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Bradshaw KJ, Leipzig ND. Applications of Regenerative Tissue-Engineered Scaffolds for Treatment of Spinal Cord Injury. Tissue Eng Part A 2025; 31:108-125. [PMID: 39556330 DOI: 10.1089/ten.tea.2024.0194] [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] [Indexed: 11/19/2024] Open
Abstract
Tissue engineering provides a path forward for emerging personalized medicine therapies as well as the ability to bring about cures for diseases or chronic injuries. Traumatic spinal cord injuries (SCIs) are an example of a chronic injury in which no cure or complete functional recovery treatment has been developed. In part, this has been due to the complex and interconnected nature of the central nervous system (CNS), the cellular makeup, its extracellular matrix (ECM), and the injury site pathophysiology. One way to combat the complex nature of an SCI has been to create functional tissue-engineered scaffolds that replace or replenish the aspects of the CNS and tissue/ECM that are damaged following the immediate injury and subsequent immune response. This can be achieved by employing the tissue-engineering triad consisting of cells, biomaterial(s), and environmental factors. Stem cells, with their innate ability to proliferate and differentiate, are a common choice for cellular therapies. Natural or synthetic biomaterials that have tunable characteristics are normally used as the scaffold base. Environmental factors can range from drugs to growth factors (GFs) or proteins, depending on if the idea would be to stimulate exogeneous or endogenous cell populations or just simply retain cells on the scaffold for effective transplantation. For functional regeneration and integration for SCI, the scaffold must promote neuroprotection and neuroplasticity. Tissue-engineering strategies have shown benefits including neuronal differentiation, axonal regeneration, axonal outgrowth, integration into the native spinal cord, and partial functional recovery. Overall, this review focuses on the background that causes SCI to be so difficult to treat, the individual components of the tissue-engineering triad, and how combinatorial scaffolds can be beneficial toward the prospects of future SCI recovery.
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Affiliation(s)
- Katherine J Bradshaw
- Department of Biomedical Engineering, Auburn Science and Engineering Center #275, The University of Akron, Akron, Ohio, USA
| | - Nic D Leipzig
- Department of Biomedical Engineering, Auburn Science and Engineering Center #275, The University of Akron, Akron, Ohio, USA
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio, USA
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Tan J, Chen J, Roxby D, Chooi WH, Nguyen TD, Ng SY, Han J, Chew SY. Using magnetic resonance relaxometry to evaluate the safety and quality of induced pluripotent stem cell-derived spinal cord progenitor cells. Stem Cell Res Ther 2024; 15:465. [PMID: 39639398 PMCID: PMC11622678 DOI: 10.1186/s13287-024-04070-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: 07/26/2024] [Accepted: 11/20/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND The emergence of induced pluripotent stem cells (iPSCs) offers a promising approach for replacing damaged neurons and glial cells, particularly in spinal cord injuries (SCI). Despite its merits, iPSC differentiation into spinal cord progenitor cells (SCPCs) is variable, necessitating reliable assessment of differentiation and validation of cell quality and safety. Phenotyping is often performed via label-based methods including immunofluorescent staining or flow cytometry analysis. These approaches are often expensive, laborious, time-consuming, destructive, and severely limits their use in large scale cell therapy manufacturing settings. On the other hand, cellular biophysical properties have demonstrated a strong correlation to cell state, quality and functionality and can be measured with ingenious label-free technologies in a rapid and non-destructive manner. METHOD In this study, we report the use of Magnetic Resonance Relaxometry (MRR), a rapid and label-free method that indicates iron levels based on its readout (T2). Briefly, we differentiated human iPSCs into SCPCs and compared key iPSC and SCPC cellular markers to their intracellular iron content (Fe3+) at different stages of the differentiation process. RESULTS With MRR, we found that intracellular iron of iPSCs and SCPCs were distinctively different allowing us to accurately reflect varying levels of residual undifferentiated iPSCs (i.e., OCT4+ cells) in any given population of SCPCs. MRR was also able to predict Day 10 SCPC OCT4 levels from Day 1 undifferentiated iPSC T2 values and identified poorly differentiated SCPCs with lower T2, indicative of lower neural progenitor (SOX1) and stem cell (Nestin) marker expression levels. Lastly, MRR was able to provide predictive indications for the extent of differentiation to Day 28 spinal cord motor neurons (ISL-1/SMI-32) based on the T2 values of Day 10 SCPCs. CONCLUSION MRR measurements of iPSCs and SCPCs has clearly indicated its capabilities to identify and quantify key phenotypes of iPSCs and SCPCs for end-point validation of safety and quality parameters. Thus, our technology provides a rapid label-free method to determine critical quality attributes in iPSC-derived progenies and is ideally suited as a quality control tool in cell therapy manufacturing.
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Affiliation(s)
- Jerome Tan
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore
- HealthTech @ NTU, Interdisciplinary Graduate Programme, Nanyang Technological University, Singapore, Singapore
- CAMP IRG, SMART Centre, CREATE, Singapore, Singapore
| | - Jiahui Chen
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore
| | - Daniel Roxby
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore
- CAMP IRG, SMART Centre, CREATE, Singapore, Singapore
| | - Wai Hon Chooi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | | | - Shi Yan Ng
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Jongyoon Han
- CAMP IRG, SMART Centre, CREATE, Singapore, Singapore.
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA.
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, USA.
| | - Sing Yian Chew
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
- CAMP IRG, SMART Centre, CREATE, Singapore, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
- School of Materials Science and Engineering, Nanyang Technological University, Singapore, Singapore.
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Dadvand A, Yavari A, Teimourpour A, Farzad-Mohajeri S. Influential factors on stem cell therapy success in canine model of spinal cord Injury: A systematic review and meta-analysis. Brain Res 2024; 1839:148997. [PMID: 38795792 DOI: 10.1016/j.brainres.2024.148997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 05/03/2024] [Accepted: 05/10/2024] [Indexed: 05/28/2024]
Abstract
Spinal cord injury (SCI) is a serious medical condition. The search for an effective cure remains a persistent challenge. Current treatments, unfortunately, are unable to sufficiently improve neurological function, often leading to lifelong disability. This systematic review and meta-analysis evaluated the effectiveness of stem cell therapy for SCI using canine models. It also explored the optimal protocol for implementing stem cell therapy. A comprehensive search of studies was conducted from 2000 to October 2022. This study focused on five outcomes: motor function score, histopathology, IHC, western blot, and SEP. The results demonstrated a significant improvement in locomotion post-SCI in dogs treated with stem cell therapy. The therapy also led to an average increase of 3.15 points in the Olby score of the treated dogs compared to the control group. These findings highlights stem cell therapy's potential as a promising SCI treatment. The meta-analysis suggests that using bone marrow stem cells, undergoing neural differentiation in vitro, applying a surgical implantation or intrathecal route of administration, associating matrigel in combination with stem cells, and a waiting period of two weeks before starting treatment can enhance SCI treatment effectiveness.
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Affiliation(s)
- Avin Dadvand
- Department of Surgery and Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Alimohammad Yavari
- Department of Surgery and Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Amir Teimourpour
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Saeed Farzad-Mohajeri
- Department of Surgery and Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran; Department of Regenerative Medicine, Institute of Biomedical Research, University of Tehran, Tehran, Iran.
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Hong SJ, Bock M, Zhang S, An SB, Han I. Therapeutic Transplantation of Human Central Nervous System Organoids for Neural Reconstruction. Int J Mol Sci 2024; 25:8540. [PMID: 39126108 PMCID: PMC11313261 DOI: 10.3390/ijms25158540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/03/2024] [Accepted: 08/03/2024] [Indexed: 08/12/2024] Open
Abstract
Damage to the central nervous system (CNS) often leads to irreversible neurological deficits, and there are currently few effective treatments available. However, recent advancements in regenerative medicine have identified CNS organoids as promising therapeutic options for addressing CNS injuries. These organoids, composed of various neurons and supporting cells, have shown potential for direct repair at injury sites. CNS organoids resemble the structure and function of actual brain tissue, which allows them to adapt and function well within the physiological environment when transplanted into injury sites. Research findings suggest that CNS organoids can replace damaged neurons, form new neural connections, and promote neural recovery. This review highlights the emerging benefits, evaluates preclinical transplantation outcomes, and explores future strategies for optimizing neuroregeneration using CNS organoids. With continued research and technological advancements, these organoids could provide new hope for patients suffering from neurological deficits.
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Affiliation(s)
- Sung Jun Hong
- Research Competency Milestones Program (RECOMP), School of Medicine, CHA University, Seongnam-si 13488, Republic of Korea;
- Department of Medicine, School of Medicine, CHA University, Seongnam-si 13496, Republic of Korea
| | - Minsung Bock
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
| | - Songzi Zhang
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
| | - Seong Bae An
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
| | - Inbo Han
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea; (M.B.); (S.Z.); (S.B.A.)
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Jeon J, Park SH, Choi J, Han SM, Kim HW, Shim SR, Hyun JK. Association between neural stem/progenitor cells and biomaterials in spinal cord injury therapies: A systematic review and network meta-analysis. Acta Biomater 2024; 183:50-60. [PMID: 38871200 DOI: 10.1016/j.actbio.2024.06.011] [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: 03/11/2024] [Revised: 06/03/2024] [Accepted: 06/06/2024] [Indexed: 06/15/2024]
Abstract
Spinal cord injury (SCI) is associated with substantial healthcare challenges, frequently resulting in enduring sensory and motor deficits alongside various chronic complications. While advanced regenerative therapies have shown promise in preclinical research, their translation into clinical application has been limited. In response, this study utilized a comprehensive network meta-analysis to evaluate the effectiveness of neural stem/progenitor cell (NSPC) transplantation across animal models of SCI. We analyzed 363 outcomes from 55 distinct studies, categorizing the treatments into NSPCs alone (cell only), NSPCs with scaffolds (cell + scaffold), NSPCs with hydrogels (cell + hydrogel), standalone scaffolds (scaffold), standalone hydrogels (hydrogel), and control groups. Our analysis demonstrated significant enhancements in motor recovery, especially in gait function, within the NSPC treatment groups. Notably, the cell only group showed considerable improvements (standardized mean difference [SMD], 2.05; 95 % credible interval [CrI]: 1.08 to 3.10, p < 0.01), as did the cell + scaffold group (SMD, 3.73; 95 % CrI: 2.26 to 5.22, p < 0.001) and the cell + hydrogel group (SMD, 3.37; 95 % CrI: 1.02 to 5.78, p < 0.05) compared to controls. These therapeutic combinations not only reduced lesion cavity size but also enhanced neuronal regeneration, outperforming the cell only treatments. By integrating NSPCs with supportive biomaterials, our findings pave the way for refining these regenerative strategies to optimize their potential in clinical SCI treatment. Although there is no overall violation of consistency, the comparison of effect sizes between individual treatments should be interpreted in light of the inconsistency. STATEMENT OF SIGNIFICANCE: This study presents a comprehensive network meta-analysis exploring the efficacy of neural stem cell (NSC) transplantation, with and without biomaterials, in animal models of spinal cord injury (SCI). We demonstrate that NSCs, particularly when combined with biomaterials like scaffolds or hydrogels, significantly enhance motor and histological recovery post-SCI. These findings underscore the potential of NSC-based therapies, augmented with biomaterials, to advance SCI treatment, offering new insights into regenerative strategies that could significantly impact clinical practices.
