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Akhlaghpasand M, Tavanaei R, Allameh F, Hosseinpoor M, Toreyhi H, Golmohammadi M, Hajarizadeh A, Alikhani A, Hafizi M, Oraee-Yazdani M, Zali A, Oraee-Yazdani S. Improvement of Neurogenic Bladder Dysfunction Following Combined Cell Therapy with Mesenchymal Stem Cell and Schwann Cell in Spinal Cord Injury: A Randomized, Open-Label, Phase II Clinical Trial. World Neurosurg 2025; 194:123402. [PMID: 39522809 DOI: 10.1016/j.wneu.2024.10.131] [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: 10/20/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
OBJECTIVE To investigate the efficacy of intrathecal combined administration of autologous bone marrow-derived mesenchymal stem cells (BMSCs) and Schwann cells (SCs) in urinary function improvement in complete spinal cord injury (SCI) patients for the first time. METHODS This study was a randomized phase II clinical trial, including treatment and control arms. Patients with traumatic complete SCI-induced neurogenic bladder were included. The treatment group received a single intrathecal combined injection of autologous BMSCs and SCs. The control group underwent no additional intervention. The outcome measures of the study were urodynamic study parameters, number of incontinence and urinary tract infection episodes, incontinence quality of life questionnaire, functional status, and sensorimotor improvements. RESULTS Among a total of 32 recruited patients, 13 and 16 were completely followed up in the treatment and control group, respectively. Changes in bladder compliance (P = 0.032), maximum pressure of detrusor during the filling phase (P = 0.013), maximum pressure of detrusor at the maximum urinary flow rate (P = 0.020), maximum urinary flow rate (P = 0.001), and postvoid residual volume (P = 0.001) after 6 months were significantly different between the 2 groups. The number of urinary incontinence episodes (P = 0.022) significantly reduced in the treatment group after 6 months compared with the baseline. The incontinence quality of life total and domain scores significantly improved in the treatment group compared with the control group after 6 months. CONCLUSIONS The combined intrathecal administration of BMSCs and SCs significantly improved the urodynamic study parameters, urinary incontinence rate, and incontinence quality of life in complete SCI-induced neurogenic bladder.
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Affiliation(s)
- Mohammadhosein Akhlaghpasand
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roozbeh Tavanaei
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Allameh
- Men's Health and Reproductive Health Research Center (IRHRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maede Hosseinpoor
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Toreyhi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Golmohammadi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Hajarizadeh
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Alikhani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Hafizi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Oraee-Yazdani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Davoudi-Monfared E, Abolghasemi R, Allahyari F, Farzanegan G. Adverse events of cell therapy clinical trials in human chronic spinal cord injury, a systematic review and meta-analysis. Regen Ther 2024; 27:381-397. [PMID: 38694447 PMCID: PMC11061649 DOI: 10.1016/j.reth.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/10/2024] [Accepted: 03/15/2024] [Indexed: 05/04/2024] Open
Abstract
Spinal cord injury is a lesion with high mortality and significant morbidities. After the primary injury, during six months, a cascade of secondary cellular and molecular events makes the lesion chronic. Recently, cell-based clinical trials as a new procedure have been gradually tested to improve the symptoms of patients. Each treatment method is associated with different adverse events. Based on the PRISMA flow diagram of the identified records, and after multistep screening, finally in 76 reviewed studies with 1633 cases and 189 controls, 64 types of adverse events in 12 categories were recorded in 45 studies. The most common adverse events were transient backache and meningism (90%) and cord malacia (80%). The cell therapy method in which the treatment was associated with more adverse events was Olfactory ensheathing cell and bone marrow mesenchymal stem cell combination therapy in 55%, and the adverse events were less with the embryonic stem cell in 2.33% of patients. In a meta-analysis, the total prevalence of adverse events in cell therapy was 19% and the highest pulled effect size belonged to urinary tract and localized adverse events. Also, the total prevalence of adverse events in 14 cell therapy methods was 18% and four cell types (neural stem cell, bone marrow hematopoietic stem cell, embryonic stem cell, and umbilical cord mesenchymal stem cell) had the most effect. None of the adverse events were reported on the 4 (life-threatening consequences) and 5 (death) grading scales. We concluded that the frequency of life-threatening adverse events following cell therapy clinical trials in chronic spinal cord injury patients is very scarce and can be ignored.
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Affiliation(s)
- Esmat Davoudi-Monfared
- Health Management Research Center & Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Reyhaneh Abolghasemi
- New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Fakhri Allahyari
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Gholamreza Farzanegan
- Trauma Research Center & Department of Neurosurgery, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Ralph PC, Choi SW, Baek MJ, Lee SJ. Regenerative medicine approaches for the treatment of spinal cord injuries: Progress and challenges. Acta Biomater 2024; 189:57-72. [PMID: 39424019 DOI: 10.1016/j.actbio.2024.10.021] [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: 07/01/2024] [Revised: 10/03/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Spinal cord injury (SCI) is a profound medical condition that significantly hampers motor function, imposing substantial limitations on daily activities and exerting a considerable financial burden on patients and their families. The constrained regenerative capacity of endogenous spinal cord tissue, exacerbated by the inflammatory response following the initial trauma, poses a formidable obstacle to effective therapy. Recent advancements in the field, stem cells, biomaterials, and molecular therapy, show promising outcomes. This review provides a comprehensive analysis of tissue engineering and regenerative medicine approaches for SCI treatment, including cell transplantation, tissue-engineered construct implantation, and other potential therapeutic strategies. Additionally, it sheds light on preclinical animal studies and recent clinical trials incorporating these modalities, providing a glimpse into the evolving landscape of SCI management. STATEMENT OF SIGNIFICANCE: The investigation into spinal cord injury (SCI) treatments focuses on reducing long-term impacts by targeting scar inhibition and enhancing regeneration through stem cells, with or without growth factors. Induced pluripotent stem cells (iPSCs) show promise for autologous use, with clinical trials confirming their safety. Challenges include low cell viability and difficulty in targeted differentiation. Biomaterial scaffolds hold potential for improving cell viability and integration, and extracellular vesicles (EVs) are emerging as a novel therapy. While EV research is in its early stages, stem cell trials demonstrate safety and potential recovery. Advancing tissue engineering approaches with biomaterial scaffolds is crucial for human trials.
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Affiliation(s)
- Patrick C Ralph
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States
| | - Sung-Woo Choi
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States; Department of Orthopedic Surgery, Soonchunhyang University Hospital Seoul, Seoul 04401, Republic of Korea
| | - Min Jung Baek
- Department of Obstetrics and Gynecology, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do 13496, Republic of Korea
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States.
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Liu Y, Zhao C, Zhang R, Pang Y, Li L, Feng S. Progression of mesenchymal stem cell regulation on imbalanced microenvironment after spinal cord injury. Stem Cell Res Ther 2024; 15:343. [PMID: 39354635 PMCID: PMC11446099 DOI: 10.1186/s13287-024-03914-x] [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: 04/27/2024] [Accepted: 09/01/2024] [Indexed: 10/03/2024] Open
Abstract
Spinal cord injury (SCI) results in significant neural damage and inhibition of axonal regeneration due to an imbalanced microenvironment. Extensive evidence supports the efficacy of mesenchymal stem cell (MSC) transplantation as a therapeutic approach for SCI. This review aims to present an overview of MSC regulation on the imbalanced microenvironment following SCI, specifically focusing on inflammation, neurotrophy and axonal regeneration. The application, limitations and future prospects of MSC transplantation are discussed as well. Generally, a comprehensive perspective is provided for the clinical translation of MSC transplantation for SCI.
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Affiliation(s)
- Yifan Liu
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
- Institute of Medical Sciences, The Second Hospital of Shandong University, Shandong University Center for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong, China
| | - Chenxi Zhao
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
| | - Rong Zhang
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
| | - Yilin Pang
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
- Department of Orthopedics, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Linquan Li
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China
| | - Shiqing Feng
- Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, 107 West Wenhua Road, Lixia District, Jinan, 250012, Shandong, China.
- Institute of Medical Sciences, The Second Hospital of Shandong University, Shandong University Center for Orthopaedics, Cheeloo College of Medicine, Shandong University, Jinan, 250033, Shandong, China.
- Department of Orthopedics, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord Injury, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
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Eivazi Zadeh Z, Nour S, Kianersi S, Jonidi Shariatzadeh F, Williams RJ, Nisbet DR, Bruggeman KF. Mining human clinical waste as a rich source of stem cells for neural regeneration. iScience 2024; 27:110307. [PMID: 39156636 PMCID: PMC11326931 DOI: 10.1016/j.isci.2024.110307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/20/2024] Open
Abstract
Neural diseases are challenging to treat and are regarded as one of the major causes of disability and morbidity in the world. Stem cells can provide a solution, by offering a mechanism to replace damaged circuitry. However, obtaining sufficient cell sources for neural regeneration remains a significant challenge. In recent years, waste-derived stem(-like) cells (WDS-lCs) extracted from both prenatal and adult clinical waste tissues/products, have gained increasing attention for application in neural tissue repair and remodeling. This often-overlooked pool of cells possesses favorable characteristics; including self-renewal, neural differentiation, secretion of neurogenic factors, cost-effectiveness, and low ethical concerns. Here, we offer a perspective regarding the biological properties, extraction protocols, and preclinical and clinical treatments where prenatal and adult WDS-lCs have been utilized for cell replacement therapy in neural applications, and the challenges involved in optimizing these approaches toward patient led therapies.
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Affiliation(s)
- Zahra Eivazi Zadeh
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
| | - Shirin Nour
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- Polymer Science Group, Department of Chemical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
| | - Sogol Kianersi
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), Biomedical Sciences, University of Galway, Galway, Ireland
| | | | - Richard J. Williams
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- iMPACT, School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia
| | - David R. Nisbet
- Department of Biomedical Engineering, University of Melbourne, Parkville, VIC 3010, Australia
- The Graeme Clark Institute, University of Melbourne, Melbourne, VIC, Australia
- ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, ANU College of Health & Medicine, Canberra, ACT, Australia
- Research School of Chemistry, ANU College of Science, Canberra, ACT, Australia
- Melbourne Medical School, Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Australia
- Founder and Scientific Advisory of Nano Status, Building 137, Sullivans Creek Rd, ANU, Acton, Canberra, ACT, Australia
| | - Kiara F. Bruggeman
- Laboratory of Advanced Biomaterials Research, School of Engineering, Australian National University, Canberra, ACT, Australia
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Yahyazadeh R, Baradaran Rahimi V, Askari VR. Stem cell and exosome therapies for regenerating damaged myocardium in heart failure. Life Sci 2024; 351:122858. [PMID: 38909681 DOI: 10.1016/j.lfs.2024.122858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Finding novel treatments for cardiovascular diseases (CVDs) is a hot topic in medicine; cell-based therapies have reported promising news for controlling dangerous complications of heart disease such as myocardial infarction (MI) and heart failure (HF). Various progenitor/stem cells were tested in various in-vivo, in-vitro, and clinical studies for regeneration or repairing the injured tissue in the myocardial to accelerate the healing. Fetal, adult, embryonic, and induced pluripotent stem cells (iPSC) have revealed the proper potency for cardiac tissue repair. As an essential communicator among cells, exosomes with specific contacts (proteins, lncRNAs, and miRNAs) greatly promote cardiac rehabilitation. Interestingly, stem cell-derived exosomes have more efficiency than stem cell transplantation. Therefore, stem cells induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), cardiac stem cells (CDC), and skeletal myoblasts) and their-derived exosomes will probably be considered an alternative therapy for CVDs remedy. In addition, stem cell-derived exosomes have been used in the diagnosis/prognosis of heart diseases. In this review, we explained the advances of stem cells/exosome-based treatment, their beneficial effects, and underlying mechanisms, which will present new insights in the clinical field in the future.
