport biologically active molecules, and OA can be characterized by altered EV counts and composition in synovial fluid. Of EV cargo, specific non-coding RNAs could have future potential as diagnostic biomarkers for early OA. EVs may contribute to the propagation of inflammation and cartilage destruction by transporting and enhancing the production of inflammatory mediators and cartilage-degrading proteinases. In addition to inducing OA-related gene expression patterns in synoviocytes and articular chondrocytes, EVs can induce anti-OA effects, including increased extracellular matrix deposition and cartilage protection. Especially mesenchymal stem cell-derived EVs can alleviate intra-articular inflammation and relieve OA pain. In addition, surgically- or chemically-induced cartilage defects have been repaired with EV therapies in animal models. While human clinical trials are still in the future, the potential of actual cures to OA by EV products is very promising.
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Affiliation(s)
- Anne-Mari Mustonen
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland;
- Department of Environmental and Biological Sciences, Faculty of Science and Forestry, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland
- Correspondence: ; Tel.: +358-294-45-1111
| | - Petteri Nieminen
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland;
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49
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Wan Q, Qin W, Ma Y, Shen M, Li J, Zhang Z, Chen J, Tay FR, Niu L, Jiao K. Crosstalk between Bone and Nerves within Bone. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003390. [PMID: 33854888 PMCID: PMC8025013 DOI: 10.1002/advs.202003390] [Citation(s) in RCA: 112] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/29/2020] [Indexed: 05/11/2023]
Abstract
For the past two decades, the function of intrabony nerves on bone has been a subject of intense research, while the function of bone on intrabony nerves is still hidden in the corner. In the present review, the possible crosstalk between bone and intrabony peripheral nerves will be comprehensively analyzed. Peripheral nerves participate in bone development and repair via a host of signals generated through the secretion of neurotransmitters, neuropeptides, axon guidance factors and neurotrophins, with additional contribution from nerve-resident cells. In return, bone contributes to this microenvironmental rendezvous by housing the nerves within its internal milieu to provide mechanical support and a protective shelf. A large ensemble of chemical, mechanical, and electrical cues works in harmony with bone marrow stromal cells in the regulation of intrabony nerves. The crosstalk between bone and nerves is not limited to the physiological state, but also involved in various bone diseases including osteoporosis, osteoarthritis, heterotopic ossification, psychological stress-related bone abnormalities, and bone related tumors. This crosstalk may be harnessed in the design of tissue engineering scaffolds for repair of bone defects or be targeted for treatment of diseases related to bone and peripheral nerves.
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Affiliation(s)
- Qian‐Qian Wan
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Wen‐Pin Qin
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Yu‐Xuan Ma
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Min‐Juan Shen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Jing Li
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Zi‐Bin Zhang
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Ji‐Hua Chen
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Franklin R. Tay
- College of Graduate StudiesAugusta UniversityAugustaGA30912USA
| | - Li‐Na Niu
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
| | - Kai Jiao
- State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of StomatologyDepartment of ProsthodonticsSchool of StomatologyThe Fourth Military Medical UniversityXi'anShaanxi710032China
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Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions. Int J Mol Sci 2021; 22:ijms22063023. [PMID: 33809632 PMCID: PMC8002312 DOI: 10.3390/ijms22063023] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 03/06/2021] [Accepted: 03/12/2021] [Indexed: 12/14/2022] Open
Abstract
Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer's disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed.
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