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Affiliation(s)
- Jooik Jeon
- Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea
| | | | - Jonghyuk Choi
- Department of Preventive Medicine, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Sun Mi Han
- Medical record team, Konyang University Hospital, Daejeon 35365, Republic of Korea
| | - Hae-Won Kim
- Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan 31116, Republic of Korea
| | - Sung Ryul Shim
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea.
| | - Jung Keun Hyun
- Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Republic of Korea; Wiregene, Co. Ltd., Osong 28160, Republic of Korea; Department of Rehabilitation Medicine, College of Medicine, Dankook University, Cheonan 31116, Republic of Korea.
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Alvi MA, Pedro KM, Quddusi AI, Fehlings MG. Advances and Challenges in Spinal Cord Injury Treatments. J Clin Med 2024; 13:4101. [PMID: 39064141 PMCID: PMC11278467 DOI: 10.3390/jcm13144101] [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: 04/16/2024] [Revised: 07/03/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024] Open
Abstract
Spinal cord injury (SCI) is a debilitating condition that is associated with long-term physical and functional disability. Our understanding of the pathogenesis of SCI has evolved significantly over the past three decades. In parallel, significant advances have been made in optimizing the management of patients with SCI. Early surgical decompression, adequate bony decompression and expansile duraplasty are surgical strategies that may improve neurological and functional outcomes in patients with SCI. Furthermore, advances in the non-surgical management of SCI have been made, including optimization of hemodynamic management in the critical care setting. Several promising therapies have also been investigated in pre-clinical studies, with some being translated into clinical trials. Given the recent interest in advancing precision medicine, several investigations have been performed to delineate the role of imaging, cerebral spinal fluid (CSF) and serum biomarkers in predicting outcomes and curating individualized treatment plans for SCI patients. Finally, technological advancements in biomechanics and bioengineering have also found a role in SCI management in the form of neuromodulation and brain-computer interfaces.
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Affiliation(s)
- Mohammed Ali Alvi
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; (M.A.A.); (K.M.P.); (A.I.Q.)
| | - Karlo M. Pedro
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; (M.A.A.); (K.M.P.); (A.I.Q.)
- Department of Surgery and Spine Program, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - Ayesha I. Quddusi
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; (M.A.A.); (K.M.P.); (A.I.Q.)
| | - Michael G. Fehlings
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; (M.A.A.); (K.M.P.); (A.I.Q.)
- Department of Surgery and Spine Program, University of Toronto, Toronto, ON M5T 1P5, Canada
- Division of Neurosurgery, Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, ON M5T 2S8, Canada
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Li M, Wang X, Qi B, Cui S, Zheng T, Guan Y, Ma L, Liu S, Li Q, Chen Z, Jian F. Treatment of Syringomyelia Characterized by Focal Dilatation of the Central Canal Using Mesenchymal Stem Cells and Neural Stem Cells. Tissue Eng Regen Med 2024; 21:625-639. [PMID: 38578425 PMCID: PMC11087409 DOI: 10.1007/s13770-024-00637-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 02/03/2024] [Accepted: 03/05/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Syringomyelia is a progressive chronic disease that leads to nerve pain, sensory dissociation, and dyskinesia. Symptoms often do not improve after surgery. Stem cells have been widely explored for the treatment of nervous system diseases due to their immunoregulatory and neural replacement abilities. METHODS In this study, we used a rat model of syringomyelia characterized by focal dilatation of the central canal to explore an effective transplantation scheme and evaluate the effect of mesenchymal stem cells and induced neural stem cells for the treatment of syringomyelia. RESULTS The results showed that cell transplantation could not only promote syrinx shrinkage but also stimulate the proliferation of ependymal cells, and the effect of this result was related to the transplantation location. These reactions appeared only when the cells were transplanted into the cavity. Additionally, we discovered that cell transplantation transformed activated microglia into the M2 phenotype. IGF1-expressing M2 microglia may play a significant role in the repair of nerve pain. CONCLUSION Cell transplantation can promote cavity shrinkage and regulate the local inflammatory environment. Moreover, the proliferation of ependymal cells may indicate the activation of endogenous stem cells, which is important for the regeneration and repair of spinal cord injury.
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Affiliation(s)
- Mo Li
- Department of Neurosurgery, China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Xinyu Wang
- Department of Neurosurgery, China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Boling Qi
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Shengyu Cui
- Department of Neurosurgery, China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Tianqi Zheng
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Yunqian Guan
- Department of Neurosurgery, China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Longbing Ma
- Department of Neurosurgery, China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Sumei Liu
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China
| | - Qian Li
- Department of Neurosurgery, China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
| | - Zhiguo Chen
- Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, 100053, China.
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China.
- Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.
| | - Fengzeng Jian
- Department of Neurosurgery, China International Neuroscience Institute, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
- Research Center of Spine and Spinal Cord, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
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Del Casale A, Modesti MN, Gentile G, Guariglia C, Ferracuti S, Simmaco M, Borro M. Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development. Curr Issues Mol Biol 2024; 46:5322-5336. [PMID: 38920990 PMCID: PMC11202070 DOI: 10.3390/cimb46060318] [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: 04/12/2024] [Revised: 05/09/2024] [Accepted: 05/21/2024] [Indexed: 06/27/2024] Open
Abstract
Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.
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Affiliation(s)
- Antonio Del Casale
- Department of Dynamic and Clinical Psychology and Health Studies, Faculty of Medicine and Psychology, Sapienza University of Rome, 00185 Rome, Italy;
- Unit of Psychiatry, Emergency and Admissions Department, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Martina Nicole Modesti
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, 00185 Rome, Italy
- Unit of Psychiatry, Mental Health Department, Santissimo Gonfalone Hospital, Local Health Service Roma 5, Monterotondo, 00015 Rome, Italy
| | - Giovanna Gentile
- Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University, 00189 Rome, Italy
- Unit of Laboratory and Advanced Molecular Diagnostics, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Cecilia Guariglia
- Department of Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, 00185 Rome, Italy
- Cognitive and Motor Rehabilitation and Neuroimaging Unit, Scientific Institute for Research, Hospitalization and Healthcare Fondazione Santa Lucia, 00179 Rome, Italy
| | - Stefano Ferracuti
- Department of Human Neuroscience, Faculty of Medicine and Dentistry, Sapienza University of Rome, 00185 Rome, Italy;
- Unit of Risk Management, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Maurizio Simmaco
- Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University, 00189 Rome, Italy
- Unit of Laboratory and Advanced Molecular Diagnostics, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Marina Borro
- Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University, 00189 Rome, Italy
- Unit of Laboratory and Advanced Molecular Diagnostics, Sant’Andrea University Hospital, 00189 Rome, Italy
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Shang WY, Ren YF, Li B, Huang XM, Zhang ZL, Huang J. Efficacy of growth factor gene-modified stem cells for motor function after spinal cord injury in rodents: a systematic review and meta‑analysis. Neurosurg Rev 2024; 47:87. [PMID: 38369598 DOI: 10.1007/s10143-024-02314-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/15/2024] [Accepted: 02/03/2024] [Indexed: 02/20/2024]
Abstract
The efficacy of growth factor gene-modified stem cells in treating spinal cord injury (SCI) remains unclear. This study aims to evaluate the effectiveness of growth factor gene-modified stem cells in restoring motor function after SCI. Two reviewers searched four databases, including PubMed, Embase, Web of Science, and Scopus, to identify relevant records. Studies on rodents assessing the efficacy of transplanting growth factor gene-modified stem cells in restoring motor function after SCI were included. The results were reported using the standardized mean difference (SMD) with a 95% confidence interval (95% CI). Analyses showed that growth factor gene-modified stem cell transplantation improved motor function recovery in rodents with SCI compared to the untreated (SMD = 3.98, 95% CI 3.26-4.70, I2 = 86.8%, P < 0.0001) and stem cell (SMD = 2.53, 95% CI 1.93-3.13, I2 = 86.9%, P < 0.0001) groups. Using growth factor gene-modified neural stem/histone cells enhanced treatment efficacy. In addition, the effectiveness increased when viral vectors were employed for gene modification and high transplantation doses were administered during the subacute phase. Stem cells derived from the human umbilical cord exhibited an advantage in motor function recovery. However, the transplantation of growth factor gene-modified stem cells did not significantly improve motor function in male rodents (P = 0.136). Transplantation of growth factor gene-modified stem cells improved motor function in rodents after SCI, but claims of enhanced efficacy should be approached with caution. The safety of gene modification remains a significant concern, requiring additional efforts to enhance its clinical translatability.
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Affiliation(s)
- Wen-Ya Shang
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Ya-Feng Ren
- The First Affiliated Hospital of Henan University of CM, Zhengzhou, China.
| | - Bing Li
- The First Affiliated Hospital of Henan University of CM, Zhengzhou, China
| | | | - Zhi-Lan Zhang
- Henan University of Chinese Medicine, Zhengzhou, China
| | - Jing Huang
- Henan University of Chinese Medicine, Zhengzhou, China
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Chen T, Zhu J, Wang G, Sun J, Ma X, Tian L, Zhang M, Wang F, Yu Z. The global state of research in stem cells therapy for spinal cord injury (2003-2022): a visualized analysis. Front Neurosci 2024; 18:1323383. [PMID: 38327844 PMCID: PMC10847251 DOI: 10.3389/fnins.2024.1323383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 01/09/2024] [Indexed: 02/09/2024] Open
Abstract
Objective Our study aimed to visualize the global status and frontiers in stem cell therapy for spinal cord injury by using bibliometric methodology. Methods Publication citation information related to stem cell therapy for spinal cord injury (SCI) studies between 2003 and 2022 was retrieved from the Web of Science Core Collection database. For the visualized study, VOS viewer software and Graph Pad Prism 9.5 were used to perform bibliometric analysis of included data and publication number statistics in stem cell therapy for the SCI domain. Results A total of 6,686 publications were retrieved. The USA and China made the highest contributions to global research with the highest number of citations and link strength. The journal Experimental Neurology ranks as the top journal, combining the publication amount and bibliometrics results. The University of Toronto, based in Canada, was the first-ranking institution. The directions of the current study could be divided into five clusters. The research of Transplantation and Regenerative Medicine and Neurosciences Mechanism Research may be the emerging frontiers in this domain. Conclusion In summary, stem cell therapy for spinal cord injuries is poised for more valuable advances.