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Affiliation(s)
- Roghayeh Yahyazadeh
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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Awidi A, Al Shudifat A, El Adwan N, Alqudah M, Jamali F, Nazer F, Sroji H, Ahmad H, Al-Quzaa N, Jafar H. Safety and potential efficacy of expanded mesenchymal stromal cells of bone marrow and umbilical cord origins in patients with chronic spinal cord injuries: a phase I/II study. Cytotherapy 2024; 26:825-831. [PMID: 38703153 DOI: 10.1016/j.jcyt.2024.03.480] [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: 09/03/2023] [Revised: 03/11/2024] [Accepted: 03/19/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND AIMS Spinal cord injury (SCI) affects patients' physical, psychological, and social well-being. Presently, treatment modalities for chronic SCI have restricted clinical effectiveness. Mesenchymal stromal cells (MSCs) demonstrate promise in addressing nervous tissue damage. This single-center, open-label, parallel-group randomized clinical trial aimed to assess the safety and efficacy of intraoperative perilesional administration of expanded autologous bone marrow-derived MSCs (BMMSCs), followed by monthly intrathecal injections, in comparison to monthly intrathecal administration of expanded allogeneic umbilical cord-derived MSCs (UCMSCs) for individuals with chronic SCI. METHODS Twenty participants, who had a minimum of 1 year of SCI duration, were enrolled. Each participant in Group A received perilesional BMMSCs, followed by monthly intrathecal BMMSCs for three injections, while Group B received monthly intrathecal UCMSCs for three injections. Safety and efficacy were evaluated using the American Spinal Cord Injury Association (ASIA) score for at least 1 year post the final injection. Statistical analysis was conducted using the Wilcoxon signed-rank test. RESULTS Group A comprised 11 participants, while Group B included 9. The mean follow-up duration was 22.65 months. Mild short-term adverse events encompassed headaches and back pain, with no instances of long-term adverse events. Both groups demonstrated significant improvements in total ASIA scores, with Group A displaying more pronounced motor improvements. CONCLUSIONS Our findings indicate that perilesional administration of expanded autologous BMMSCs, followed by monthly intrathecal BMMSCs for three injections, or monthly intrathecal UCMSCs for three injections appear to be safe and hold promise for individuals with chronic SCI. Nonetheless, larger-scale clinical trials are imperative to validate these observations.
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Affiliation(s)
- Abdalla Awidi
- School of Medicine, University of Jordan, Amman, Jordan
| | | | | | | | - Fatima Jamali
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Fathy Nazer
- The University of Jordan School of Medicine, Amman, Jordan
| | - Halla Sroji
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Hady Ahmad
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Nahla Al-Quzaa
- The University of Jordan Cell Therapy Centre, Amman, Jordan
| | - Hanan Jafar
- The University of Jordan Cell Therapy Centre, Amman, Jordan
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Shen R, Lu Y, Cai C, Wang Z, Zhao J, Wu Y, Zhang Y, Yang Y. Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury. Stem Cell Res Ther 2024; 15:196. [PMID: 38956734 PMCID: PMC11218107 DOI: 10.1186/s13287-024-03797-y] [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: 12/17/2023] [Accepted: 06/10/2024] [Indexed: 07/04/2024] Open
Abstract
Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions-comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function-aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation.
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Affiliation(s)
- Ruoqi Shen
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Yubao Lu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Chaoyang Cai
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Ziming Wang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Jiayu Zhao
- Department of Neuro-Oncological Surgery, Neurosurgery Center, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Yingjie Wu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China
| | - Yinian Zhang
- Department of Neuro-Oncological Surgery, Neurosurgery Center, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
| | - Yang Yang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
- National Medical Products Administration (NMPA) Key Laboratory for Quality Research and Evaluation of Cell Products, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
- Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
- Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, No. 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, China.
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Abolghasemi R, Davoudi-Monfared E, Allahyari F, Farzanegan G. Systematic Review of Cell Therapy Efficacy in Human Chronic Spinal Cord Injury. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:254-269. [PMID: 37917104 DOI: 10.1089/ten.teb.2023.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Spinal cord injury (SCI) is one of the most debilitating problems for humans. About 6 months after the initial injury, a cascade of secondary cellular and molecular events occurs and the primary damage enters the chronic phase. Current treatments are not curative. One of the new treatment methods is the use of cell therapy, which is gradually being tested in clinical trials to improve the symptoms of SCI patients. In this review article, we investigated the effect of different cell therapy trials in improving patients' symptoms and their paraclinical indicators. In the 72 final reviewed studies with 1144 cases and 186 controls, 20 scores were recorded as outcomes. We categorized the scores into seven groups. In upper extremity motor score, daily living function, trunk stability, postural hypotension, somatosensory evoked potential, and motor evoked potential scores, the bone marrow hematopoietic stem cell therapy had a more healing effect. In the International Association of Neurorestoratology SCI Functional Rating Scale, light touch score, bowel function, decreased spasticity, Visual Analog Scale, and electromyography scores, the bone marrow mesenchymal stem cell had more impact. The olfactory ensheathing cell had a greater effect on lower extremity motor score and pinprick scores than other cells. The embryonic stem cell had the greatest effect in improving the important score of the American Spinal Injury Association scale. Based on the obtained results, it seems that a special cell should be used to improve each symptom of patients with chronic SCI, and if the improvement of several harms is involved, the combination of cells may be effective. Impact statement Compared to similar review articles published so far, we reviewed the largest number of published articles, and so the largest number of cases and controls, and the variety of cells we examined was more than other published articles. We concluded that different cells are effective for improving the symptoms and paraclinical indicators of patients with chronic spinal cord injury. Bone marrow hematopoietic stem cell and bone marrow mesenchymal stem cell have had the higher overall mean effect in more scores (each in six scores). If the improvement of several harms is involved, the combination of cells may be effective.
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Affiliation(s)
- Reyhaneh Abolghasemi
- New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Esmat Davoudi-Monfared
- Health Management Research Center and Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Fakhri Allahyari
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Gholamreza Farzanegan
- Trauma Research Center and Department of Neurosurgery, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Patel GD, Liu L, Li A, Yang YH, Shen CC, Brand-Saberi B, Yang X. Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: a systematic review. Front Med (Lausanne) 2024; 11:1361723. [PMID: 38601118 PMCID: PMC11004389 DOI: 10.3389/fmed.2024.1361723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 03/13/2024] [Indexed: 04/12/2024] Open
Abstract
Background Millions of people across the globe are affected by conditions like Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and Traumatic Brain Injury (TBI), although most occurrences are common in the elderly population. This systematic review aims to highlight the safety of the procedures, their tolerability, and efficacy of the available therapies conducted over the years using mesenchymal stem cells (MSCs) in treating the neurological conditions mentioned above. Methods PubMed was used to search for published data from clinical trials performed using mesenchymal stem cells. Studies that provided the necessary information that mentioned the efficacy and adverse effects of the treatment in patients were considered for this review. Results In total, 43 manuscripts were selected after a strategic search, and these studies have been included in this systematic review. Most included studies reported the safety of the procedures used and the treatment's good tolerability, with mild adverse events such as fever, headache, mild pain at the injection site, or nausea being common. A few studies also reported death of some patients, attributed to the progression of the disease to severe stages before the treatment. Other severe events, such as respiratory or urinary infections reported in some studies, were not related to the treatment. Different parameters were used to evaluate the efficacy of the treatment based on the clinical condition of the patient. Conclusion Mesenchymal stem cells transplantation has so far proven to be safe and tolerable in select studies and patient types. This systematic review includes the results from the 43 selected studies in terms of safety and tolerability of the procedures, and several adverse events and therapeutic benefits during the follow-up period after administration of MSCs.
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Affiliation(s)
- Gaurav Deepak Patel
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
| | - Lichao Liu
- Division of Histology and Embryology, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
| | - Ailian Li
- School of Stomatology, Southwest Medical University, Guangzhou, China
| | - Yun-Hsuan Yang
- School of Stomatology, Jinan University, Guangzhou, China
| | - Chia-Chi Shen
- School of Stomatology, Jinan University, Guangzhou, China
| | - Beate Brand-Saberi
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
| | - Xuesong Yang
- Division of Histology and Embryology, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
- Clinical Research Center, Clifford Hospital, Guangzhou, China
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11
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Agosti E, Zeppieri M, Pagnoni A, Fontanella MM, Fiorindi A, Ius T, Panciani PP. Current status and future perspectives on stem cell transplantation for spinal cord injury. World J Transplant 2024; 14:89674. [PMID: 38576751 PMCID: PMC10989472 DOI: 10.5500/wjt.v14.i1.89674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/04/2023] [Accepted: 12/29/2023] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Previous assessments of stem cell therapy for spinal cord injuries (SCI) have encountered challenges and constraints. Current research primarily emphasizes safety in early-phase clinical trials, while systematic reviews prioritize effectiveness, often overlooking safety and translational feasibility. This situation prompts inquiries regarding the readiness for clinical adoption. AIM To offer an up-to-date systematic literature review of clinical trial results con cerning stem cell therapy for SCI. METHODS A systematic search was conducted across major medical databases [PubMed, Embase, Reference Citation Analysis (RCA), and Cochrane Library] up to October 14, 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "spinal cord", "injury", "clinical trials", "stem cells", "functional outcomes", and "adverse events". Studies included in this review consisted of randomized controlled trials and non-randomized controlled trials reporting on the use of stem cell therapies for the treatment of SCI. RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI, 496 papers were initially identified, with 237 chosen for full-text analysis. Among them, 236 were deemed eligible after excluding 170 for various reasons. These studies encompassed 1086 patients with varying SCI levels, with cervical injuries being the most common (42.2%). Bone marrow stem cells were the predominant stem cell type used (71.1%), with various administration methods. Follow-up durations averaged around 84.4 months. The 32.7% of patients showed functional impro vement from American spinal injury association Impairment Scale (AIS) A to B, 40.8% from AIS A to C, 5.3% from AIS A to D, and 2.1% from AIS B to C. Sensory improvements were observed in 30.9% of patients. A relatively small number of adverse events were recorded, including fever (15.1%), headaches (4.3%), muscle tension (3.1%), and dizziness (2.6%), highlighting the potential for SCI recovery with stem cell therapy. CONCLUSION In the realm of SCI treatment, stem cell-based therapies show promise, but clinical trials reveal potential adverse events and limitations, underscoring the need for meticulous optimization of transplantation conditions and parameters, caution against swift clinical implementation, a deeper understanding of SCI pathophysiology, and addressing ethical, tumorigenicity, immunogenicity, and immunotoxicity concerns before gradual and careful adoption in clinical practice.
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Affiliation(s)
- Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Andrea Pagnoni
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Maria Fontanella
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia 25123, BS, Italy
| | - Alessandro Fiorindi
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Tamara Ius
- Neurosurgery Unit, Head-Neck and NeuroScience Department, University Hospital of Udine, Udine 33100, Italy
| | - Pier Paolo Panciani
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
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12
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Zipser CM, Curt A. Disease-specific interventions using cell therapies for spinal cord disease/injury. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:263-282. [PMID: 39341658 DOI: 10.1016/b978-0-323-90120-8.00007-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Traumatic spinal cord injury (SCI) may occur across the lifespan and is of global relevance. Damage of the spinal cord results in para- or tetraplegia and is associated with neuropathic pain, spasticity, respiratory, and autonomic dysfunction (i.e., control of bladder-bowel function). While the acute surgical treatment aims at stabilizing the spine and decompressing the damaged spinal cord, SCI patients require neurorehabilitation to restore neural function and to compensate for any impairments including motor disability, pain treatment, and bladder/bowel management. However, the spinal cord has a limited capacity to regenerate and much of the disability may persist, depending on the initial lesion severity and level of injury. For this reason, and the lack of effective drug treatments, there is an emerging interest and urgent need in promoting axonal regeneration and remyelination after SCI through cell- and stem-cell based therapies. This review briefly summarizes the state-of the art management of acute SCI and its neurorehabilitation to critically appraise phase I/II trials from the last two decades that have investigated cell-based therapies (i.e., Schwann cells, macrophages, and olfactory ensheathing cells) and stem cell-based therapies (i.e., neural stem cells, mesenchymal, and hematopoietic stem cells). Recently, two large multicenter trials provided evidence for the safety and feasibility of neural stem cell transplantation into the injured cord, whilst two monocenter trials also showed this to be the case for the transplantation of Schwann cells into the posttraumatic cord cavity. These are milestone studies that will facilitate further interventional trials. However, the clinical adoption of such approaches remains unproven, as there is only limited encouraging data, often in single patients, and no proven trial evidence to support regulatory approval.