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Affiliation(s)
- Taoyu Chen
- Department of Orthopedics, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Jiaying Zhu
- College of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Gang Wang
- Department of Orthopedics, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Jinlei Sun
- Department of Orthopedics, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Xiaofeng Ma
- Department of Orthopedics, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Lijun Tian
- Department of Orthopedics, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Meiling Zhang
- Department of Orthopedics, 981st Hospital of the Chinese People’s Liberation Army Joint Logistics Support Force, Chengde, China
| | - Fengyan Wang
- Department of Orthopedics, 981st Hospital of the Chinese People’s Liberation Army Joint Logistics Support Force, Chengde, China
| | - Ze Yu
- Department of Orthopedics, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
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11
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Dong X, Hong H, Cui Z. Function of GSK‑3 signaling in spinal cord injury (Review). Exp Ther Med 2023; 26:541. [PMID: 37869638 PMCID: PMC10587879 DOI: 10.3892/etm.2023.12240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 08/10/2023] [Indexed: 10/24/2023] Open
Abstract
Spinal cord injury (SCI) is a major social problem with a heavy burden on patient physiology and psychology. Glial scar formation and irreversible neuron loss are the two key points during SCI progression. During the acute phase of spinal cord injury, glial scars form, limiting the progression of inflammation. However, in the subacute or chronic phase, glial scarring inhibits axon regeneration. Following spinal cord injury, irreversible loss of neurons leads to further aggravation of spinal cord injury. Several therapies have been developed to improve either glial scar or neuron loss; however, few therapies reach the stage of clinical trials and there are no mainstream therapies for SCI. Exploring the key mechanism of SCI is crucial for finding further treatments. Glycogen synthase kinase-3 (GSK-3) is a widely expressed kinase with important physiological and pathophysiological functions in vivo. Dysfunction of the GSK-3 signaling pathway during SCI has been widely discussed for controlling neurite growth in vitro and in vivo, improving the proliferation and neuronal differentiation of endogenous neural stem cells and functional recovery from spinal cord injury. SCI can decrease the phosphorylated (p)/total (t)-GSK-3β ratio, which leads to an increase in apoptosis, whereas treatment with GSK-3 inhibitors can promote neurogenesis. In addition, several therapies for the treatment of SCI involve signaling pathways associated with GSK-3. Furthermore, signaling pathways associated with GSK-3 also participate in the pathological process of neuropathic pain that remains following SCI. The present review summarized the roles of GSK-3 signaling in SCI to aid in the understanding of GSK-3 signaling during the pathological processes of SCI and to provide evidence for the development of comprehensive treatments.
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Affiliation(s)
- Xiong Dong
- Department of Spinal Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Hongxiang Hong
- Department of Spinal Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Zhiming Cui
- Department of Spinal Surgery, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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12
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Toloui A, Ramawad HA, Gharin P, Vaccaro AR, Zarei H, Hosseini M, Yousefifard M, Rahimi-Movaghar V. The Role of Exercise in the Alleviation of Neuropathic Pain Following Traumatic Spinal Cord Injuries: A Systematic Review and Meta-analysis. Neurospine 2023; 20:1073-1087. [PMID: 37798999 PMCID: PMC10562228 DOI: 10.14245/ns.2346588.294] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/31/2023] [Accepted: 08/04/2023] [Indexed: 10/07/2023] Open
Abstract
OBJECTIVE The objective of this systematic review and meta-analysis was to assess the efficacy of exercise in neuropathic pain following traumatic spinal cord injuries. METHODS The search was conducted in MEDLINE, Embase, Scopus, and Web of Science by the end of 2022. Two independent researchers included the articles based on the inclusion and exclusion criteria. A standardized mean difference was calculated for each data and they were pooled to calculate an overall effect size. To assess the heterogeneity between studies, I2 and chi-square tests were utilized. In the case of heterogeneity, meta-regression was performed to identify the potential source. RESULTS Fifteen preclinical studies were included. Meta-analysis demonstrated that exercise significantly improves mechanical allodynia (standardized mean difference [SMD], -1.59; 95% confidence interval [CI], -2.16 to -1.02; p < 0.001; I2 = 90.37%), thermal hyperalgesia (SMD, 1.95; 95% CI, 0.96-2.94; p < 0.001), and cold allodynia (SMD, -2.92; 95% CI, -4.4 to -1.43; p < 0.001). The improvement in mechanical allodynia is significantly more in animals with a compression model of SCI (meta-regression coefficient, -1.33; 95% CI, -1.84 to -0.57; p < 0.001) and in mild SCI (p < 0.001). Additionally, the improvement was more prominent if the training was started 7 to 8 days postinjury (coefficient, -2.54; 95% CI, -3.85 to -1.23; p < 0.001) and was continued every day (coefficient, -1.99; 95% CI, -3.07 to -0.9; p < 0.001). Likewise, voluntary exercise demonstrated a significantly more effect size (coefficient, -1.45; 95% CI, -2.67 to -0.23; p = 0.02). CONCLUSION Exercise is effective in the amelioration of neuropathic pain. This effect in mechanical allodynia is more prominent if voluntary, continuous training is initiated in the subacute phase of mild SCI.
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Affiliation(s)
- Amirmohammad Toloui
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamzah Adel Ramawad
- Department of Emergency Medicine, NYC Health + Hospitals, Coney Island, New York, NY, USA
| | - Pantea Gharin
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Alexander R. Vaccaro
- Department of Orthopedics and Neurosurgery, Rothman Institute, Thomas Jefferson University, Philadelphia, PA, USA
| | - Hamed Zarei
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mostafa Hosseini
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Yousefifard
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Vafa Rahimi-Movaghar
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Brain and Spinal Injuries Research Center (BASIR), Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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13
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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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14
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Neishaboori AM, Tavallaei MJ, Toloui A, Ahmadzadeh K, Alavi SNR, Lauran M, Hosseini M, Yousefifard M. Effects of Epothilone Administration on Locomotion Recovery after Spinal Cord Injury: A Systematic Review of Animal Studies. Asian Spine J 2023; 17:761-769. [PMID: 37062538 PMCID: PMC10460658 DOI: 10.31616/asj.2022.0005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 06/05/2022] [Accepted: 06/30/2022] [Indexed: 04/18/2023] Open
Abstract
This is a systematic review and meta-analysis of existing evidence regarding the possible effects of epothilones on spinal cord injury (SCI). This study aimed to investigate the possible effects of epothilone administration on locomotion recovery in animal models of SCI. Despite increasing rates of SCI and its burden on populations, no consensus has been reached about the possible treatment modality for SCI. Meanwhile, low-dose epothilones have been reported to have positive effects on SCI outcomes. Electronic databases of Web of Science, Scopus, Embase, and Medline were searched using keywords related to epothilones and SCI until the end of 2020. Two researchers screened the articles, and extracted data were analyzed using STATA ver. 14.0. Final results are reported as a standardized mean difference (SMD) with a 95% confidence interval (CI). After the screening, five studies were included in the analysis. Rats were used in all the studies. Two types of epothilones were used via intraperitoneal injection and were shown to have positive effects on the motor outcomes of samples with SCI (SMD, 0.87; 95% CI, 0.51 to 1.23; p =0.71). Although a slightly better effect was observed when using epothilone B, the difference was not significant (coefficient, -0.50; 95% CI, -1.52 to 0.52; p =0.246). The results of this study suggest that epothilones have positive effects on the improvement of motor function in rats, when administered intraperitoneally until a maximum of 1 day after SCI. However, current evidence regarding the matter is still scarce.
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Affiliation(s)
| | | | - Amirmohammad Toloui
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Koohyar Ahmadzadeh
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Martin Lauran
- GKT School of Medical Education, King’s College London, London, UK
| | - Mostafa Hosseini
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Yousefifard
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
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15
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Kalhori MR, Soleimani M, Alibakhshi R, Kalhori AA, Mohamadi P, Azreh R, Farzaei MH. The Potential of miR-21 in Stem Cell Differentiation and its Application in Tissue Engineering and Regenerative Medicine. Stem Cell Rev Rep 2023; 19:1232-1251. [PMID: 36899116 DOI: 10.1007/s12015-023-10510-8] [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: 01/18/2023] [Indexed: 03/12/2023]
Abstract
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two important types of non-coding RNAs that are not translated into protein. These molecules can regulate various biological processes, including stem cell differentiation and self-renewal. One of the first known miRNAs in mammals is miR-21. Cancer-related studies have shown that this miRNA has proto-oncogene activity and is elevated in cancers. However, it is confirmed that miR-21 inhibits stem cell pluripotency and self-renewal and induces differentiation by targeting various genes. Regenerative medicine is a field of medical science that tries to regenerate and repair damaged tissues. Various studies have shown that miR-21 plays an essential role in regenerative medicine by affecting stem cell proliferation and differentiation. In this review, we will discuss the function of miR-21 in regenerative medicine of the liver, nerve, spinal cord, wound, bone, and dental tissues. In addition, the function of natural compounds and lncRNAs will be analyzed as potential regulators of miR-21 expression in regenerative medicine.
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Affiliation(s)
- Mohammad Reza Kalhori
- Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Reza Alibakhshi
- Department of Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Amir Ali Kalhori
- Regenerative Medicine Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Parisa Mohamadi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical, Sciences, Tehran, Iran
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Rasoul Azreh
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hosien Farzaei
- Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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16
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Srikandarajah N, Alvi MA, Fehlings MG. Current insights into the management of spinal cord injury. J Orthop 2023; 41:8-13. [PMID: 37251726 PMCID: PMC10220467 DOI: 10.1016/j.jor.2023.05.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/28/2023] [Accepted: 05/15/2023] [Indexed: 05/31/2023] Open
Abstract
Background Traumatic spinal cord injury (SCI) is a serious disorder that results in severe impairment of neurological function as well as disability, ultimately reducing a patient's quality of life. The pathophysiology of SCI involves a primary and secondary phase, which causes neurological injury. Methods Narrative review on current clinical management of spinal cord injury and emerging therapies. Results This review explores the management of SCI through early decompressive surgery, optimizing mean arterial pressure, steroid therapy and focused rehabilitation. These management strategies reduce secondary injury mechanisms to prevent the propagation of further neurological damage. The literature regarding emerging research is also explored in cell-based, gene, pharmacological and neuromodulation therapies, which aim to repair the spinal cord following the primary injury mechanism. Conclusions Outcomes for patients with SCI can be enhanced and improved if primary and secondary phases of SCI can be addressed.
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Affiliation(s)
- Nisaharan Srikandarajah
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Mohammed Ali Alvi
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Michael G. Fehlings
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Division of Genetics and Development, Krembil Brain Institute, University Health Network, Toronto, ON, Canada
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17
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Jeong SY, Lee HL, Wee S, Lee H, Hwang G, Hwang S, Yoon S, Yang YI, Han I, Kim KN. Co-Administration of Resolvin D1 and Peripheral Nerve-Derived Stem Cell Spheroids as a Therapeutic Strategy in a Rat Model of Spinal Cord Injury. Int J Mol Sci 2023; 24:10971. [PMID: 37446149 DOI: 10.3390/ijms241310971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/27/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Spinal cord injury (SCI), primarily caused by trauma, leads to permanent and lasting loss of motor, sensory, and autonomic functions. Current therapeutic strategies are focused on mitigating secondary injury, a crucial aspect of SCI pathophysiology. Among these strategies, stem cell therapy has shown considerable therapeutic potential. This study builds on our previous work, which demonstrated the functional recovery and neuronal regeneration capabilities of peripheral nerve-derived stem cell (PNSC) spheroids, which are akin to neural crest stem cells, in SCI models. However, the limited anti-inflammatory capacity of PNSC spheroids necessitates a combined therapeutic approach. As a result, we investigated the potential of co-administering resolvin D1 (RvD1), known for its anti-inflammatory and neuroprotective properties, with PNSC spheroids. In vitro analysis confirmed RvD1's anti-inflammatory activity and its inhibitory effect on pro-inflammatory cytokines. In vivo studies involving a rat SCI model demonstrated that combined therapy of RvD1 and PNSC spheroids outperformed monotherapies, exhibiting enhanced neuronal regeneration and anti-inflammatory effects as validated through behavior tests, quantitative reverse transcription polymerase chain reaction, and immunohistochemistry. Thus, our findings suggest that the combined application of RvD1 and PNSC spheroids may represent a novel therapeutic approach for SCI management.
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Affiliation(s)
- Seung-Young Jeong
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Hye-Lan Lee
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - SungWon Wee
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - HyeYeong Lee
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - GwangYong Hwang
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - SaeYeon Hwang
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
- Graduate Program in Bioindustrial Engineering, Yonsei University, Seoul 03722, Republic of Korea
| | - SolLip Yoon
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
| | - Young-Il Yang
- Paik Imje Memorial Institute for Clinical Research, InJe University College of Medicine, Busan 47392, Republic of Korea
| | - Inbo Han
- Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si 13496, Republic of Korea
| | - Keung-Nyun Kim
- Spine & Spinal Cord Institute, Department of Neurosurgery, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea
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18
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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: 218] [Impact Index Per Article: 109.0] [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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Chang J, Qian Z, Wang B, Cao J, Zhang S, Jiang F, Kong R, Yu X, Cao X, Yang L, Chen H. Transplantation of A2 type astrocytes promotes neural repair and remyelination after spinal cord injury. Cell Commun Signal 2023; 21:37. [PMID: 36797790 PMCID: PMC9936716 DOI: 10.1186/s12964-022-01036-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 12/28/2022] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Limited progress in terms of an effective treatment for spinal cord injury (SCI) emphasizes the urgent need for novel therapies. As a vital central nervous system component, the resident astrocytes play crucial roles in regulating recovery after SCI. In this study, recovery after SCI was compared following the transplantation of either A1 or A2 astrocytes. A1 astrocytes are harmful as they upregulate the neurotoxic classical complement cascade genes. Conversely, A2 astrocytes are characterized as neuroprotective as they upregulate the production of many neurotrophic factors. METHODS We used different supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4 to generate A1 and A2 astrocytes. We detected the influence of astrocytes on neurons by co-culturing A1 and A2 astrocytes with neurons. We transplanted astrocytes into the lesion site of the spinal cord and assessed lesion progression, neural restoration, glia formation and locomotor recovery. RESULTS Astrocytes were polarized into A1 and A2 phenotypes following culture in the supernatant obtained from microglia stimulated with lipopolysaccharide or interleukin-4, respectively. Furthermore, co-culturing A2 astrocytes with neurons significantly suppressed glutamate-induced neuronal apoptosis and promoted the degree of neuron arborization. Transplantation of these A2 astrocytes into the lesion site of the spinal cord of mice significantly improved motor function recovery, preserved spared supraspinal pathways, decreased glia scar deposition, and increased neurofilament formation at the site of injury compared to the transplantation of A1 astrocytes. Additionally, enhanced A2 astrocytes with potentially beneficial A2-like genes were also detected in the A2 group. Moreover, luxol fast blue staining and electron microscopy indicated increased preservation of myelin with organized structure after transplantation of A2 astrocytes than of A1 astrocytes. CONCLUSIONS A2 astrocyte transplantation could be a promising potential therapy for SCI. Video abstract.
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Affiliation(s)
- Jie Chang
- Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.,Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Zhanyang Qian
- Spine Center, Zhongda Hospital of Southeast University, Nanjing, Jiangsu, China
| | - Binyu Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Jiang Cao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Sheng Zhang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Fan Jiang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Renyi Kong
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Xiao Yu
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China
| | - Xiaojian Cao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.
| | - Lei Yang
- Department of Orthopedics, Taizhou People's Hospital, Nanjing Medical University, No. 366 Taihu Road, Taizhou, 225300, Jiangsu, China. .,School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Hongtao Chen
- Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, China.
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20
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Tucker A, Dulin JN. The Emerging Role of Biological Sex in Cell Therapy for Spinal Cord Injury. Neurosci Insights 2023; 18:26331055231153128. [PMID: 36798608 PMCID: PMC9925999 DOI: 10.1177/26331055231153128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 02/13/2023] Open
Abstract
Neural progenitor cell (NPC) transplantation is a promising potential therapy for replacing spinal cord neurons and glial cells following spinal cord injury (SCI). Despite the rapid advancement of NPC transplantation to SCI clinical trials, we still lack understanding of fundamental biology underlying how NPC grafts interact with the injured host nervous system. Our recent study demonstrated a potent effect of biological sex mismatch between donor and host on graft immune rejection. Here we discuss the implications of this study in the context of clinical trials for SCI, and important topics for future research in SCI cell transplantation.
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Affiliation(s)
- Ashley Tucker
- Department of Biology, Texas A&M
University, College Station, TX, USA
- Texas A&M Institute for
Neuroscience, Texas A&M University, College Station, TX, USA
| | - Jennifer N Dulin
- Department of Biology, Texas A&M
University, College Station, TX, USA
- Texas A&M Institute for
Neuroscience, Texas A&M University, College Station, TX, USA
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21
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Stepanova OV, Fursa GA, Andretsova SS, Shishkina VS, Voronova AD, Chadin AV, Karsuntseva EK, Reshetov IV, Chekhonin VP. Prospects for the use of olfactory mucosa cells in bioprinting for the treatment of spinal cord injuries. World J Clin Cases 2023; 11:322-331. [PMID: 36686356 PMCID: PMC9850961 DOI: 10.12998/wjcc.v11.i2.322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/28/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
The review focuses on the most important areas of cell therapy for spinal cord injuries. Olfactory mucosa cells are promising for transplantation. Obtaining these cells is safe for patients. The use of olfactory mucosa cells is effective in restoring motor function due to the remyelination and regeneration of axons after spinal cord injuries. These cells express neurotrophic factors that play an important role in the functional recovery of nerve tissue after spinal cord injuries. In addition, it is possible to increase the content of neurotrophic factors, at the site of injury, exogenously by the direct injection of neurotrophic factors or their delivery using gene therapy. The advantages of olfactory mucosa cells, in combination with neurotrophic factors, open up wide possibilities for their application in three-dimensional and four-dimensional bioprinting technology treating spinal cord injuries.
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Affiliation(s)
- Olga Vladislavovna Stepanova
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Neurohumoral and Immunological Research, National Medical Research Center of Cardiology, Moscow 121552, Russia
| | - Grigorii Andreevich Fursa
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | - Svetlana Sergeevna Andretsova
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Biology, Moscow State University, Moscow 119991, Russia
| | - Valentina Sergeevna Shishkina
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | - Anastasia Denisovna Voronova
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | - Andrey Viktorovich Chadin
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | | | | | - Vladimir Pavlovich Chekhonin
- Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Medical Nanobiotechnologу, N.I. Pirogov Russian National Research Medical University, Moscow 117997, Russia
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22
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Shang Z, Wang M, Zhang B, Wang X, Wanyan P. Subacute traumatic spinal cord injury: a systematic review and network meta-analysis of therapeutic strategies based on bone marrow mesenchymal stromal cells in animal models. Cytotherapy 2022; 24:1181-1189. [PMID: 36117057 DOI: 10.1016/j.jcyt.2022.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/21/2022] [Accepted: 08/11/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND AIMS To explore the optimal transplantation strategy of bone marrow mesenchymal stem cells in subacute traumatic spinal cord injury in animal experiments in order to provide reference for future animal studies and clinical research. METHODS The PubMed, Embase and Web of Science databases were systematically searched (inception to January 4, 2022). Literature search, data extraction and bias assessment were performed by two independent reviewers. RESULTS A total of 50 articles were included for analysis. Results of both traditional meta-analysis and network meta-analysis showed that high-dose (≥1 × 106) transplantation was significantly better than low-dose (<1 × 106) transplantation and intralesional transplantation was significantly better than intravenous transplantation. CONCLUSIONS Given the limited quality of evidence from current animal studies, more high-quality head-to-head comparisons are needed in the future to delve into the optimal transplantation strategy for stem cells.
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Affiliation(s)
- Zhizhong Shang
- First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Mingchuan Wang
- First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Baolin Zhang
- First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Xin Wang
- First Clinical Medical College of Lanzhou University, Lanzhou, China; Chengren Institute of Traditional Chinese Medicine, Lanzhou, China; Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, China.
| | - Pingping Wanyan
- Gansu University of Chinese Medicine, Lanzhou, China; The Second Hospital of Lanzhou University, Lanzhou, China.
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23
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Lee S, Nam H, Joo KM, Lee SH. Advances in Neural Stem Cell Therapy for Spinal Cord Injury: Safety, Efficacy, and Future Perspectives. Neurospine 2022; 19:946-960. [PMID: 36351442 PMCID: PMC9816608 DOI: 10.14245/ns.2244658.329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating central nervous system injury that leads to severe disabilities in motor and sensory functions, causing significant deterioration in patients' quality of life. Owing to the complexity of SCI pathophysiology, there has been no effective treatment for reversing neural tissue damage and recovering neurological functions. Several novel therapies targeting different stages of pathophysiological mechanisms of SCI have been developed. Among these, treatments using stem cells have great potential for the regeneration of damaged neural tissues. In this review, we have summarized recent preclinical and clinical studies focusing on neural stem cells (NSCs). NSCs are multipotent cells with specific differentiation capabilities for neural lineage. Several preclinical studies have demonstrated the regenerative effects of transplanted NSCs in SCI animal models through both paracrine effects and direct neuronal differentiation, restoring synaptic connectivity and neural networks. Based on the positive results of several preclinical studies, phase I and II clinical trials using NSCs have been performed. Despite several hurdles and issues that need to be addressed in the clinical use of NSCs in patients with SCI, gradual progress in the technical development and therapeutic efficacy of NSCs treatments has enhanced the prospects for cell-based treatments in SCI.
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Affiliation(s)
- Sungjoon Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Nam
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Stem Cell and Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea,Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Kyeung-Min Joo
- Stem Cell and Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea,Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea,Corresponding Author Kyeung-Min Joo Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea
| | - Sun-Ho Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Stem Cell and Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea,Co-corresponding Author Sun-Ho Lee Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
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24
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Liu C, Liu Y, Ma B, Zhou M, Zhao X, Fu X, Kan S, Hu W, Zhu R. Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review. Medicine (Baltimore) 2022; 101:e31930. [PMID: 36401438 PMCID: PMC9678589 DOI: 10.1097/md.0000000000031930] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Spinal cord injury is a severe central nervous system injury that results in the permanent loss of motor, sensory, and autonomic functions below the level of injury with limited recovery. The pathological process of spinal cord injury includes primary and secondary injuries, characterized by a progressive cascade. Secondary injury impairs the ability of the mitochondria to maintain homeostasis and leads to calcium overload, excitotoxicity, and oxidative stress, further exacerbating the injury. The defective mitochondrial function observed in these pathologies accelerates neuronal cell death and inhibits regeneration. Treatment of spinal cord injury by preserving mitochondrial biological function is a promising, although still underexplored, therapeutic strategy. This review aimed to explore mitochondrial-based therapeutic advances after spinal cord injury. Specifically, it briefly describes the characteristics of spinal cord injury. It then broadly discusses the drugs used to protect the mitochondria (e.g., cyclosporine A, acetyl-L-carnitine, and alpha-tocopherol), phenomena associated with mitochondrial damage processes (e.g., mitophagy, ferroptosis, and cuproptosis), mitochondrial transplantation for nerve cell regeneration, and innovative mitochondrial combined protection therapy.