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Affiliation(s)
- Carl Moritz Zipser
- Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland
| | - Armin Curt
- Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland.
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13
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Kharazinejad E, Hassanzadeh G, Sahebkar A, Yousefi B, Reza Sameni H, Majidpoor J, Golchini E, Taghdiri Nooshabadi V, Mousavi M. The Comparative Effects of Schwann Cells and Wharton's Jelly Mesenchymal Stem Cells on the AIM2 Inflammasome Activity in an Experimental Model of Spinal Cord Injury. Neuroscience 2023; 535:1-12. [PMID: 37890609 DOI: 10.1016/j.neuroscience.2023.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 10/15/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023]
Abstract
Inflammasome activation and the consequent release of pro-inflammatory cytokines play a crucial role in the development of sensory/motor deficits following spinal cord injury (SCI). Immunomodulatory activities are exhibited by Schwann cells (SCs) and Wharton's jelly mesenchymal stem cells (WJ-MSCs). In this study, we aimed to compare the effectiveness of these two cell sources in modulating the absent in melanoma 2 (AIM2) inflammasome complex in rats with SCI. The Basso, Beattie, Bresnahan (BBB) test, Nissl staining, and Luxol fast blue (LFB) staining were performed to evaluate locomotor function, neuronal survival, and myelination, respectively. Real-time polymerase chain reaction (RT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA) were employed to analyze the gene and protein expressions of inflammasome components, including AIM2, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18. Both gene and protein expressions of all evaluated factors were decreased after SC or WJ-MSC treatment, with a more pronounced effect observed in the SCs group (P < 0.05). Additionally, SCs promoted neuronal survival and myelination. Moreover, the administration of 3 × 105 cells resulted in motor recovery improvement in both treatment groups (P < 0.05). Although not statistically significant, these effects were more prominent in the SC-treated animals. In conclusion, SC therapy demonstrated greater efficacy in targeting AIM2 inflammasome activation and the associated inflammatory pathway in SCI experiments compared to WJ-MSCs.
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Affiliation(s)
- Ebrahim Kharazinejad
- Department of Anatomy, Faculty of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Gholamreza Hassanzadeh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Digital Health, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Behpour Yousefi
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran; Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Hamid Reza Sameni
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran; Department of Tissue Engineering and Applied Cell Science, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Jamal Majidpoor
- Department of Anatomy, Faculty of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Ehsan Golchini
- Department of Operating Room, School of Paramedical Sciences, Alborz University of Medical Sciences, Karaj, Iran
| | - Vajihe Taghdiri Nooshabadi
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran; Department of Tissue Engineering and Applied Cell Science, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahboubeh Mousavi
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran; Department of Anatomy, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
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14
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Ou YC, Huang CC, Kao YL, Ho PC, Tsai KJ. Stem Cell Therapy in Spinal Cord Injury-Induced Neurogenic Lower Urinary Tract Dysfunction. Stem Cell Rev Rep 2023; 19:1691-1708. [PMID: 37115409 DOI: 10.1007/s12015-023-10547-9] [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: 04/14/2023] [Indexed: 04/29/2023]
Abstract
Spinal cord injury (SCI) is a devastating condition that enormously affects an individual's health and quality of life. Neurogenic lower urinary tract dysfunction (NLUTD) is one of the most important sequelae induced by SCI, causing complications including urinary tract infection, renal function deterioration, urinary incontinence, and voiding dysfunction. Current therapeutic methods for SCI-induced NLUTD mainly target on the urinary bladder, but the outcomes are still far from satisfactory. Stem cell therapy has gained increasing attention for years for its ability to rescue the injured spinal cord directly. Stem cell differentiation and their paracrine effects, including exosomes, are the proposed mechanisms to enhance the recovery from SCI. Several animal studies have demonstrated improvement in bladder function using mesenchymal stem cells (MSCs) and neural stem cells (NSCs). Human clinical trials also provide promising results in urodynamic parameters after MSC therapy. However, there is still uncertainty about the ideal treatment window and application protocol for stem cell therapy. Besides, data on the therapeutic effects regarding NSCs and stem cell-derived exosomes in SCI-related NLUTD are scarce. Therefore, there is a pressing need for further well-designed human clinical trials to translate the stem cell therapy into a formal therapeutic option for SCI-induced NLUTD.
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Affiliation(s)
- Yin-Chien Ou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Chen Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Lin Kao
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Chuan Ho
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
| | - Kuen-Jer Tsai
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan.
- Research Center of Clinical Medicine, National Cheng Kung University Hospital , College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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15
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Montoto-Meijide R, Meijide-Faílde R, Díaz-Prado SM, Montoto-Marqués A. Mesenchymal Stem Cell Therapy in Traumatic Spinal Cord Injury: A Systematic Review. Int J Mol Sci 2023; 24:11719. [PMID: 37511478 PMCID: PMC10380897 DOI: 10.3390/ijms241411719] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Recovery from a traumatic spinal cord injury (TSCI) is challenging due to the limited regenerative capacity of the central nervous system to restore cells, myelin, and neural connections. Cell therapy, particularly with mesenchymal stem cells (MSCs), holds significant promise for TSCI treatment. This systematic review aims to analyze the efficacy, safety, and therapeutic potential of MSC-based cell therapies in TSCI. A comprehensive search of PUBMED and COCHRANE databases until February 2023 was conducted, combining terms such as "spinal cord injury," "stem cells," "stem cell therapy," "mesenchymal stem cells," and "traumatic spinal cord injury". Among the 53 studies initially identified, 22 (21 clinical trials and 1 case series) were included. Findings from these studies consistently demonstrate improvements in AIS (ASIA Impairment Scale) grades, sensory scores, and, to a lesser extent, motor scores. Meta-analyses further support these positive outcomes. MSC-based therapies have shown short- and medium-term safety, as indicated by the absence of significant adverse events within the studied timeframe. However, caution is required when drawing generalized recommendations due to the limited scientific evidence available. Further research is needed to elucidate the long-term safety and clinical implications of these advancements. Although significant progress has been made, particularly with MSC-based therapies, additional studies exploring other potential future therapies such as gene therapies, neurostimulation techniques, and tissue engineering approaches are essential for a comprehensive understanding of the evolving TSCI treatment landscape.
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Affiliation(s)
- Rodrigo Montoto-Meijide
- Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Rosa Meijide-Faílde
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Instituto de Investigación Biomédica de A Coruña (INIBIC), Centro Interdisciplinar de Química y Biología (CICA), Universidade da Coruña, 15071 A Coruña, Spain
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
| | - Silvia María Díaz-Prado
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Instituto de Investigación Biomédica de A Coruña (INIBIC), Centro Interdisciplinar de Química y Biología (CICA), Universidade da Coruña, 15071 A Coruña, Spain
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
| | - Antonio Montoto-Marqués
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain
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16
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Ribeiro BF, da Cruz BC, de Sousa BM, Correia PD, David N, Rocha C, Almeida RD, Ribeiro da Cunha M, Marques Baptista AA, Vieira SI. Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential. Brain 2023; 146:2672-2693. [PMID: 36848323 DOI: 10.1093/brain/awad047] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 12/23/2022] [Accepted: 01/29/2023] [Indexed: 03/01/2023] Open
Abstract
Spinal cord injury (SCI) is an as yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential, but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and which cell types result in higher neurological and functional recovery remains under debate. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analysed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages and various types of stem cells have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale, motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic aetiology and did not display a randomized comparative control arm. Bone marrow stem cells and OECs were the most commonly tested cells, while open surgery and injection were the main methods of delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest ASIA Impairment Scale (AIS) grade conversion rates (improvements in ∼40% of transplanted patients), which surpassed the spontaneous improvement rate expected for complete chronic SCI patients within 1 year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated and neural stem cells, offer potential for improving patient recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may contribute highly to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials and how these are reported. It is therefore crucial to standardize these trials when aiming for higher value clinical evidence-based conclusions.
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Affiliation(s)
- Beatriz F Ribeiro
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bruna C da Cruz
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bárbara M de Sousa
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Patrícia D Correia
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Nuno David
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Camila Rocha
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ramiro D Almeida
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Maria Ribeiro da Cunha
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
- Spinal Cord Injury Rehabilitation Unit, Centro de Reabilitação do Norte (CRN), Centro Hospitalar de Vila Nova de Gaia e Espinho (CHVNG/E), 4400-129 Vila Nova de Gaia, Portugal
| | - António A Marques Baptista
- Department of Neurosurgery, Centro Hospitalar de Vila Nova de Gaia e Espinho (CHVNG/E), 4400-129 Vila Nova de Gaia, Portugal
| | - Sandra I Vieira
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
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Hu X, Xu W, Ren Y, Wang Z, He X, Huang R, Ma B, Zhao J, Zhu R, Cheng L. Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8:245. [PMID: 37357239 DOI: 10.1038/s41392-023-01477-6] [Citation(s) in RCA: 212] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 03/22/2023] [Accepted: 05/07/2023] [Indexed: 06/27/2023] Open
Abstract
Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate. The challenges of SCI repair include its complex pathological mechanisms and the difficulties of neural regeneration in the central nervous system. In the past few decades, researchers have attempted to completely elucidate the pathological mechanism of SCI and identify effective strategies to promote axon regeneration and neural circuit remodeling, but the results have not been ideal. Recently, new pathological mechanisms of SCI, especially the interactions between immune and neural cell responses, have been revealed by single-cell sequencing and spatial transcriptome analysis. With the development of bioactive materials and stem cells, more attention has been focused on forming intermediate neural networks to promote neural regeneration and neural circuit reconstruction than on promoting axonal regeneration in the corticospinal tract. Furthermore, technologies to control physical parameters such as electricity, magnetism and ultrasound have been constantly innovated and applied in neural cell fate regulation. Among these advanced novel strategies and technologies, stem cell therapy, biomaterial transplantation, and electromagnetic stimulation have entered into the stage of clinical trials, and some of them have already been applied in clinical treatment. In this review, we outline the overall epidemiology and pathophysiology of SCI, expound on the latest research progress related to neural regeneration and circuit reconstruction in detail, and propose future directions for SCI repair and clinical applications.
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Affiliation(s)
- Xiao Hu
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Wei Xu
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Yilong Ren
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Zhaojie Wang
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Xiaolie He
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Runzhi Huang
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Bei Ma
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Jingwei Zhao
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China
| | - Rongrong Zhu
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China.
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China.
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China.
| | - Liming Cheng
- Division of Spine, Department of Orthopaedics, Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, China.
- Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, 200065, Shanghai, China.
- Clinical Center For Brain And Spinal Cord Research, Tongji University, 200065, Shanghai, China.
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18
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Raue KD, David BT, Fessler RG. Spinal Cord-Gut-Immune Axis and its Implications Regarding Therapeutic Development for Spinal Cord Injury. J Neurotrauma 2023; 40:793-806. [PMID: 36509451 DOI: 10.1089/neu.2022.0264] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) affects ∼1,300,000 people living in the United States. Most research efforts have been focused on reversing paralysis, as this is arguably the most defining feature of SCI. The damage caused by SCI, however, extends past paralysis and includes other debilitating outcomes including immune dysfunction and gut dysbiosis. Recent efforts are now investigating the pathophysiology of and developing therapies for these more distal manifestations of SCI. One exciting avenue is the spinal cord-gut-immune axis, which proposes that gut dysbiosis amplifies lesion inflammation and impairs SCI recovery. This review will highlight the most recent findings regarding gut and immune dysfunction following SCI, and discuss how the central nervous system (CNS), gut, and immune system all coalesce to form a bidirectional axis that can impact SCI recovery. Finally, important considerations regarding how the spinal cord-gut-immune axis fits within the larger framework of therapeutic development (i.e., probiotics, fecal transplants, dietary modifications) will be discussed, emphasizing the lack of interdepartmental investigation and the missed opportunity to maximize therapeutic benefit in SCI.