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Affiliation(s)
- Chengjiang Liu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Yidong Liu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Boyuan Ma
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Mengmeng Zhou
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Xinyan Zhao
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Xuanhao Fu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Shunli Kan
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Wei Hu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
| | - Rusen Zhu
- Department of Spine Surgery, Tianjin Union Medical Center Tianjin, Tianjin, China
- *Correspondence: Rusen Zhu, Department of Spine Surgery, Tianjin Union Medical Center190jieyuan Road, Honggiao District, Tianjin 300121, China (e-mail: )
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25
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Hashimoto M, Takeichi K, Murata K, Kozakai A, Yagi A, Ishikawa K, Suzuki-Nakagawa C, Kasuya Y, Fukamizu A, Nakagawa T. Regulation of neural stem cell proliferation and survival by protein arginine methyltransferase 1. Front Neurosci 2022; 16:948517. [PMID: 36440275 PMCID: PMC9685794 DOI: 10.3389/fnins.2022.948517] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/17/2022] [Indexed: 12/22/2024] Open
Abstract
Protein arginine methyltransferase 1 (PRMT1), a major type I arginine methyltransferase in mammals, methylates histone and non-histone proteins to regulate various cellular functions, such as transcription, DNA damage response, and signal transduction. PRMT1 is highly expressed in neural stem cells (NSCs) and embryonic brains, suggesting that PRMT1 is essential for early brain development. Although our previous reports have shown that PRMT1 positively regulates oligodendrocyte development, it has not been studied whether PRMT1 regulates NSC proliferation and its survival during development. To examine the role of PRMT1 in NSC activity, we cultured NSCs prepared from embryonic mouse forebrains deficient in PRMT1 specific for NSCs and performed neurosphere assays. We found that the primary neurospheres of PRMT1-deficient NSCs were small and the number of spheres was decreased, compared to those of control NSCs. Primary neurospheres deficient in PRMT1 expressed an increased level of cleaved caspase-3, suggesting that PRMT1 deficiency-induced apoptosis. Furthermore, p53 protein was significantly accumulated in PRMT1-deficient NSCs. In parallel, p53-responsive pro-apoptotic genes including Pmaip1 and Perp were upregulated in PRMT1-deficient NSCs. p53-target p21 mRNA and its protein levels were shown to be upregulated in PRMT1-deficient NSCs. Moreover, the 5-bromo-2'-deoxyuridine (BrdU) incorporation assay showed that the loss of PRMT1 led to cell cycle defects in the embryonic NSCs. In contrast to the above in vitro observations, NSCs normally proliferated and survived in the fetal brains of NSC-specific PRMT1-deficient mice. We also found that Lama1, which encodes the laminin subunit α1, was significantly upregulated in the embryonic brains of PRMT1-deficient mice. These data implicate that extracellular factors provided by neighboring cells in the microenvironment gave a trophic support to NSCs in the PRMT1-deficient brain and recovered NSC activity to maintain brain homeostasis. Our study implies that PRMT1 plays a cell-autonomous role in the survival and proliferation of embryonic NSCs.
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Affiliation(s)
- Misuzu Hashimoto
- Laboratory of Biological Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Kaho Takeichi
- Laboratory of Biological Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Kazuya Murata
- Laboratory Animal Resource Center in Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Aoi Kozakai
- Laboratory of Biological Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Atsushi Yagi
- Laboratory of Biological Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Kohei Ishikawa
- Laboratory of Biological Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Chiharu Suzuki-Nakagawa
- Laboratory of Biological Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
| | - Yoshitoshi Kasuya
- Department of Biochemistry and Molecular Pharmacology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akiyoshi Fukamizu
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Japan
- World Premier International Research Center Initiative, International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan
- AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Tsutomu Nakagawa
- Laboratory of Biological Chemistry, Faculty of Applied Biological Sciences, Gifu University, Gifu, Japan
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26
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Yousefifard M, Askarian-Amiri S, Nasseri Maleki S, Rafiei Alavi SN, Madani Neishaboori A, Haghani L, Vaccaro AR, Harrop JS, Lu Y, Rahimi-Movaghar V, Hosseini M. Combined application of neural stem/progenitor cells and scaffolds on locomotion recovery following spinal cord injury in rodents: a systematic review and meta-analysis. Neurosurg Rev 2022; 45:3469-3488. [DOI: 10.1007/s10143-022-01859-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 07/20/2022] [Accepted: 09/01/2022] [Indexed: 11/29/2022]
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27
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Pitonak M, Aceves M, Kumar PA, Dampf G, Green P, Tucker A, Dietz V, Miranda D, Letchuman S, Jonika MM, Bautista D, Blackmon H, Dulin JN. Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice. Nat Commun 2022; 13:5380. [PMID: 36104357 PMCID: PMC9474813 DOI: 10.1038/s41467-022-33134-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 09/02/2022] [Indexed: 12/03/2022] Open
Abstract
Despite advancement of neural progenitor cell transplantation to spinal cord injury clinical trials, there remains a lack of understanding of how biological sex of transplanted cells influences outcomes after transplantation. To address this, we transplanted GFP-expressing sex-matched, sex-mismatched, or mixed donor cells into sites of spinal cord injury in adult male and female mice. Biological sex of the donor cells does not influence graft neuron density, glial differentiation, formation of the reactive glial cell border, or graft axon outgrowth. However, male grafts in female hosts feature extensive hypervascularization accompanied by increased vascular diameter and perivascular cell density. We show greater T-cell infiltration within male-to-female grafts than other graft types. Together, these findings indicate a biological sex-specific immune response of female mice to male donor cells. Our work suggests that biological sex should be considered in the design of future clinical trials for cell transplantation in human injury. In this study, Pitonak et al. report that transplantation of neural progenitor cells derived from male donors trigger an immune rejection response following transplantation into sites of spinal cord injury in female mice.
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28
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Li RF, Gui F, Yu C, Luo YM, Guo L. Protective role of muscones on astrocytes under a mechanical-chemical damage model. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:927. [PMID: 36172099 PMCID: PMC9511184 DOI: 10.21037/atm-22-3848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/06/2022] [Indexed: 11/21/2022]
Abstract
Background Traumatic spinal cord injury (SCI) is a major clinical concern and a life-changing neurological condition with substantial socioeconomic implications. The initial mechanical force applied to the spinal cord at the time of injury is known as the primary injury. After the primary injury, ischemia and hypoxia induce cell death and autolysis, which are associated with the release of a group of inflammatory factors and biologically active substances, such as superoxide dismutase (SOD), malonaldehyde (MDA), lactate dehydrogenase (LDH), and tumor necrosis factor-α (TNF-α). These processes are called the secondary injury, and may lead to an excess of extracellular glutamate (Glu), which in turn promotes the neuronal injuries. Muscone has been shown to have anti-inflammatory effects in the treatment of brain diseases and other diseases. However, to date, no study has examined the effects of muscone in the treatment of SCI. Methods Astrocytes were separated and purified by the method of short-term exposure combining with differential sticking wall. Astrocyte was identified by glial fibers acidic protein (GFAP) selecting cell immunochemical staining. A mechanical-chemical damage (MCD) model was established via the primary spinal astrocytes of rats, and treatment was administered with different concentrations of muscone. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) was detected at 6, 12, 24, 48 and 72 h. SOD, MDA, LDH, TNF-alpha and intracellular calcium was detected at 3, 6 and 12 h. Glu in supernatant was detected respectively at 3, 6 and 12 h by enzyme-linked immunosorbent assay (ELISA) method. Intracellular calcium was detected respectively at 3, 6 and 12 h by flow cytometry method. MRNA expression of excitatory amino acid transporters (EAATs) and GFAP were detected by the quantitative reverse transcription polymerase chain reaction (qRT-PCR) method and protein expression of those by western blot at 6 h. Results Muscone reduced the levels of LDH, TNF-α, and MDA after injury, and upregulated the level of SOD. Muscone also reduced the density of extracellular Glu and suppressed the intracellular calcium level. Additionally, it decreased the expression levels of EAATs and GFAPs. Conclusions Muscone has a protective effect on astrocytes in a MCD and inhibits astrocytes’ proliferation.
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Affiliation(s)
- Rui-Fu Li
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Fei Gui
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Chao Yu
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan-Meng Luo
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Liang Guo
- Department of Orthopedics, University-Town Hospital of Chongqing Medical University, Chongqing, China
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29
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Guo W, Zhang X, Zhai J, Xue J. The roles and applications of neural stem cells in spinal cord injury repair. Front Bioeng Biotechnol 2022; 10:966866. [PMID: 36105599 PMCID: PMC9465243 DOI: 10.3389/fbioe.2022.966866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 07/28/2022] [Indexed: 12/05/2022] Open
Abstract
Spinal cord injury (SCI), which has no current cure, places a severe burden on patients. Stem cell-based therapies are considered promising in attempts to repair injured spinal cords; such options include neural stem cells (NSCs). NSCs are multipotent stem cells that differentiate into neuronal and neuroglial lineages. This feature makes NSCs suitable candidates for regenerating injured spinal cords. Many studies have revealed the therapeutic potential of NSCs. In this review, we discuss from an integrated view how NSCs can help SCI repair. We will discuss the sources and therapeutic potential of NSCs, as well as representative pre-clinical studies and clinical trials of NSC-based therapies for SCI repair.
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Affiliation(s)
- Wen Guo
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xindan Zhang
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China
| | - Jiliang Zhai
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Jiliang Zhai, ; Jiajia Xue,
| | - Jiajia Xue
- Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing, China
- *Correspondence: Jiliang Zhai, ; Jiajia Xue,
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30
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Karami N, Azari H, Rahimi M, Aligholi H, Kalantari T. A study on the effect of JNJ-10397049 on proliferation and differentiation of neural precursor cells. Anat Cell Biol 2022; 55:179-189. [PMID: 35466086 PMCID: PMC9256489 DOI: 10.5115/acb.21.202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 12/18/2021] [Accepted: 12/27/2021] [Indexed: 11/27/2022] Open
Abstract
The orexin 2 receptor plays a central role in maintaining sleep and wakefulness. Recently, it has been shown that sleep and wakefulness orchestrate the proliferation and differentiation of oligodendrocytes. Here, we explored the role of a selective orexin 2 receptor antagonist (JNJ-10397049) in proliferation and differentiation of neural progenitor cells (NPCs). We evaluated the proliferation potential of NPCs after exposure to different concentrations of JNJ-10397049 by using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide and neurosphere assays. Moreover, the expression of differentiation markers was assessed by immunocytochemistry and real-time polymerase chain reaction. JNJ-10397049 significantly increased the proliferation of NPCs at lower concentrations. In addition, orexin 2 receptor antagonist facilitated progression of differentiation of NPCs towards oligodendroglial lineage by considerable expression of Olig2 and 2’,3’-cyclic-nucleotide 3’-phosphodiesterase as well as decreased expression of nestin marker. The results open a new avenue for future investigations in which the production of more oligodendrocytes from NPCs is needed.
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Affiliation(s)
- Neda Karami
- Division of Medical Biotechnology, Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hassan Azari
- Neural Stem Cell Laboratory, Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Moosa Rahimi
- Laboratory of Basic Sciences, Mohammad Rasul Allah Research Tower, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hadi Aligholi
- Department of Neuroscience, School of Advanced Medical Sciences and Technology, Shiraz University of Medical Sciences, Shiraz, Iran.,Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Kalantari
- Division of Medical Biotechnology, Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran.,Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
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31
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Wang S, Li L, Cook C, Zhang Y, Xia Y, Liu Y. A potential fate decision landscape of the TWEAK/Fn14 axis on stem and progenitor cells: a systematic review. Stem Cell Res Ther 2022; 13:270. [PMID: 35729659 PMCID: PMC9210594 DOI: 10.1186/s13287-022-02930-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/19/2022] [Indexed: 11/21/2022] Open
Abstract
Stem and progenitor cells (SPCs) possess self-remodeling ability and differentiation potential and are responsible for the regeneration and development of organs and tissue systems. However, the precise mechanisms underlying the regulation of SPC biology remain unclear. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) acts on miscellaneous cells via binding to fibroblast growth factor-inducible 14 (Fn14) and exerts pleiotropic functions in the regulation of divergent stem cell fates. TWEAK/Fn14 signaling can regulate the proliferation, differentiation, and migration of multiple SPCs as well as tumorigenesis in certain contexts. Although TWEAK’s roles in modulating multiple SPCs are sparsely reported, the systemic effector functions of this multifaceted protein have not been fully elucidated. In this review, we summarized the fate decisions of TWEAK/Fn14 signaling on multiple stem cells and characterized its potential in stem cell therapy.
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Affiliation(s)
- Sijia Wang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Liang Li
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Christopher Cook
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Yufei Zhang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Yumin Xia
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China.
| | - Yale Liu
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China.
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32
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Shang Z, Li D, Chen J, Wang R, Wang M, Zhang B, Wang X, Wanyan P. What Is the Optimal Timing of Transplantation of Neural Stem Cells in Spinal Cord Injury? A Systematic Review and Network Meta-Analysis Based on Animal Studies. Front Immunol 2022; 13:855309. [PMID: 35371014 PMCID: PMC8965614 DOI: 10.3389/fimmu.2022.855309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 02/15/2022] [Indexed: 01/13/2023] Open
Abstract
Objective The optimal transplantation timing of neural stem cells in spinal cord injury is fully explored in animal studies to reduce the risk of transformation to clinical practice and to provide valuable reference for future animal studies and clinical research. Method Seven electronic databases, namely, PubMed, Web of Science, Embase, Wanfang, Chinese Scientific Journal Database (CSJD-VIP), China Biomedical Literature Database (CBM), and China National Knowledge Infrastructure (CNKI), were searched. The studies were retrieved from inception to November 2021. Two researchers independently screened the literature, extracted data, and evaluated the methodological quality based on the inclusion criteria. Results and Discussion Thirty-nine studies were incorporated into the final analyses. Based on the subgroup of animal models and transplantation dose, the results of network meta-analysis showed that the effect of transplantation in the subacute phase might be the best. However, the results of traditional meta-analysis were inconsistent. In the moderate-dose group of moderate spinal cord injury model and the low-dose group of severe spinal cord injury model, transplantation in the subacute phase did not significantly improve motor function. Given the lack of evidence for direct comparison between different transplantation phases, the indirectness of our network meta-analysis, and the low quality of evidence in current animal studies, our confidence in recommending cell transplantation in the subacute phase is limited. In the future, more high-quality, direct comparative studies are needed to explore this issue in depth.
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Affiliation(s)
- Zhizhong Shang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Dongliang Li
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Jinlei Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - RuiRui Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Mingchuan Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Baolin Zhang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Xin Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China.,Chengren Institute of Traditional Chinese Medicine, Lanzhou, China.,Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Pingping Wanyan
- Basic Medical College, Gansu University of Chinese Medicine, Lanzhou, China.,Department of Nephrology, The Second Hospital of Lanzhou University, Lanzhou, China
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Shang Z, Wang R, Li D, Chen J, Zhang B, Wang M, Wang X, Wanyan P. Spinal Cord Injury: A Systematic Review and Network Meta-Analysis of Therapeutic Strategies Based on 15 Types of Stem Cells in Animal Models. Front Pharmacol 2022; 13:819861. [PMID: 35359872 PMCID: PMC8964098 DOI: 10.3389/fphar.2022.819861] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/04/2022] [Indexed: 12/13/2022] Open
Abstract
Objective: The optimal therapeutic strategies of stem cells for spinal cord injury (SCI) are fully explored in animal studies to promote the translation of preclinical findings to clinical practice, also to provide guidance for future animal experiments and clinical studies. Methods: PubMed, Web of Science, Embase, CNKI, Wangfang, VIP, and CBM were searched from inception to September 2021. Screening of search results, data extraction, and references quality evaluation were undertaken independently by two reviewers. Results and Discussion: A total of 188 studies were included for data analysis. Results of traditional meta-analysis showed that all 15 diverse types of stem cells could significantly improve locomotor function of animals with SCI, and results of further network meta-analysis showed that adipose-derived mesenchymal stem cells had the greatest therapeutic potential for SCI. Moreover, a higher dose (≥1 × 106) of stem cell transplantation had better therapeutic effect, transplantation in the subacute phase (3–14 days, excluding 3 days) was the optimal timing, and intralesional transplantation was the optimal route. However, the evidence of current animal studies is of limited quality, and more high-quality research is needed to further explore the optimal therapeutic strategies of stem cells, while the design and implementation of experiments, as well as measurement and reporting of results for animal studies, need to be further improved and standardized to reduce the risk when the results of animal studies are translated to the clinic. Systematic Review Registration: [website], identifier [registration number].
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Affiliation(s)
- Zhizhong Shang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Ruirui Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Dongliang Li
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Jinlei Chen
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Baolin Zhang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Mingchuan Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
| | - Xin Wang
- The First Clinical Medical School of Lanzhou University, Lanzhou, China
- Chengren Institute of Traditional Chinese Medicine, Lanzhou, China
- Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, China
- *Correspondence: Xin Wang, ; Pingping Wanyan,
| | - Pingping Wanyan
- Gansu University of Chinese Medicine, Lanzhou, China
- The Second Hospital of Lanzhou University, Lanzhou, China
- *Correspondence: Xin Wang, ; Pingping Wanyan,
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The Sonic Hedgehog Pathway Modulates Survival, Proliferation, and Differentiation of Neural Progenitor Cells under Inflammatory Stress In Vitro. Cells 2022; 11:cells11040736. [PMID: 35203385 PMCID: PMC8869809 DOI: 10.3390/cells11040736] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/27/2022] [Accepted: 02/17/2022] [Indexed: 12/15/2022] Open
Abstract
The Sonic Hedgehog protein (Shh) has been extensively researched since its discovery in 1980. Its crucial role in early neurogenesis and endogenous stem cells of mature brains, as well as its recently described neuroprotective features, implicate further important effects on neuronal homeostasis. Here, we investigate its potential role in the survival, proliferation, and differentiation of neural precursors cells (NPCs) under inflammatory stress as a potential adjunct for NPC-transplantation strategies in spinal cord injury (SCI) treatment. To this end, we simulated an inflammatory environment in vitro using lipopolysaccharide (LPS) and induced the Shh-pathway using recombinant Shh or blocked it using Cyclopamine, a potent Smo inhibitor. We found that Shh mediates the proliferation and neuronal differentiation potential of NPCs in vitro, even in an inflammatory stress environment mimicking the subacute phase after SCI. At the same time, our results indicate that a reduction of the Shh-pathway activation by blockage with Cyclopamine is associated with reduced NPC-survival, reduced neuronal differentiation and increased astroglial differentiation. Shh might thus, play a role in endogenous NPC-mediated neuroregeneration or even be a potent conjunct to NPC-based therapies in the inflammatory environment after SCI.
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Strategies for effective neural circuit reconstruction after spinal cord injury: use of stem cells and biomaterials. World Neurosurg 2022; 161:82-89. [PMID: 35144032 DOI: 10.1016/j.wneu.2022.02.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 01/11/2023]
Abstract
Spinal cord injury (SCI), a serious disease of the central nervous system, often with irreversible loss of motor or sensory functions. Failure of axon connection and inhibition of microenvironment after SCI severely hinder the regeneration of damaged tissue and neuron function. Therefore, the new perspective of treatment of spinal cord injury is the reconstruction of neural circuit. Stem cells are a kind of cells with differentiation potential. They reconstruct local circulation by differentiating into neurons to replace damaged cells. It can also secrete various factors to regulate the host microenvironment and play a therapeutic role. Biomaterials can fill the cavity at the site of spinal cord injury, load therapeutic drugs, provide adsorption sites for transplanted cells and play a bridging role. In this review, the therapeutic role of stem cells and biomaterials is discussed, together with their properties, advantages, limitations, and future perspectives, providing a reference for basic and clinical research on SCI treatment.
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36
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Suzuki H, Imajo Y, Funaba M, Nishida N, Sakamoto T, Sakai T. Current Concepts of Neural Stem/Progenitor Cell Therapy for Chronic Spinal Cord Injury. Front Cell Neurosci 2022; 15:794692. [PMID: 35185471 PMCID: PMC8850278 DOI: 10.3389/fncel.2021.794692] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/20/2021] [Indexed: 11/13/2022] Open
Abstract
Chronic spinal cord injury (SCI) is a devastating condition that results in major neurological deficits and social burden. It continues to be managed symptomatically, and no real therapeutic strategies have been devised for its treatment. Neural stem/neural progenitor cells (NSCs/NPCs) being used for the treatment of chronic SCI in experimental SCI models can not only replace the lost cells and remyelinate axons in the injury site but also support their growth and provide neuroprotective factors. Currently, several clinical studies using NSCs/NPCs are underway worldwide. NSCs/NPCs also have the potential to differentiate into all three neuroglial lineages to regenerate neural circuits, demyelinate denuded axons, and provide trophic support to endogenous cells. This article explains the challenging pathophysiology of chronic SCI and discusses key NSC/NPC-based techniques having the greatest potential for translation over the next decade.
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Flack JA, Sharma KD, Xie JY. Delving into the recent advancements of spinal cord injury treatment: a review of recent progress. Neural Regen Res 2022; 17:283-291. [PMID: 34269189 PMCID: PMC8463999 DOI: 10.4103/1673-5374.317961] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Spinal cord injury (SCI) research is a very complex field lending to why reviews of SCI literatures can be beneficial to current and future researchers. This review focuses on recent articles regarding potential modalities for the treatment and management of SCI. The modalities were broken down into four categories: neuroprotection-pharmacologic, neuroprotection-non-pharmacologic, neuroregeneration-pharmacologic, neuroregeneration-non-pharmacologic. Peer-reviewed articles were found using PubMed with search terms: "spinal cord injury", "spinal cord injury neuroregeneration", "olfactory ensheathing cells spinal cord injury", "rho-rock inhibitors spinal cord injury", "neural stem cell", "scaffold", "neural stem cell transplantation", "exosomes and SCI", "epidural stimulation SCI", "brain-computer interfaces and SCI". Most recent articles spanning two years were chosen for their relevance to the categories of SCI management and treatment. There has been a plethora of pre-clinical studies completed with their results being difficult to replicate in clinical studies. Therefore, scientists should focus on understanding and applying the results of previous research to develop more efficacious preclinical studies and clinical trials.