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Affiliation(s)
- Kristen D Raue
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Brian T David
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
| | - Richard G Fessler
- Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA
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19
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Sanchez-Petitto G, Rezvani K, Daher M, Rafei H, Kebriaei P, Shpall EJ, Olson A. Umbilical Cord Blood Transplantation: Connecting Its Origin to Its Future. Stem Cells Transl Med 2023; 12:55-71. [PMID: 36779789 PMCID: PMC9985112 DOI: 10.1093/stcltm/szac086] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 10/16/2022] [Indexed: 02/14/2023] Open
Abstract
Transplantation of umbilical cord blood (UCB) is an attractive alternative source of hematopoietic stem cells (HSCs). The unique properties of cord blood and its distinct immune tolerance and engraftment kinetics compared to bone marrow (BM) and peripheral blood progenitor cells, permit a wider disparity in human leukocyte antigen levels between a cord blood donor and recipient after an unrelated umbilical cord blood transplant (UCBT). In addition, it is readily available and has a lowered risk of graft-versus-host disease (GvHD), with similar long-term clinical outcomes, compared to BM transplants. However, the relatively low number of cells administered by UCB units, as well as the associated delayed engraftment and immune reconstitution, pose limitations to the wide application of UCBT. Research into several aspects of UCBT has been evaluated, including the ex vivo expansion of cord blood HSCs and the process of fucosylation to enhance engraftment. Additionally, UCB has also been used in the treatment of several neurodegenerative and cardiovascular disorders with varying degrees of success. In this article, we will discuss the biology, clinical indications, and benefits of UCBT in pediatric and adult populations. We will also discuss future directions for the use of cord blood.
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Affiliation(s)
- Gabriela Sanchez-Petitto
- Department of Stem Cell Transplant and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Katayoun Rezvani
- Department of Stem Cell Transplant and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - May Daher
- Department of Stem Cell Transplant and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Hind Rafei
- Department of Stem Cell Transplant and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Partow Kebriaei
- Department of Stem Cell Transplant and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth J Shpall
- Department of Stem Cell Transplant and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Amanda Olson
- Department of Stem Cell Transplant and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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20
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Xia Y, Zhu J, Yang R, Wang H, Li Y, Fu C. Mesenchymal stem cells in the treatment of spinal cord injury: Mechanisms, current advances and future challenges. Front Immunol 2023; 14:1141601. [PMID: 36911700 PMCID: PMC9999104 DOI: 10.3389/fimmu.2023.1141601] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/13/2023] [Indexed: 03/14/2023] Open
Abstract
Spinal cord injury (SCI) has considerable impact on patient physical, mental, and financial health. Secondary SCI is associated with inflammation, vascular destruction, and subsequent permanent damage to the nervous system. Mesenchymal stem cells (MSCs) have anti-inflammatory properties, promoting vascular regeneration and the release neuro-nutrients, and are a promising strategy for the treatment of SCI. Preclinical studies have shown that MSCs promote sensory and motor function recovery in rats. In clinical trials, MSCs have been reported to improve the American Spinal Injury Association (ASIA) sensory and motor scores. However, the effectiveness of MSCs in treating patients with SCI remains controversial. MSCs promote tumorigenesis and ensuring the survival of MSCs in the hostile environment of SCI is challenging. In this article we examine the evidence on the pathophysiological changes occurring after SCI. We then review the underlying mechanisms of MSCs in the treatment of SCI and summarize the potential application of MSCs in clinical practice. Finally, we highlight the challenges surrounding the use of MSCs in the treatment of SCI and discuss future applications.
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Affiliation(s)
- Yuanliang Xia
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Jianshu Zhu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Ruohan Yang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Hengyi Wang
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Yuehong Li
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
| | - Changfeng Fu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun,
China
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21
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Mou C, Wang X, Li W, Li Z, Liu N, Xu Y. Efficacy of mesenchymal stromal cells intraspinal transplantation for patients with different degrees of spinal cord injury: A systematic review and meta-analysis. Cytotherapy 2023; 25:530-536. [PMID: 36805381 DOI: 10.1016/j.jcyt.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 01/06/2023] [Accepted: 01/24/2023] [Indexed: 02/22/2023]
Abstract
BACKGROUND AIMS Several studies have reported that mesenchymal stromal cells (MSCs) may improve neurological functions in patients with spinal cord injury (SCI). In this study, we conducted a systematic review and meta-analysis to summarize the effects of MSC treatment on different degrees of severity of SCI. METHODS Systematic searching of studies reporting outcomes of MSCs on specific injury severities of patients with SCI was performed in The National Library of Medicine (MEDLINE), Embase and Cochrane for published articles up to the 6 July 2022. Two investigators independently reviewed the included studies and extracted the relevant data. The standardized mean differences of American Spinal Injury Association (ASIA) motor score, ASIA light touch scores, ASIA pinprick scores and the Barthel index between baseline and follow-ups were pooled. RESULTS A total of eight studies were included. A large majority focused on patients with ASIA grade A classification. The pooled mean differences of ASIA motor scores, ASIA light touch scores, ASIA pinprick scores and the Barthel index were -2.78 (95% confidence interval [CI] -5.12 to -0.43, P = 0.02), -18.26 (95% CI -26.09 to -10.43, P < 0.01), -17.08 (95% CI -24.10 to -10.07, P < 0.01) and -4.37 (95% CI -10.96 to 2.22, P = 0.19), respectively. CONCLUSIONS MSC transplantation was a significantly effective therapy for patients with SCI with ASIA grade A. In the future, further studies are warranted to confirm the potential beneficial effects of MSC therapy.
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Affiliation(s)
- Chunlin Mou
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Xiujuan Wang
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Wei Li
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Zhengnan Li
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Nian Liu
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China
| | - Yongsheng Xu
- Technology Department, Everunion Biotechnology Co. Ltd., Tianjin, China.
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22
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Sterner RC, Sterner RM. Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Front Immunol 2023; 13:1084101. [PMID: 36685598 PMCID: PMC9853461 DOI: 10.3389/fimmu.2022.1084101] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology of SCI is complex and occurs in two phases. First, the mechanical damage from the trauma causes immediate acute cell dysfunction and cell death. Then, secondary mechanisms of injury further propagate the cell dysfunction and cell death over the course of days, weeks, or even months. Among the secondary injury mechanisms, inflammation has been shown to be a key determinant of the secondary injury severity and significantly worsens cell death and functional outcomes. Thus, in addition to surgical management of SCI, selectively targeting the immune response following SCI could substantially decrease the progression of secondary injury and improve patient outcomes. In order to develop such therapies, a detailed molecular understanding of the timing of the immune response following SCI is necessary. Recently, several studies have mapped the cytokine/chemokine and cell proliferation patterns following SCI. In this review, we examine the immune response underlying the pathophysiology of SCI and assess both current and future therapies including pharmaceutical therapies, stem cell therapy, and the exciting potential of extracellular vesicle therapy.
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Affiliation(s)
- Robert C. Sterner
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Rosalie M. Sterner
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States,*Correspondence: Rosalie M. Sterner,
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23
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Multiple strategies enhance the efficacy of MSCs transplantation for spinal cord injury. Biomed Pharmacother 2023; 157:114011. [PMID: 36410123 DOI: 10.1016/j.biopha.2022.114011] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/05/2022] [Accepted: 11/11/2022] [Indexed: 11/19/2022] Open
Abstract
Spinal cord injury (SCI) is a serious complication of the central nervous system (CNS) after spine injury, often resulting in severe sensory, motor, and autonomic dysfunction below the level of injury. To date, there is no effective treatment strategy for SCI. Recently, stem cell therapy has brought hope to patients with neurological diseases. Mesenchymal stem cells (MSCs) are considered to be the most promising source of cellular therapy after SCI due to their immunomodulatory, neuroprotective and angiogenic potential. Considering the limited therapeutic effect of MSCs due to the complex pathophysiological environment following SCI, this paper not only reviews the specific mechanism of MSCs to facilitate SCI repair, but also further discusses the research status of these pluripotent stem cells combined with other therapeutic approaches to promote anatomical and functional recovery post-SCI.
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24
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Rodríguez-Eguren A, Gómez-Álvarez M, Francés-Herrero E, Romeu M, Ferrero H, Seli E, Cervelló I. Human Umbilical Cord-Based Therapeutics: Stem Cells and Blood Derivatives for Female Reproductive Medicine. Int J Mol Sci 2022; 23:ijms232415942. [PMID: 36555583 PMCID: PMC9785531 DOI: 10.3390/ijms232415942] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/04/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
There are several conditions that lead to female infertility, where traditional or conventional treatments have limited efficacy. In these challenging scenarios, stem cell (SC) therapies have been investigated as alternative treatment strategies. Human umbilical cord (hUC) mesenchymal stem cells (hUC-MSC), along with their secreted paracrine factors, extracts, and biomolecules, have emerged as promising therapeutic alternatives in regenerative medicine, due to their remarkable potential to promote anti-inflammatory and regenerative processes more efficiently than other autologous treatments. Similarly, hUC blood derivatives, such as platelet-rich plasma (PRP), or isolated plasma elements, such as growth factors, have also demonstrated potential. This literature review aims to summarize the recent therapeutic advances based on hUC-MSCs, hUC blood, and/or other plasma derivatives (e.g., extracellular vesicles, hUC-PRP, and growth factors) in the context of female reproductive medicine. We present an in-depth analysis of the principal molecules mediating tissue regeneration, compiling the application of these therapies in preclinical and clinical studies, within the context of the human reproductive tract. Despite the recent advances in bioengineering strategies that sustain delivery and amplify the scope of the therapeutic benefits, further clinical trials are required prior to the wide implementation of these alternative therapies in reproductive medicine.
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Affiliation(s)
- Adolfo Rodríguez-Eguren
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
| | | | - Emilio Francés-Herrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, 46010 Valencia, Spain
| | - Mónica Romeu
- Gynecological Service, Consortium General University Hospital of Valencia, 46014 Valencia, Spain
| | - Hortensia Ferrero
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
| | - Emre Seli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT 05610, USA
- IVIRMA New Jersey, Basking Ridge, NJ 07920, USA
| | - Irene Cervelló
- IVI Foundation, Health Research Institute La Fe, 46026 Valencia, Spain
- Correspondence: or
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25
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Hall A, Fortino T, Spruance V, Niceforo A, Harrop JS, Phelps PE, Priest CA, Zholudeva LV, Lane MA. Cell transplantation to repair the injured spinal cord. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 166:79-158. [PMID: 36424097 PMCID: PMC10008620 DOI: 10.1016/bs.irn.2022.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Adam Hall
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Tara Fortino
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Victoria Spruance
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Division of Kidney, Urologic, & Hematologic Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Alessia Niceforo
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - James S Harrop
- Department of Neurological and Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Patricia E Phelps
- Department of Integrative Biology & Physiology, UCLA, Los Angeles, CA, United States
| | | | - Lyandysha V Zholudeva
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Gladstone Institutes, San Francisco, CA, United States
| | - Michael A Lane
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States.