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Affiliation(s)
- Joseph A Flack
- Department of Basic Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, USA
| | - Krishna Deo Sharma
- Department of Biological Sciences and Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR, USA
| | - Jennifer Yanhua Xie
- Department of Basic Sciences, New York Institute of Technology College of Osteopathic Medicine at Arkansas State University, Jonesboro, AR, USA
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38
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Sng KS, Li G, Zhou LY, Song YJ, Chen XQ, Wang YJ, Yao M, Cui XJ. Ginseng extract and ginsenosides improve neurological function and promote antioxidant effects in rats with spinal cord injury: A meta-analysis and systematic review. J Ginseng Res 2022; 46:11-22. [PMID: 35058723 PMCID: PMC8753526 DOI: 10.1016/j.jgr.2021.05.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 04/26/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023] Open
Abstract
Spinal cord injury (SCI) is defined as damage to the spinal cord that temporarily or permanently changes its function. There is no definite treatment established for neurological complete injury patients. This study investigated the effect of ginseng extract and ginsenosides on neurological recovery and antioxidant efficacies in rat models following SCI and explore the appropriate dosage. Searches were done on PubMed, Embase, and Chinese databases, and animal studies matches the inclusion criteria were selected. Pair-wise meta-analysis and subgroup analysis were performed. Ten studies were included, and the overall methodological qualities were low quality. The result showed ginseng extract and ginsenosides significantly improve neurological function, through the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale (pooled MD = 4.40; 95% CI = 3.92 to 4.88; p < 0.00001), significantly decrease malondialdehyde (MDA) (n = 290; pooled MD = −2.19; 95% CI = −3.16 to −1.22; p < 0.0001) and increase superoxide dismutase (SOD) levels (n = 290; pooled MD = 2.14; 95% CI = 1.45 to 2.83; p < 0.00001). Both low (<25 mg/kg) and high dosage (≥25 mg/kg) showed significant improvement in the motor function recovery in SCI rats. Collectively, this review suggests ginseng extract and ginsenosides has a protective effect on SCI, with good safety and a clear mechanism of action and may be suitable for future clinical trials and applications.
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Zhang HA, Yuan CX, Liu KF, Yang QF, Zhao J, Li H, Yang QH, Song D, Quan ZZ, Qing H. Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy. Neural Regen Res 2022; 17:152-162. [PMID: 34100451 PMCID: PMC8451553 DOI: 10.4103/1673-5374.314324] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The mechanisms of the transplantation of neural stem cells (NSCs) in the treatment of Alzheimer’s disease remain poorly understood. In this study, NSCs were transplanted into the hippocampal CA1 region of the rTg (tau P301L) 4510 mouse model, a tauopathy model that is thought to reflect the tau pathology associated with Alzheimer’s disease. The results revealed that NSC transplantation reduced the abnormal aggregation of tau, resulting in significant improvements in the short-term memory of the tauopathy model mice. Compared with wild-type and phosphate-buffered saline (PBS)-treated mice, mice that received NSC transplantations were characterized by changes in the expression of multiple proteins in brain tissue, particularly those related to the regulation of tau aggregation or misfolding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) function analysis revealed that these proteins were primarily enriched in pathways associated with long-term potentiation, neurogenesis, and other neurobiological processes. Changes in the expression levels of key proteins were verified by western blot assays. These data provided clues to improve the understanding of the functional capacity associated with NSC transplantation in Alzheimer’s disease treatment. This study was approved by the Beijing Animal Ethics Association and Ethics Committee of Beijing Institute of Technology (approval No. SYXK-BIT-school of life science-2017-M03) in 2017.
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Affiliation(s)
- He-Ao Zhang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Chun-Xu Yuan
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Ke-Fu Liu
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Qi-Fan Yang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Juan Zhao
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Hui Li
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Qing-Hu Yang
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Da Song
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Zhen-Zhen Quan
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China
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40
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Wang L, Gu S, Gan J, Tian Y, Zhang F, Zhao H, Lei D. Neural Stem Cells Overexpressing Nerve Growth Factor Improve Functional Recovery in Rats Following Spinal Cord Injury via Modulating Microenvironment and Enhancing Endogenous Neurogenesis. Front Cell Neurosci 2021; 15:773375. [PMID: 34924958 PMCID: PMC8675903 DOI: 10.3389/fncel.2021.773375] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [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: 01/15/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating event characterized by severe motor, sensory, and autonomic dysfunction. Currently, there is no effective treatment. Previous studies showed neural growth factor (NGF) administration was a potential treatment for SCI. However, its targeted delivery is still challenging. In this study, neural stem cells (NSCs) were genetically modified to overexpress NGF, and we evaluated its therapeutic value following SCI. Four weeks after transplantation, we observed that NGF-NSCs significantly enhanced the motor function of hindlimbs after SCI and alleviated histopathological damage at the lesion epicenter. Notably, the survival NGF-NSCs at lesion core maintained high levels of NGF. Further immunochemical assays demonstrated the graft of NGF-NSCs modulated the microenvironment around lesion core via reduction of oligodendrocyte loss, attenuation of astrocytosis and demyelination, preservation of neurons, and increasing expression of multiple growth factors. More importantly, NGF-NSCs seemed to crosstalk with and activate resident NSCs, and high levels of NGF activated TrkA, upregulated cAMP-response element binding protein (CREB) and microRNA-132 around the lesion center. Taken together, the transplantation of NGF-NSCs in the subacute stage of traumatic SCI can facilitate functional recovery by modulating the microenvironment and enhancing endogenous neurogenesis in rats. And its neuroprotective effect may be mediated by activating TrkA, up-regulation of CREB, and microRNA-132.
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Affiliation(s)
- Lei Wang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sujie Gu
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinlu Gan
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Tian
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fangcheng Zhang
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyang Zhao
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Deqiang Lei
- Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Long-Term Effects of Neural Precursor Cell Transplantation on Secondary Injury Processes and Functional Recovery after Severe Cervical Contusion-Compression Spinal Cord Injury. Int J Mol Sci 2021; 22:ijms222313106. [PMID: 34884911 PMCID: PMC8658203 DOI: 10.3390/ijms222313106] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 01/21/2023] Open
Abstract
Cervical spinal cord injury (SCI) remains a devastating event without adequate treatment options despite decades of research. In this context, the usefulness of common preclinical SCI models has been criticized. We, therefore, aimed to use a clinically relevant animal model of severe cervical SCI to assess the long-term effects of neural precursor cell (NPC) transplantation on secondary injury processes and functional recovery. To this end, we performed a clip contusion-compression injury at the C6 level in 40 female Wistar rats and a sham surgery in 10 female Wistar rats. NPCs, isolated from the subventricular zone of green fluorescent protein (GFP) expressing transgenic rat embryos, were transplanted ten days after the injury. Functional recovery was assessed weekly, and FluoroGold (FG) retrograde fiber-labeling, as well as manganese-enhanced magnetic resonance imaging (MEMRI), were performed prior to the sacrifice of the animals eight weeks after SCI. After cryosectioning of the spinal cords, immunofluorescence staining was conducted. Results were compared between the treatment groups (NPC, Vehicle, Sham) and statistically analyzed (p < 0.05 was considered significant). Despite the severity of the injury, leading to substantial morbidity and mortality during the experiment, long-term survival of the engrafted NPCs with a predominant differentiation into oligodendrocytes could be observed after eight weeks. While myelination of the injured spinal cord was not significantly improved, NPC treated animals showed a significant increase of intact perilesional motor neurons and preserved spinal tracts compared to untreated Vehicle animals. These findings were associated with enhanced preservation of intact spinal cord tissue. However, reactive astrogliosis and inflammation where not significantly reduced by the NPC-treatment. While differences in the Basso–Beattie–Bresnahan (BBB) score and the Gridwalk test remained insignificant, animals in the NPC group performed significantly better in the more objective CatWalk XT gait analysis, suggesting some beneficial effects of the engrafted NPCs on the functional recovery after severe cervical SCI.
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42
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Martin-Lopez M, Fernandez-Muñoz B, Canovas S. Pluripotent Stem Cells for Spinal Cord Injury Repair. Cells 2021; 10:cells10123334. [PMID: 34943842 PMCID: PMC8699436 DOI: 10.3390/cells10123334] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/20/2021] [Accepted: 11/25/2021] [Indexed: 12/19/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating condition of the central nervous system that strongly reduces the patient’s quality of life and has large financial costs for the healthcare system. Cell therapy has shown considerable therapeutic potential for SCI treatment in different animal models. Although many different cell types have been investigated with the goal of promoting repair and recovery from injury, stem cells appear to be the most promising. Here, we review the experimental approaches that have been carried out with pluripotent stem cells, a cell type that, due to its inherent plasticity, self-renewal, and differentiation potential, represents an attractive source for the development of new cell therapies for SCI. We will focus on several key observations that illustrate the potential of cell therapy for SCI, and we will attempt to draw some conclusions from the studies performed to date.
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Affiliation(s)
- Maria Martin-Lopez
- Cellular Reprogramming and Production Unit, Andalusian Network for the Design and Translation of Advanced Therapies, 41092 Sevilla, Spain;
- Correspondence: (M.M.-L.); (S.C.)
| | - Beatriz Fernandez-Muñoz
- Cellular Reprogramming and Production Unit, Andalusian Network for the Design and Translation of Advanced Therapies, 41092 Sevilla, Spain;
| | - Sebastian Canovas
- Physiology of Reproduction Group, Physiology Department, Mare Nostrum Campus, University of Murcia, 30100 Murcia, Spain
- Biomedical Research Institute of Murcia, IMIB-Arrixaca-UMU, 30120 Murcia, Spain
- Correspondence: (M.M.-L.); (S.C.)
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Stem Cell Secretome for Spinal Cord Repair: Is It More than Just a Random Baseline Set of Factors? Cells 2021; 10:cells10113214. [PMID: 34831436 PMCID: PMC8625005 DOI: 10.3390/cells10113214] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 11/02/2021] [Accepted: 11/16/2021] [Indexed: 11/29/2022] Open
Abstract
Hundreds of thousands of people suffer spinal cord injuries each year. The experimental application of stem cells following spinal cord injury has opened a new era to promote neuroprotection and neuroregeneration of damaged tissue. Currently, there is great interest in the intravenous administration of the secretome produced by mesenchymal stem cells in acute or subacute spinal cord injuries. However, it is important to highlight that undifferentiated neural stem cells and induced pluripotent stem cells are able to adapt to the damaged environment and produce the so-called lesion-induced secretome. This review article focuses on current research related to the secretome and the lesion-induced secretome and their roles in modulating spinal cord injury symptoms and functional recovery, emphasizing different compositions of the lesion-induced secretome in various models of spinal cord injury.
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Chen X, Wang Y, Zhou G, Hu X, Han S, Gao J. The combination of nanoscaffolds and stem cell transplantation: Paving a promising road for spinal cord injury regeneration. Biomed Pharmacother 2021; 143:112233. [PMID: 34649357 DOI: 10.1016/j.biopha.2021.112233] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/05/2021] [Accepted: 09/19/2021] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI), one of the most devastating traumas, has caused long-term disability in millions of people worldwide. The pathophysiology of SCI primarily occurs in two stages classified as primary injury and secondary injury. Due to the rupture of axons and the apoptosis of neurons, patients lose their motor, sensory, and reflex functions, which also imposes a huge burden on families and society. However, traditional surgery does not facilitate neuronal regeneration. Although neural stem cells (NSCs) have the potential for multidirectional differentiation, the probability of differentiation into neurons and survival are still low. Surprisingly, the unique properties of nanotechnologies enable targeted drug delivery while reducing adverse reactions, assisting NSCs in differentiating into neurons. Here, recent studies on promising nanoscaffolds are highlighted, and their strengths and drawbacks are evaluated. Although the treatment of SCI remains fraught with challenges, the combination of nanoscaffolds and NSCs pave a promising road for SCI regeneration.