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26
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Shang Z, Wang M, Zhang B, Wang X, Wanyan P. Clinical translation of stem cell therapy for spinal cord injury still premature: results from a single-arm meta-analysis based on 62 clinical trials. BMC Med 2022; 20:284. [PMID: 36058903 PMCID: PMC9442938 DOI: 10.1186/s12916-022-02482-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND How much scientific evidence is there to show that stem cell therapy is sufficient in preclinical and clinical studies of spinal cord injury before it is translated into clinical practice? This is a complicated problem. A single, small-sample clinical trial is difficult to answer, and accurate insights into this question can only be given by systematically evaluating all the existing evidence. METHODS The PubMed, Ovid-Embase, Web of Science, and Cochrane databases were searched from inception to February 10, 2022. Two independent reviewers performed the literature search, identified and screened the studies, and performed a quality assessment and data extraction. RESULTS In total, 62 studies involving 2439 patients were included in the analysis. Of these, 42 were single-arm studies, and 20 were controlled studies. The meta-analysis showed that stem cells improved the ASIA impairment scale score by at least one grade in 48.9% [40.8%, 56.9%] of patients with spinal cord injury. Moreover, the rate of improvement in urinary and gastrointestinal system function was 42.1% [27.6%, 57.2%] and 52.0% [23.6%, 79.8%], respectively. However, 28 types of adverse effects were observed to occur due to stem cells and transplantation procedures. Of these, neuropathic pain, abnormal feeling, muscle spasms, vomiting, and urinary tract infection were the most common, with an incidence of > 20%. While no serious adverse effects such as tumorigenesis were reported, this could be due to the insufficient follow-up period. CONCLUSIONS Overall, the results demonstrated that although the efficacy of stem cell therapy is encouraging, the subsequent adverse effects remain concerning. In addition, the clinical trials had problems such as small sample sizes, poor design, and lack of prospective registration, control, and blinding. Therefore, the current evidence is not sufficiently strong to support the clinical translation of stem cell therapy for spinal cord injury, and several problems remain. Additional well-designed animal experiments and high-quality clinical studies are warranted to address these issues.
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Affiliation(s)
- Zhizhong Shang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Mingchuan Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Baolin Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Xin Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China.
- Chengren Institute of Traditional Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
- Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
| | - Pingping Wanyan
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- The Second Hospital of Lanzhou University, Lanzhou, 730000, China
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27
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Master YL, Wei-Meng Tian B, Xing-Fang Jin M, Zong-Liu Hou P, Jing-Ping-Wang B, Yun-Shan Zhang B, Feng-Yun Luo B, Jian-Pei Su M, Jun Wang B, Ming-Hui Meng P, Yan He P. A clinical research of 11cases of human umbilical cord mesenchymal stem cells for curing senile vascular dementia. Transpl Immunol 2022; 74:101669. [PMID: 35835295 DOI: 10.1016/j.trim.2022.101669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/08/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Patients affected by senile vascular dementia (VaD) suffer from a gradual deterioration in their cognitive expressions as well as the ability of taking care for themselves. This study aimed to investigate the clinical efficacy and safety of improving cognitive function and daily life activities of patients with VaD by transplanting human umbilical cord mesenchymal stem cells (HUCMSCs). METHODS A total number of 11 patients with senile VaD, who were admitted through outpatient treatment and hospitalized between February 2013 and February 2016, were selected. The diagnosis was based on CT and MRI examinations. The cultivated HUCMSCs (106 /kg) were injected by intravenous (i.v.) infusion on three occasions. Patients were evaluated for the Mini-Mental State Examination (MMSE) with 25-30 as normal, 21-24 as mild dementia, 10-20 as moderate dementia, and 0-9 as severe dementia. In addition, the Barthel index (BI) was used for a standardized activities of daily living (ADLs) with 0-20 as total dependence, 21-60 as severe dependence, 61-90 as moderate dependence, and 91-95 slight dependence. The t-test was performed to compare statistical significance. RESULTS The study included 11 subjects, one of whom fell out due to an event unrelated to the study. The results show descriptive statistics at different time points. No matter MMSE score or Barthel index, the difference between before treatment and after treatment or follow-up was statistically significant (P < 0.001).Result interpretation: this intervention method has a significant therapeutic effect, and in the 3-month follow-up period, the intervention effect is still significant compared with that before treatment. CONCLUSIONS Our preliminary clinical observations suggest that the i.v. infusion of HUCMSCs significantly improved the cognitive function (MMSE) and daily life activities (BI) of patients with senile VaD. This approach may prove to be safe and relatively simple method to be applied for the treatment of senile VaD.
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Affiliation(s)
- You Li Master
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Wei-Meng Tian
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China.
| | - Master Xing-Fang Jin
- Department of Geriatric, Yan'an Hospital of Kunming City, Kunming, Yunnan 650051, China
| | | | - Bachelor Jing-Ping-Wang
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Yun-Shan Zhang
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Feng-Yun Luo
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Master Jian-Pei Su
- Department of Geriatric, The Second People's Hospital of Kunming, Kunming, Yunnan 650204, China
| | - Bachelor Jun Wang
- Department of Geriatric, Yan'an Hospital of Kunming City, Kunming, Yunnan 650051, China
| | | | - Postgraduates Yan He
- Department of Geriatric, Yan'an Hospital of Kunming City, Kunming, Yunnan 650051, China
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28
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Kvistad CE, Kråkenes T, Gjerde C, Mustafa K, Rekand T, Bø L. Safety and Clinical Efficacy of Mesenchymal Stem Cell Treatment in Traumatic Spinal Cord Injury, Multiple Sclerosis and Ischemic Stroke - A Systematic Review and Meta-Analysis. Front Neurol 2022; 13:891514. [PMID: 35711260 PMCID: PMC9196044 DOI: 10.3389/fneur.2022.891514] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/22/2022] [Indexed: 12/11/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) is an attractive candidate in regenerative research and clinical trials have assessed their therapeutic potential in different neurological conditions with disparate etiologies. In this systematic review, we aimed to assess safety and clinical effect of MSC treatment in traumatic spinal cord injury (TSCI), multiple sclerosis (MS) and ischemic stroke (IS). Methods A systematic search was performed 2021-12-10 in MEDLINE, EMBASE, Web of Science and Cochrane where clinical studies assessing MSC treatment in TSCI, MS or IS were included. Studies without control group were excluded for efficacy analysis, but included in the safety analysis. For efficacy, AIS score, EDSS score and mRS were used as clinical endpoints and assessed in a meta-analysis using the random effects model. Findings Of 5,548 identified records, 54 studies were included. Twenty-six studies assessed MSC treatment in TSCI, 14 in MS and nine in IS, of which seven, seven and five studies were controlled, respectively. There were seven serious adverse events (SAEs), of which four were related to the surgical procedure and included one death due to complications following the implantation of MSCs. Three SAEs were considered directly related to the MSC treatment and all these had a transient course. In TSCI, a meta-analysis showed no difference in conversion from AIS A to C and a trend toward more patients treated with MSCs improving from AIS A to B as compared to controls (p = 0.05). A subgroup analysis performed per protocol, showed more MSC treated patients improving from AIS A to C in studies including patients within 8 weeks after injury (p = 0.04). In MS and IS, there were no significant differences in clinical outcomes between MSC treated patients and controls as measured by EDSS and mRS, respectively. Interpretation MSC-treatment is safe in patients with TSCI, MS and IS, although surgical implantation of MSC led to one fatal outcome in TSCI. There was no clear clinical benefit of MSC treatment, but this is not necessarily a proof of inefficacy due to the low number of controlled studies. Future studies assessing efficacy of MSC treatment should aim to do this in randomized, controlled studies.
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Affiliation(s)
| | - Torbjørn Kråkenes
- Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Cecilie Gjerde
- Tissue Engineering Group, Department of Clinical Dentistry, University of Bergen, Bergen, Norway
| | - Kamal Mustafa
- Tissue Engineering Group, Department of Clinical Dentistry, University of Bergen, Bergen, Norway
| | - Tiina Rekand
- Department of Neurology, Haukeland University Hospital, Bergen, Norway.,Institute for Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Lars Bø
- Department of Neurology, Haukeland University Hospital, Bergen, Norway.,Department of Clinical Medicine, University of Bergen, Bergen, Norway
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29
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Effects of mesenchymal stem cell transplantation on spinal cord injury patients. Cell Tissue Res 2022; 389:373-384. [PMID: 35697943 DOI: 10.1007/s00441-022-03648-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 06/02/2022] [Indexed: 11/02/2022]
Abstract
Spinal cord injury (SCI) is a traumatic injury with sensory and motor deficits that more than 1 million patients worldwide suffer from disability due to it. Many pharmacological therapies help reduce SCI-related injury and protect CNS from more damage but no current therapy could improve the axonal repair. In this regard, stem cell therapy is considered a regenerative method for SCI patient treatment. The neurotrophic and immunomodulatory factor secretion, differentiation, neuroprotecting, and remyelinating properties have made mesenchymal stem cells (MSCs) principally useful in this field. There are studies on the role of MSCs in patients suffering from SCI. However, low number of SCI patients and the lack of control groups in these studies, the cell transplantation appropriate methods, including cell source, dose, route of delivery, and transplantation timing, are various in trials. This study reviews the beneficial effects of MSC transplantation in SCI clinical studies with a special focus on the MSC properties and limitations of MSC transplantation.
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30
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Xie JL, Wang XR, Li MM, Tao ZH, Teng WW, Saijilafu. Mesenchymal Stromal Cell Therapy in Spinal Cord Injury: Mechanisms and Prospects. Front Cell Neurosci 2022; 16:862673. [PMID: 35722621 PMCID: PMC9204037 DOI: 10.3389/fncel.2022.862673] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/09/2022] [Indexed: 12/13/2022] Open
Abstract
Spinal cord injury (SCI) often leads to severe motor, sensory, and autonomic dysfunction in patients and imposes a huge economic cost to individuals and society. Due to its complicated pathophysiological mechanism, there is not yet an optimal treatment available for SCI. Mesenchymal stromal cells (MSCs) are promising candidate transplant cells for use in SCI treatment. The multipotency of MSCs, as well as their rich trophic and immunomodulatory abilities through paracrine signaling, are expected to play an important role in neural repair. At the same time, the simplicity of MSCs isolation and culture and the bypassing of ethical barriers to stem cell transplantation make them more attractive. However, the MSCs concept has evolved in a specific research context to encompass different populations of cells with a variety of biological characteristics, and failure to understand this can undermine the quality of research in the field. Here, we review the development of the concept of MSCs in order to clarify misconceptions and discuss the controversy in MSCs neural differentiation. We also summarize a potential role of MSCs in SCI treatment, including their migration and trophic and immunomodulatory effects, and their ability to relieve neuropathic pain, and we also highlight directions for future research.
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Affiliation(s)
- Ji-Le Xie
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Xing-Ran Wang
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Mei-Mei Li
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Zi-Han Tao
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Wen-Wen Teng
- Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China
| | - Saijilafu
- Department of Orthopaedics, The First Affiliated Hospital, Soochow University, Suzhou, China,Orthopaedic Institute, School of Medicine, Soochow University, Suzhou, China,*Correspondence: Saijilafu,
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Ahn H, Lee SY, Jung WJ, Lee KH. Treatment of syringomyelia using uncultured umbilical cord mesenchymal stem cells: A case report and review of literature. World J Stem Cells 2022; 14:303-309. [PMID: 35662863 PMCID: PMC9136562 DOI: 10.4252/wjsc.v14.i4.303] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/28/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Syringomyelia is a disease caused by the formation of a cavity inside the spinal cord and is accompanied by such symptoms as pain, paresthesia, and urination and defecation disorders, and in severe cases causes various paralyses. Currently, there are only surgical methods for the treatment of syringomyelia, but these methods carry the possibility of failure, recurrence, and side effects.
CASE SUMMARY The patient was a 59-year-old woman who suffered from pain due to syringomyelia. For treatment, the patient received transplant of uncultured umbilical cord-derived mesenchymal stem cells. As intended, the patient's pain was relieved after treatment. Interestingly, an additional benefit was found in that the size of the cavity also decreased. After 2 years from the last treatment, the patient's cavity had almost completely disappeared and her syringomyelia was deemed cured.
CONCLUSION Using uncultured umbilical cord-derived mesenchymal stem cells may be a new treatment alternative for syringomyelia.
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Affiliation(s)
- Hyunjun Ahn
- Stem Cell Treatment and Research Institute (STRI), bio Beauty and Health Company (bBHC), Seoul 04420, South Korea
| | - Sang Yeon Lee
- Stem Cell Treatment and Research Institute (STRI), bio Beauty and Health Company (bBHC), Seoul 04420, South Korea
| | - Won-Ju Jung
- Stem Cell Treatment, 97.7 Beauty and Health Clinic, Seoul 04420, South Korea
| | - Kye-Ho Lee
- Stem Cell Treatment and Research Institute (STRI), bio Beauty and Health Company (bBHC), Seoul 04420, South Korea
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Xu X, Liang Z, Lin Y, Rao J, Lin F, Yang Z, Wang R, Chen C. Comparing the Efficacy and Safety of Cell Transplantation for Spinal Cord Injury: A Systematic Review and Bayesian Network Meta-Analysis. Front Cell Neurosci 2022; 16:860131. [PMID: 35444516 PMCID: PMC9013778 DOI: 10.3389/fncel.2022.860131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveTo compare the safety and effectiveness of transplanted cells from different sources for spinal cord injury (SCI).DesignA systematic review and Bayesian network meta-analysis.Data SourcesMedline, Embase, and the Cochrane Central Register of Controlled Trials.Study SelectionWe included randomized controlled trials, case–control studies, and case series related to cell transplantation for SCI patients, that included at least 1 of the following outcome measures: American Spinal Cord Injury Association (ASIA) Impairment Scale (AIS grade), ASIA motor score, ASIA sensory score, the Functional Independence Measure score (FIM), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), or adverse events. Follow-up data were analyzed at 6 and 12 months.ResultsForty-four eligible trials, involving 1,266 patients, investigated 6 treatments: olfactory ensheathing cells (OECs), neural stem cells/ neural progenitor cells (NSCs), mesenchymal stem cells (MSCs), Schwann cells, macrophages, and combinations of cells (MSCs plus Schwann cells). Macrophages improved the AIS grade at 12 months (mean 0.42, 95% credible interval: 0–0.91, low certainty) and FIM score at 12 months (42.83, 36.33–49.18, very low certainty). MSCs improved the AIS grade at 6 months (0.42, 0.15–0.73, moderate certainty), the motor score at 6 months (4.43, 0.91–7.78, moderate certainty), light touch at 6 (10.01, 5.81–13.88, moderate certainty) and 12 months (11.48, 6.31–16.64, moderate certainty), pinprick score at 6 (14.54, 9.76–19.46, moderate certainty) and 12 months (12.48, 7.09–18.12, moderate certainty), and the IANR-SCIFRS at 6 (3.96, 0.62–6.97, moderate certainty) and 12 months (5.54, 2.45–8.42, moderate certainty). OECs improved the FIM score at 6 months (9.35, 1.71–17.00, moderate certainty). No intervention improved the motor score significantly at 12 months. The certainty of other interventions was low or very low. Overall, the number of adverse events associated with transplanted cells was low.ConclusionsPatients with SCI who receive transplantation of macrophages, MSCs, NSCs, or OECs may have improved disease prognosis. MSCs are the primary recommendations. Further exploration of the mechanism of cell transplantation in the treatment of SCI, transplantation time window, transplantation methods, and monitoring of the number of transplanted cells and cell survival is needed.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD 42021282043.
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Clinical Trials Using Mesenchymal Stem Cells for Spinal Cord Injury: Challenges in Generating Evidence. Cells 2022; 11:cells11061019. [PMID: 35326470 PMCID: PMC8946989 DOI: 10.3390/cells11061019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 12/12/2022] Open
Abstract
Spinal cord injury (SCI) remains an important public health problem which often causes permanent loss of muscle strength, sensation, and function below the site of the injury, generating physical, psychological, and social impacts throughout the lives of the affected individuals, since there are no effective treatments available. The use of stem cells has been investigated as a therapeutic approach for the treatment of SCI. Although a significant number of studies have been conducted in pre-clinical and clinical settings, so far there is no established cell therapy for the treatment of SCI. One aspect that makes it difficult to evaluate the efficacy is the heterogeneity of experimental designs in the clinical trials that have been published. Cell transplantation methods vary widely among the trials, and there are still no standardized protocols or recommendations for the therapeutic use of stem cells in SCI. Among the different cell types, mesenchymal stem/stromal cells (MSCs) are the most frequently tested in clinical trials for SCI treatment. This study reviews the clinical applications of MSCs for SCI, focusing on the critical analysis of 17 clinical trials published thus far, with emphasis on their design and quality. Moreover, it highlights the need for more evidence-based studies designed as randomized controlled trials and potential challenges to be addressed in context of stem cell therapies for SCI.
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Gao T, Huang F, Wang W, Xie Y, Wang B. Interleukin-10 genetically modified clinical-grade mesenchymal stromal cells markedly reinforced functional recovery after spinal cord injury via directing alternative activation of macrophages. Cell Mol Biol Lett 2022; 27:27. [PMID: 35300585 PMCID: PMC8931978 DOI: 10.1186/s11658-022-00325-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/22/2022] [Indexed: 12/19/2022] Open
Abstract
Background After spinal cord injury (SCI), dysregulated or nonresolving inflammatory processes can severely disturb neuronal homeostasis and drive neurodegeneration. Although mesenchymal stromal cell (MSC)-based therapies have showed certain therapeutic efficacy, no MSC therapy has reached its full clinical goal. In this study, we examine interleukin-10 (IL10) genetically modified clinical-grade MSCs (IL10-MSCs) and evaluate their clinical safety, effectiveness, and therapeutic mechanism in a completely transected SCI mouse model. Methods We established stable IL10-overexpressing human umbilical-cord-derived MSCs through electric transduction and screened out clinical-grade IL10-MSCs according to the criteria of cell-based therapeutic products, which were applied to mice with completely transected SCI by repeated tail intravenous injections. Then we comprehensively investigated the motor function, histological structure, and nerve regeneration in SCI mice, and further explored the potential therapeutic mechanism after IL10-MSC treatment. Results IL10-MSC treatment markedly reinforced locomotor improvement, accompanied with decreased lesion volume, regeneration of axons, and preservation of neurons, compared with naïve unmodified MSCs. Further, IL10-MSC transplantation increased the ratio of microglia to infiltrated alternatively activated macrophages (M2), and reduced the ratio of classically activated macrophages (M1) at the injured spinal cord, meanwhile increasing the percentage of Treg and Th2 cells, and reducing the percentage of Th1 cells in the peripheral circulatory system. In addition, IL10-MSC administration could prevent apoptosis and promote neuron differentiation of neural stem cells (NSCs) under inflammatory conditions in vitro. Conclusions IL10-MSCs exhibited a reliable safety profile and demonstrated promising therapeutic efficacy in SCI compared with naïve MSCs, providing solid support for future clinical application of genetically engineered MSCs. Supplementary Information The online version contains supplementary material available at 10.1186/s11658-022-00325-9.
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Affiliation(s)
- Tianyun Gao
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Feifei Huang
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Wenqing Wang
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Yuanyuan Xie
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Bin Wang
- Center for Clinic Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.
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Van den Bos J, Ouaamari YE, Wouters K, Cools N, Wens I. Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis. Biomolecules 2022; 12:340. [PMID: 35204840 PMCID: PMC8869169 DOI: 10.3390/biom12020340] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/14/2022] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD) and Alzheimer's disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01-0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes.
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Affiliation(s)
- Jasper Van den Bos
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
| | - Yousra El Ouaamari
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
| | - Kristien Wouters
- Clinical Trial Center (CTC), CRC Antwerp, Antwerp University Hospital, University of Antwerp, Drie Eikenstraat 655, B-2650 Edegem, Belgium;
| | - Nathalie Cools
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
- Center for Cell Therapy and Regenerative Medicine (CCRG), Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
| | - Inez Wens
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
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Tang QR, Xue H, Zhang Q, Guo Y, Xu H, Liu Y, Liu JM. Evaluation of the Clinical Efficacy of Stem Cell Transplantation in the Treatment of Spinal Cord Injury: A Systematic Review and Meta-analysis. Cell Transplant 2021; 30:9636897211067804. [PMID: 34939443 PMCID: PMC8725233 DOI: 10.1177/09636897211067804] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Stem cell transplantation has been applied to treat spinal cord injury (SCI) in
clinical trials for many years. However, the clinical efficacies of stem cell
transplantation in SCI have been quite diverse. The purpose of our study was to
systematically investigate the efficacy of stem cell transplantation in patients
with SCI. The PubMed, Web of Science, Ovid-Medline, Cochrane Library, China
National Knowledge Infrastructure, VIP, Wanfang, and SinoMed databases were
searched until October 27, 2020. Quantitative and qualitative data were analyzed
by Review Manager 5.3 and R. Nine studies (n = 328) were
included, and the overall risk of bias was moderate. The ASIA Impairment Scale
(AIS) grading improvement rate was analyzed in favor of stem cell
transplantation group [odds ratio (OR) = 6.06, 95% confidence interval (CI):
3.16–11.62, P < 0.00001]. Urodynamic indices also showed
improvement in bladder function. In subgroup analyses, the results indicated
that in patients with complete (AIS A) SCI, with the application of cell numbers
between n*(107–108), two cell types
(i.e., bone marrow–derived mesenchymal stem cells and bone marrow mononuclears),
and treatment time of more than 6 months, stem cell transplantation was more
beneficial for sensorimotor function (P < 0.05 for all
groups). The risk of fever incidence in the stem cell transplantation group was
4.22 (95% CI: 1.7–10.22, P = 0.001), and principal component
analysis (PCA) suggested it was more related to transplanted cell numbers. Thus,
stem cell transplantation can promote functional recovery in SCI patients.
Moreover, the type and quantity of transplanted stem cells and treatment time
are important factors affecting the therapeutic effect of stem cell
transplantation in SCI. Further studies are needed to evaluate the effects and
elucidate the mechanisms of these factors on stem cell therapy in SCI.
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Affiliation(s)
- Qiao-Rui Tang
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Hui Xue
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Qiao Zhang
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Ying Guo
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Hao Xu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Ying Liu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Jia-Mei Liu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
- Ying Liu, Department of Histology and
Embryology, College of Basic Medical Sciences, Jilin University, Changchun
130021, Jilin Province, P.R. China.
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Liu S, Zhang H, Wang H, Huang J, Yang Y, Li G, Yu K, Yang L. A comparative study of different stem cells transplantation for spinal cord injury: a systematic review and network meta-analysis. World Neurosurg 2021; 159:e232-e243. [PMID: 34954058 DOI: 10.1016/j.wneu.2021.12.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 10/19/2022]
Abstract
OBJECTIVE This study aimed to evaluate the efficacy and safety of different stem cell types for spinal cord injury (SCI) therapy and find out the superior treatment for SCI. METHODS A systematic literature search was performed using PubMed, Embase, the Cochrane Library, Web of Science, VIP, CNKI, and Wan Fang from database initiation to January 30, 2021. A Bayesian network meta-analysis was performed using ADDIS software. The PROSPERO registration number was CRD42020129635. RESULTS Twelve studies with 642 patients were enrolled in this study. Network meta-analysis revealed that bone mesenchymal stem cells combined with rehabilitation training (BMSCs + R) were significantly more effective than rehabilitation training alone (R) in improving American Spinal Injury Association (ASIA) impairment scale (AIS)-grading improvement rate (OR=94.25, 95% CI: 6.71 to 9321.95), ASIA motor score (WMD=6.67, 95% CI: 0.83 to 12.73), ASIA Sensory Functional score (WMD=12.41, 95%CI: 3.42 to 21.72), and Barthel Index (BI) score (WMD=7.24, 95% CI: 0.21 to 14.30). However, no statistically significant differences were observed between marrow mononuclear cells combined with rehabilitation training (MNCs + R), umbilical cord-derived mesenchymal stem cells combined with rehabilitation training (UCMSCs + R), or UCMSCs alone and R on all indicators. In terms of safety, there were no serious and permanent adverse effects after transplantation of BMSCs, MNCs, or UCMSCs. CONCLUSION BMSCs + R may be superior to the other stem cell treatments for SCI in improving AIS grading, ASIA motor score, ASIA Sensory Functional score, and BI score. The therapeutic effects of UCMSCs and MNCs remain to be confirmed.
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Affiliation(s)
- Shuangyan Liu
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huai Zhang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Haiyan Wang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Juan Huang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Yi Yang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China
| | - Guoxiang Li
- Medical School, Shihezi University, Shihezi 832000, China
| | - Kuai Yu
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Lei Yang
- Medical School, Hangzhou Normal University, Hangzhou 310000, China.
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Pang QM, Chen SY, Xu QJ, Fu SP, Yang YC, Zou WH, Zhang M, Liu J, Wan WH, Peng JC, Zhang T. Neuroinflammation and Scarring After Spinal Cord Injury: Therapeutic Roles of MSCs on Inflammation and Glial Scar. Front Immunol 2021; 12:751021. [PMID: 34925326 PMCID: PMC8674561 DOI: 10.3389/fimmu.2021.751021] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/15/2021] [Indexed: 12/27/2022] Open
Abstract
Transected axons are unable to regenerate after spinal cord injury (SCI). Glial scar is thought to be responsible for this failure. Regulating the formation of glial scar post-SCI may contribute to axonal regrow. Over the past few decades, studies have found that the interaction between immune cells at the damaged site results in a robust and persistent inflammatory response. Current therapy strategies focus primarily on the inhibition of subacute and chronic neuroinflammation after the acute inflammatory response was executed. Growing evidences have documented that mesenchymal stem cells (MSCs) engraftment can be served as a promising cell therapy for SCI. Numerous studies have shown that MSCs transplantation can inhibit the excessive glial scar formation as well as inflammatory response, thereby facilitating the anatomical and functional recovery. Here, we will review the effects of inflammatory response and glial scar formation in spinal cord injury and repair. The role of MSCs in regulating neuroinflammation and glial scar formation after SCI will be reviewed as well.
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Affiliation(s)
- Qi-Ming Pang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Si-Yu Chen
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qi-Jing Xu
- Department of Human Anatomy, Zunyi Medical University, Zunyi, China
| | - Sheng-Ping Fu
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China.,Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yi-Chun Yang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wang-Hui Zou
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Meng Zhang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Juan Liu
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wei-Hong Wan
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jia-Chen Peng
- Department of Orthopedics, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Tao Zhang
- Key Laboratory of Cell Engineering of Guizhou Province and Regenerative Medicine Centre, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Kim GU, Sung SE, Kang KK, Choi JH, Lee S, Sung M, Yang SY, Kim SK, Kim YI, Lim JH, Seo MS, Lee GW. Therapeutic Potential of Mesenchymal Stem Cells (MSCs) and MSC-Derived Extracellular Vesicles for the Treatment of Spinal Cord Injury. Int J Mol Sci 2021; 22:13672. [PMID: 34948463 PMCID: PMC8703906 DOI: 10.3390/ijms222413672] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/15/2022] Open
Abstract
Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For ameliorating the neuroinflammatory cascades, MSC has been regarded as a therapeutic agent. The animal SCI research has demonstrated that MSC can be a valuable therapeutic agent with several growth factors and cytokines that may induce anti-inflammatory and regenerative effects. However, the therapeutic efficacy of MSCs in animal SCI models is inconsistent, and the optimal method of MSCs remains debatable. Moreover, there are several limitations to developing these therapeutic agents for humans. Therefore, identifying novel agents for regenerative medicine is necessary. Extracellular vesicles are a novel source for regenerative medicine; they possess nucleic acids, functional proteins, and bioactive lipids and perform various functions, including damaged tissue repair, immune response regulation, and reduction of inflammation. MSC-derived exosomes have advantages over MSCs, including small dimensions, low immunogenicity, and no need for additional procedures for culture expansion or delivery. Certain studies have demonstrated that MSC-derived extracellular vesicles (EVs), including exosomes, exhibit outstanding chondroprotective and anti-inflammatory effects. Therefore, we reviewed the principles and patho-mechanisms and summarized the research outcomes of MSCs and MSC-derived EVs for SCI, reported to date.
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Affiliation(s)
- Gang-Un Kim
- Department of Orthopedic Surgery, Hanil General Hospital, 308 Uicheon-ro, Dobong-gu, Seoul 01450, Korea;
| | - Soo-Eun Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Kyung-Ku Kang
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Joo-Hee Choi
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Sijoon Lee
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Minkyoung Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Seung Yun Yang
- Department of Biomaterials Science, Life and Industry Convergence Institute, Pusan National University, Miryang 50463, Korea;
| | - Seul-Ki Kim
- Efficacy Evaluation Team, Food Science R&D Center, KolmarBNH CO., LTD, 61Heolleungro 8-gil, Seocho-gu, Seoul 06800, Korea;
| | | | - Ju-Hyeon Lim
- New Drug Development Center, Osong Medical Innovation Foundation, Chungbuk 28160, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
| | - Min-Soo Seo
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Gun Woo Lee
- Cellexobio, Co. Ltd., Daegu 42415, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
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Assunção Silva RC, Pinto L, Salgado AJ. Cell transplantation and secretome based approaches in spinal cord injury regenerative medicine. Med Res Rev 2021; 42:850-896. [PMID: 34783046 DOI: 10.1002/med.21865] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 07/12/2021] [Accepted: 10/07/2021] [Indexed: 01/01/2023]
Abstract
The axonal growth-restrictive character of traumatic spinal cord injury (SCI) makes finding a therapeutic strategy a very demanding task, due to the postinjury events impeditive to spontaneous axonal outgrowth and regeneration. Considering SCI pathophysiology complexity, it has been suggested that an effective therapy should tackle all the SCI-related aspects and provide sensory and motor improvement to SCI patients. Thus, the current aim of any therapeutic approach for SCI relies in providing neuroprotection and support neuroregeneration. Acknowledging the current SCI treatment paradigm, cell transplantation is one of the most explored approaches for SCI with mesenchymal stem cells (MSCs) being in the forefront of many of these. Studies showing the beneficial effects of MSC transplantation after SCI have been proposing a paracrine action of these cells on the injured tissues, through the secretion of protective and trophic factors, rather than attributing it to the action of cells itself. This manuscript provides detailed information on the most recent data regarding the neuroregenerative effect of the secretome of MSCs as a cell-free based therapy for SCI. The main challenge of any strategy proposed for SCI treatment relies in obtaining robust preclinical evidence from in vitro and in vivo models, before moving to the clinics, so we have specifically focused on the available vertebrate and mammal models of SCI currently used in research and how can SCI field benefit from them.
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Affiliation(s)
- Rita C Assunção Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Clinical application of stem cell therapy in neurogenic bladder: a systematic review and meta-analysis. Int Urogynecol J 2021; 33:2081-2097. [PMID: 34767058 DOI: 10.1007/s00192-021-04986-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/23/2021] [Indexed: 01/26/2023]
Abstract
INTRODUCTION AND HYPOTHESIS This review aims to investigate the effect of stem cell (SC) therapy on the management of neurogenic bladder (NGB) in four neurological diseases, including spinal cord injury (SCI), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, in the clinical setting. METHODS An electronic database search was conducted in the Cochrane Library, EMBASE, Proquest, Clinicaltrial.gov , WHO, Google Scholar, MEDLINE via PubMed, Ovid, Web of Science, Scopus, ongoing trial registers, and conference proceedings in June 2019 and updated by hand searching on 1 February 2021. All randomized controlled trials (RCTs), quasi RCTs, phase I/II clinical trials, case-control, retrospective cohorts, and comprehensive case series that evaluated the regenerative potential of SCs on the management of NGB were included. Cochrane appraisal risk of bias checklist and the standardized critical appraisal instrument from the JBI Meta-Analysis of Statistics, Assessment, and Review Instrument (JBI-MAStARI) were used to appraise the studies. RESULTS Twenty-six studies among 1282 relevant publications met our inclusion criteria. Only SC therapy was applied for SCI or MS patients. Phase I/II clinical trials (without control arm) were the most conducted studies, and only four were RCTs. Four studies with 153 participants were included in the meta-analysis. The main route of transplantation was via lumbar puncture. There were no serious adverse events. Only nine studies in SCI and one in MS have used urodynamics, and the others have reported improvement based on patient satisfaction. SC therapy did not significantly improve residual urine volume, detrusor pressure, and maximum bladder capacity. Also, the quality of these publications was low or unclear. CONCLUSION Although most clinical trials provide evidence of the safety and effectiveness of MSCs on the management of NGB, the meta-analysis results did not show a significant improvement; however, the interpretation of study results is difficult because of the lack of placebo controls.
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Kouchakian MR, Baghban N, Moniri SF, Baghban M, Bakhshalizadeh S, Najafzadeh V, Safaei Z, Izanlou S, Khoradmehr A, Nabipour I, Shirazi R, Tamadon A. The Clinical Trials of Mesenchymal Stromal Cells Therapy. Stem Cells Int 2021; 2021:1634782. [PMID: 34745268 PMCID: PMC8566082 DOI: 10.1155/2021/1634782] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/22/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a heterogeneous population of adult stem cells, which are multipotent and possess the ability to differentiate/transdifferentiate into mesodermal and nonmesodermal cell lineages. MSCs display broad immunomodulatory properties since they are capable of secreting growth factors and chemotactic cytokines. Safety, accessibility, and isolation from patients without ethical concern make MSCs valuable sources for cell therapy approaches in autoimmune, inflammatory, and degenerative diseases. Many studies have been conducted on the application of MSCs as a new therapy, but it seems that a low percentage of them is related to clinical trials, especially completed clinical trials. Considering the importance of clinical trials to develop this type of therapy as a new treatment, the current paper is aimed at describing characteristics of MSCs and reviewing relevant clinical studies registered on the NIH database during 2016-2020 to discuss recent advances on MSC-based therapeutic approaches being used in different diseases.
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Affiliation(s)
- Mohammad Reza Kouchakian
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Neda Baghban
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Seyedeh Farzaneh Moniri
- Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mandana Baghban
- Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shabnam Bakhshalizadeh
- Reproductive Development, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
| | - Vahid Najafzadeh
- Department of Veterinary and Animal Sciences, Anatomy & Biochemistry Section, University of Copenhagen, Copenhagen, Denmark
| | - Zahra Safaei
- Department of Obstetrics and Gynecology, School of Medicine, Amir Al Mo'menin Hospital, Amir Al Mo'menin IVF Center, Arak University of Medical Sciences, Arak, Iran
| | - Safoura Izanlou
- Department of Nursing, School of Nursing, Larestan University of Medical Sciences, Larestan, Iran
| | - Arezoo Khoradmehr
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Reza Shirazi
- Department of Anatomy, School of Medical Sciences, Medicine & Health, UNSW Sydney, Sydney, Australia
| | - Amin Tamadon
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
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Köhli P, Otto E, Jahn D, Reisener MJ, Appelt J, Rahmani A, Taheri N, Keller J, Pumberger M, Tsitsilonis S. Future Perspectives in Spinal Cord Repair: Brain as Saviour? TSCI with Concurrent TBI: Pathophysiological Interaction and Impact on MSC Treatment. Cells 2021; 10:2955. [PMID: 34831179 PMCID: PMC8616497 DOI: 10.3390/cells10112955] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/08/2021] [Accepted: 10/21/2021] [Indexed: 11/30/2022] Open
Abstract
Traumatic spinal cord injury (TSCI), commonly caused by high energy trauma in young active patients, is frequently accompanied by traumatic brain injury (TBI). Although combined trauma results in inferior clinical outcomes and a higher mortality rate, the understanding of the pathophysiological interaction of co-occurring TSCI and TBI remains limited. This review provides a detailed overview of the local and systemic alterations due to TSCI and TBI, which severely affect the autonomic and sensory nervous system, immune response, the blood-brain and spinal cord barrier, local perfusion, endocrine homeostasis, posttraumatic metabolism, and circadian rhythm. Because currently developed mesenchymal stem cell (MSC)-based therapeutic strategies for TSCI provide only mild benefit, this review raises awareness of the impact of TSCI-TBI interaction on TSCI pathophysiology and MSC treatment. Therefore, we propose that unravelling the underlying pathophysiology of TSCI with concomitant TBI will reveal promising pharmacological targets and therapeutic strategies for regenerative therapies, further improving MSC therapy.
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Affiliation(s)
- Paul Köhli
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ellen Otto
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Denise Jahn
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Marie-Jacqueline Reisener
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
| | - Jessika Appelt
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Adibeh Rahmani
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Nima Taheri
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
| | - Johannes Keller
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany;
- University Hospital Hamburg-Eppendorf, Department of Trauma Surgery and Orthopaedics, Martinistraße 52, 20246 Hamburg, Germany
| | - Matthias Pumberger
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany;
| | - Serafeim Tsitsilonis
- Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, Augustenburger Platz 1, 13353 Berlin, Germany; (P.K.); (E.O.); (D.J.); (M.-J.R.); (J.A.); (A.R.); (N.T.)
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany;
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Amadeo F, Trivino Cepeda K, Littlewood J, Wilm B, Taylor A, Murray P. Mesenchymal stromal cells: what have we learned so far about their therapeutic potential and mechanisms of action? Emerg Top Life Sci 2021; 5:549-562. [PMID: 34495324 PMCID: PMC8589440 DOI: 10.1042/etls20210013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/11/2021] [Accepted: 08/27/2021] [Indexed: 01/10/2023]
Abstract
Mesenchymal stromal cells (MSCs) have been found to be safe and effective in a wide range of animal models of human disease. MSCs have been tested in thousands of clinical trials, but results show that while these cells appear to be safe, they tend to lack efficacy. This has raised questions about whether animal models are useful for predicting efficacy in patients. However, a problem with animal studies is that there is a lack of standardisation in the models and MSC therapy regimes used; there appears to be publication bias towards studies reporting positive outcomes; and the reproducibility of results from animal experiments tends not to be confirmed prior to clinical translation. A further problem is that while some progress has been made towards investigating the mechanisms of action (MoA) of MSCs, we still fail to understand how they work. To make progress, it is important to ensure that prior to clinical translation, the beneficial effects of MSCs in animal studies are real and can be repeated by independent research groups. We also need to understand the MoA of MSCs to assess whether their effects are likely to be beneficial across different species. In this review, we give an overview of the current clinical picture of MSC therapies and discuss what we have learned from animal studies. We also give a comprehensive update of what we know about the MoA of MSCs, particularly in relation to their role in immunomodulation.
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Affiliation(s)
- Francesco Amadeo
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Katherine Trivino Cepeda
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - James Littlewood
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Bettina Wilm
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Arthur Taylor
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
| | - Patricia Murray
- Department of Molecular Physiology and Cell Signalling, Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
- Centre for Pre-clinical Imaging, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Crown Street, L69 3GE Liverpool, U.K
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Shinozaki M, Nagoshi N, Nakamura M, Okano H. Mechanisms of Stem Cell Therapy in Spinal Cord Injuries. Cells 2021; 10:cells10102676. [PMID: 34685655 PMCID: PMC8534136 DOI: 10.3390/cells10102676] [Citation(s) in RCA: 29] [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: 09/07/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 12/13/2022] Open
Abstract
Every year, 0.93 million people worldwide suffer from spinal cord injury (SCI) with irretrievable sequelae. Rehabilitation, currently the only available treatment, does not restore damaged tissues; therefore, the functional recovery of patients remains limited. The pathophysiology of spinal cord injuries is heterogeneous, implying that potential therapeutic targets differ depending on the time of injury onset, the degree of injury, or the spinal level of injury. In recent years, despite a significant number of clinical trials based on various types of stem cells, these aspects of injury have not been effectively considered, resulting in difficult outcomes of trials. In a specialty such as cancerology, precision medicine based on a patient’s characteristics has brought indisputable therapeutic advances. The objective of the present review is to promote the development of precision medicine in the field of SCI. Here, we first describe the multifaceted pathophysiology of SCI, with the temporal changes after injury, the characteristics of the chronic phase, and the subtypes of complete injury. We then detail the appropriate targets and related mechanisms of the different types of stem cell therapy for each pathological condition. Finally, we highlight the great potential of stem cell therapy in cervical SCI.
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Affiliation(s)
- Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;
| | - Narihito Nagoshi
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (M.N.)
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (M.N.)
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;
- Correspondence:
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Biktimirov A, Pak O, Bryukhovetskiy I, Sharma A, Sharma HS. Neuromodulation as a basic platform for neuroprotection and repair after spinal cord injury. PROGRESS IN BRAIN RESEARCH 2021; 266:269-300. [PMID: 34689861 DOI: 10.1016/bs.pbr.2021.06.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Spinal cord injury (SCI) is one of the most challenging medical issues. Spasticity is a major complication of SCI. A combination of spinal cord stimulation, new methods of neuroprotection and biomedical cellular products provides fundamentally new options for SCI treatment and rehabilitation. The paper attempts to critically analyze the effectiveness of using these procedures for patients with SCI, suggesting a protocol for a step-by-step personalized treatment of SCI, based on continuity of modern conservative and surgical methods. The study argues the possibility of using neuromodulation as a basis for rehabilitating patients with SCI.
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Affiliation(s)
- Artur Biktimirov
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
| | - Oleg Pak
- Department of Neurosurgery, Medical Center, Far Eastern Federal University, Vladivostok, Russia
| | - Igor Bryukhovetskiy
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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Mukai T, Sei K, Nagamura-Inoue T. Mesenchymal Stromal Cells Perspective: New Potential Therapeutic for the Treatment of Neurological Diseases. Pharmaceutics 2021; 13:pharmaceutics13081159. [PMID: 34452120 PMCID: PMC8401282 DOI: 10.3390/pharmaceutics13081159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 12/13/2022] Open
Abstract
Several studies have shown that mesenchymal stromal/stem cells (MSCs) exert their neuroprotective and neurorestorative efficacy via the secretion of neurotrophic factors. Based on these studies, many clinical trials using MSCs for the treatment of neurological disorders have been conducted, and results regarding their feasibility and efficacy have been reported. The present review aims to highlight the characteristics and basic research regarding the role of MSCs in neurological disease and to discuss the recent progress in clinical trials using MSCs to treat various neurological disorders.
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Affiliation(s)
- Takeo Mukai
- Department of Pediatrics, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
- Correspondence: ; Tel.: +81-3-3815-5411; Fax: 81-3-5449-5452
| | - Kenshi Sei
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
| | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; (K.S.); (T.N.-I.)
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Suzuki H, Sakai T. Current Concepts of Stem Cell Therapy for Chronic Spinal Cord Injury. Int J Mol Sci 2021; 22:ijms22147435. [PMID: 34299053 PMCID: PMC8308009 DOI: 10.3390/ijms22147435] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic spinal cord injury (SCI) is a catastrophic condition associated with significant neurological deficit and social and financial burdens. It is currently being managed symptomatically with no real therapeutic strategies available. In recent years, a number of innovative regenerative strategies have emerged and have been continuously investigated in clinical trials. In addition, several more are coming down the translational pipeline. Among ongoing and completed trials are those reporting the use of mesenchymal stem cells, neural stem/progenitor cells, induced pluripotent stem cells, olfactory ensheathing cells, and Schwann cells. The advancements in stem cell technology, combined with the powerful neuroimaging modalities, can now accelerate the pathway of promising novel therapeutic strategies from bench to bedside. Various combinations of different molecular therapies have been combined with supportive scaffolds to facilitate favorable cell–material interactions. In this review, we summarized some of the most recent insights into the preclinical and clinical studies using stem cells and other supportive drugs to unlock the microenvironment in chronic SCI to treat patients with this condition. Successful future therapies will require these stem cells and other synergistic approaches to address the persistent barriers to regeneration, including glial scarring, loss of structural framework, and immunorejection.
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Shu J, Cheng F, Gong Z, Ying L, Wang C, Yu C, Zhou X, Xiao M, Wang J, Xia K, Huang X, Tao Y, Shi K, Liu Y, Liang C, Chen Q, Feng X, Li F. Transplantation Strategies for Spinal Cord Injury Based on Microenvironment Modulation. Curr Stem Cell Res Ther 2021; 15:522-530. [PMID: 32316901 DOI: 10.2174/1574888x15666200421112622] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/27/2020] [Accepted: 03/02/2020] [Indexed: 12/20/2022]
Abstract
Spinal cord injury (SCI) is different from peripheral nerve injury; it results in devastating and permanent damage to the spine, leading to severe motor, sensory and autonomic dysfunction. SCI produces a complex microenvironment that can result in hemorrhage, inflammation and scar formation. Not only does it significantly limit regeneration, but it also challenges a multitude of transplantation strategies. In order to promote regeneration, researchers have recently begun to focus their attention on strategies that manipulate the complicated microenvironment produced by SCI. And some have achieved great therapeutic effects. Hence, reconstructing an appropriate microenvironment after transplantation could be a potential therapeutic solution for SCI. In this review, first, we aim to summarize the influential compositions of the microenvironment and their different effects on regeneration. Second, we highlight recent research that used various transplantation strategies to modulate different microenvironments produced by SCI in order to improve regeneration. Finally, we discuss future transplantation strategies regarding SCI.
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Affiliation(s)
- Jiawei Shu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Feng Cheng
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Zhe Gong
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Liwei Ying
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Chenggui Wang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Chao Yu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Xiaopeng Zhou
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Mu Xiao
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jingkai Wang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Kaishun Xia
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Xianpeng Huang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Yiqing Tao
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Kesi Shi
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Yuemei Liu
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chengzhen Liang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Qixin Chen
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Xinhua Feng
- The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fangcai Li
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
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Chen WC, Liu WF, Bai YY, Zhou YY, Zhang Y, Wang CM, Lin S, He HF. Transplantation of mesenchymal stem cells for spinal cord injury: a systematic review and network meta-analysis. J Transl Med 2021; 19:178. [PMID: 33910588 PMCID: PMC8082850 DOI: 10.1186/s12967-021-02843-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 04/18/2021] [Indexed: 12/17/2022] Open
Abstract
Spinal cord injury (SCI) is a severe traumatic disease of the central nervous system, with a global prevalence of 236–4187 per million people. This meta-analysis aimed to evaluate the safety and efficacy of mesenchymal stem cells (MSCs) in treating patients with SCI as well as the optimal source and transplantation method of MSCs. PubMed, OVID, Cochrane, Web of Science, and China Biomedical Database were searched up until April 01, 2021. The study was conducted for five endpoints: American Spinal Injury Association (ASIA) motor and sensory score, ASIA grade improvement, Barthel Index (BI), and adverse reactions. Standard meta-analysis and network meta-analysis were performed using Stata 14.0. Eighteen studies with a total of 949 patients, were included in the meta-analysis. Standard meta-analysis showed that MSCs significantly improved ASIA motor score (P < 0.001), sensory score (P < 0.001), ASIA grade (P < 0.001), and BI (P < 0.001) compared to rehabilitation. In addition, in the network meta-analysis, autologous MSCs significantly improved the ASIA motor [MD = 8.01, 95% CI (4.27, 11.76)], sensory score [MD = 17.98, 95% CI (10.04, 25.91)], and BI [MD = 7.69, 95% CI (2.10, 13.29)] compared to rehabilitation. Similarly, compared to rehabilitation, intrathecal injection (IT) of MSCs significantly improved the ASIA motor [MD = 7.97, 95% CI (4.40, 11.53)] and sensory score [MD = 19.60, 95% CI (9.74, 29.46)]. Compared to rehabilitation, however, only the IL of MSCs was associated with more adverse reactions [OR = 17.82, 95% CI (2.48, 128.22)]. According to the results of SUCRA, both autologous MSCs and IT transplantation approaches most improved the neurological function in SCI patients. Cell transplantation using MSCs is effective in patients with SCI and IT of autologous MSCs may be more beneficial.
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Affiliation(s)
- Wei-Can Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Wei-Feng Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yu-Yan Bai
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Ying-Ying Zhou
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yan Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Cong-Mei Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China. .,Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China. .,Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia.
| | - He-Fan He
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
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