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Affiliation(s)
- Xiaokun Chen
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiyang Wang
- School of Medicine, Tsinghua University, Haidian District, Beijing, China
| | - Gang Zhou
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianghui Hu
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shiyuan Han
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jun Gao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Smith MJ, Paton MCB, Fahey MC, Jenkin G, Miller SL, Finch-Edmondson M, McDonald CA. Neural stem cell treatment for perinatal brain injury: A systematic review and meta-analysis of preclinical studies. Stem Cells Transl Med 2021; 10:1621-1636. [PMID: 34542242 PMCID: PMC8641092 DOI: 10.1002/sctm.21-0243] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/26/2021] [Accepted: 08/29/2021] [Indexed: 12/15/2022] Open
Abstract
Perinatal brain injury can lead to significant neurological and cognitive deficits and currently no therapies can regenerate the damaged brain. Neural stem cells (NSCs) have the potential to engraft and regenerate damaged brain tissue. The aim of this systematic review was to evaluate the preclinical literature to determine whether NSC administration is more effective than controls in decreasing perinatal brain injury. Controlled interventional studies of NSC therapy using animal models of perinatal brain injury were identified using MEDLINE and Embase. Primary outcomes were brain infarct size, motor, and cognitive function. Data for meta‐analysis were synthesized and expressed as standardized mean difference (SMD) with 95% confidence intervals (CI), using a random effects model. We also reported secondary outcomes including NSC survival, migration, differentiation, and effect on neuroinflammation. Eighteen studies met inclusion criteria. NSC administration decreased infarct size (SMD 1.09; CI: 0.44, 1.74, P = .001; I2 = 74%) improved motor function measured via the impaired forelimb preference test (SMD 2.27; CI: 0.85, 3.69, P = .002; I2 = 86%) and the rotarod test (SMD 1.88; CI: 0.09, 3.67, P = .04; I2 = 95%). Additionally, NSCs improved cognitive function measured via the Morris water maze test (SMD of 2.41; CI: 1.16, 3.66, P = .0002; I2 = 81%). Preclinical evidence suggests that NSC therapy is promising for the treatment of perinatal brain injury. We have identified key knowledge gaps, including the lack of large animal studies and uncertainty regarding the necessity of immunosuppression for NSC transplantation in neonates. These knowledge gaps should be addressed before NSC treatment can effectively progress to clinical trial.
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Affiliation(s)
- Madeleine J Smith
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Madison Claire Badawy Paton
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Michael C Fahey
- Department of Paediatrics, Monash University, Clayton, Victoria, Australia
| | - Graham Jenkin
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Suzanne L Miller
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
| | - Megan Finch-Edmondson
- Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Courtney A McDonald
- The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia
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Toloui A, Madani Neishaboori A, Rafiei Alavi SN, Gubari MIM, Zareie Shab Khaneh A, Karimi Ghahfarokhi M, Amraei F, Behroozi Z, Hosseini M, Ahmadi S, Yousefifard M. The Value of Physiological Scoring Criteria in Predicting the In-Hospital Mortality of Acute Patients; a Systematic Review and Meta-Analysis. ARCHIVES OF ACADEMIC EMERGENCY MEDICINE 2021; 9:e60. [PMID: 34580658 PMCID: PMC8464013 DOI: 10.22037/aaem.v9i1.1274] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION There is no comprehensive meta-analysis on the value of physiological scoring systems in predicting the mortality of critically ill patients. Therefore, the present study intended to conduct a systematic review and meta-analysis to collect the available clinical evidence on the value of physiological scoring systems in predicting the in-hospital mortality of acute patients. METHOD An extensive search was performed on Medline, Embase, Scopus, and Web of Science databases until the end of year 2020. Physiological models included Rapid Acute Physiology Score (RAPS), Rapid Emergency Medicine Score (REMS), modified REMS (mREMS), and Worthing Physiological Score (WPS). Finally, the data were summarized and the findings were presented as summary receiver operating characteristics (SROC), sensitivity, specificity and diagnostic odds ratio (DOR). RESULTS Data from 25 articles were included. The overall analysis showed that the area under the SROC curve of REMS, RAPS, mREMS, and WPS criteria were 0.83 (95% CI: 0.79-0.86), 0.89 (95% CI: 0.86-0.92), 0.64 (95% CI: 0.60-0.68) and 0.86 (95% CI: 0.83-0.89), respectively. DOR for REMS, RAPS, mREMS and WPS models were 11 (95% CI: 8-16), 13 (95% CI: 4-41), 2 (95% CI: 2-4) and 17 (95% CI: 5-59) respectively. When analyses were limited to trauma patients, the DOR of the REMS and RAPS models were 112 and 431, respectively. Due to the lack of sufficient studies, it was not possible to limit the analyses for mREMS and WPS. CONCLUSION The findings of the present study showed that three models of RAPS, REMS and WPS have a high predictive value for in-hospital mortality. In addition, the value of these models in trauma patients is much higher than other patient settings.
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Affiliation(s)
- Amirmohammad Toloui
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
- First and second authors have contributed equally
| | - Arian Madani Neishaboori
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
- First and second authors have contributed equally
| | | | - Mohammed I M Gubari
- Community Medicine, College of Medicine, University of Sulaimani, Sulaimani, Iraq
| | - Amirali Zareie Shab Khaneh
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Karimi Ghahfarokhi
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Amraei
- Emergency Medicine Research Team, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Behroozi
- Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mostafa Hosseini
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajjad Ahmadi
- Department of Emergency Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahmoud Yousefifard
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
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Rafiei Alavi SN, Madani Neishaboori A, Hossein H, Sarveazad A, Yousefifard M. Efficacy of adipose tissue-derived stem cells in locomotion recovery after spinal cord injury: a systematic review and meta-analysis on animal studies. Syst Rev 2021; 10:213. [PMID: 34330329 PMCID: PMC8325264 DOI: 10.1186/s13643-021-01771-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 07/21/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Considerable disparities exist on the use of adipose tissue-derived stem cells (ADSCs) for treatment of spinal cord injury (SCI). Hence, the current systematic review aimed to investigate the efficacy of ADSCs in locomotion recovery following SCI in animal models. METHODS A search was conducted in electronic databases of MEDLINE, Embase, Scopus, and Web of Science until the end of July 2019. Reference and citation tracking and searching Google and Google Scholar search engines were performed to achieve more studies. Animal studies conducted on rats having SCI which were treated with ADSCs were included in the study. Exclusion criteria were lacking a non-treated control group, not evaluating locomotion, non-rat studies, not reporting the number of transplanted cells, not reporting isolation and preparation methods of stem cells, review articles, combination therapy, use of genetically modified ADSCs, use of induced pluripotent ADSCs, and human trials. Risk of bias was assessed using Hasannejad et al.'s proposed method for quality control of SCI-animal studies. Data were analyzed in STATA 14.0 software, and based on a random effect model, pooled standardized mean difference with a 95% confidence interval was presented. RESULTS Of 588 non-duplicated papers, data from 18 articles were included. Overall risk of bias was high risk in 8 studies, some concern in 9 studies and low risk in 1 study. Current evidence demonstrated that ADSCs transplantation could improve locomotion following SCI (standardized mean difference = 1.71; 95%CI 1.29-2.13; p < 0.0001). A considerable heterogeneity was observed between the studies (I2 = 72.0%; p < 0.0001). Subgroup analysis and meta-regression revealed that most of the factors like injury model, the severity of SCI, treatment phase, injury location, and number of transplanted cells did not have a significant effect on the efficacy of ADSCs in improving locomotion following SCI (pfor odds ratios > 0.05). CONCLUSION We conclude that any number of ADSCs by any prescription routes can improve locomotion recovery in an SCI animal model, at any phase of SCI, with any severity. Given the remarkable bias about blinding, clinical translation of the present results is tough, because in addition to the complexity of the nervous system and the involvement of far more complex motor circuits in the human, blinding compliance and motor outcome assessment tests in animal studies and clinical trials are significantly different.
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Affiliation(s)
| | - Arian Madani Neishaboori
- Physiology Research Center, Iran University of Medical Sciences, Hemmat Highway, P.O Box: 14665-354, Tehran, Iran
| | - Hasti Hossein
- Physiology Research Center, Iran University of Medical Sciences, Hemmat Highway, P.O Box: 14665-354, Tehran, Iran
| | - Arash Sarveazad
- Colorectal Research Center, Iran University of Medical Sciences, Niayesh St, Satarkhan Av, P.O Box: 14665-354, 1449614535, Tehran, Iran. .,Nursing Care Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Mahmoud Yousefifard
- Physiology Research Center, Iran University of Medical Sciences, Hemmat Highway, P.O Box: 14665-354, Tehran, Iran.
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Alavi SNR, Neishaboori AM, Yousefifard M. Extracorporeal shockwave therapy in spinal cord injury, early to advance to clinical trials? A systematic review and meta-analysis on animal studies. Neuroradiol J 2021; 34:552-561. [PMID: 34224252 DOI: 10.1177/19714009211026899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND As there is no consensus over the efficacy of extracorporeal shockwave therapy in the management of spinal cord injury complications, the current meta-analysis aims to investigate preclinical evidence on the matter. METHODS The search strategy was developed based on keywords related to 'spinal cord injury' and 'extracorporeal shockwave therapy'. A primary search was conducted in Medline, Embase, Scopus and Web of Science until the end of 2020. Studies which administered extracorporeal shockwave therapy on spinal cord injury animal models and evaluated motor function and/or histological findings were included. The standardised mean difference with a 95% confidence interval (CI) were calculated. RESULTS Seven articles were included. Locomotion was significantly improved in the extracorporeal shockwave therapy treated group (standardised mean difference 1.68, 95% CI 1.05-2.31, P=0.032). It seems that the efficacy of extracorporeal shockwave therapy with an energy flux density of 0.1 mJ/mm2 is higher than 0.04 mJ/mm2 (P=0.044). Shockwave therapy was found to increase axonal sprouting (standardised mean difference 1.31, 95% CI 0.65, 1.96), vascular endothelial growth factor tissue levels (standardised mean difference 1.36, 95% CI 0.54, 2.18) and cell survival (standardised mean difference 2.49, 95% CI 0.93, 4.04). It also significantly prevents axonal degeneration (standardised mean difference 2.25, 95% CI 1.47, 3.02). CONCLUSION Extracorporeal shockwave therapy significantly improves locomotor recovery in spinal cord injury animal models through neural tissue regeneration. Nonetheless, in spite of the promising results and clinical application of extracorporeal shockwave therapy in various conditions, current evidence implies that designing clinical trials on extracorporeal shockwave therapy in the management of spinal cord injury may not be soon. Hence, further preclinical studies with the effort to reach the safest and the most efficient treatment protocol are needed.
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Affiliation(s)
| | | | - Mahmoud Yousefifard
- Physiology Research Center, 440827Iran University of Medical Sciences, Tehran, Iran
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Tang Y, Xie Z, Ma M, Duan K, Li Y, Ye J. LncRNA and mRNA Expression Profiles in Methylprednisolone Stimulated Neural Stem Cells. Front Neurosci 2021; 15:669224. [PMID: 34248482 PMCID: PMC8262496 DOI: 10.3389/fnins.2021.669224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/18/2021] [Indexed: 11/13/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating neurological disorder that affects thousands of individuals each year. Previously, our study in non-human primates with SCI demonstrated that methylprednisolone (MP) resulted in the dysfunction of neural stem cells (NSCs), which may help to explain the controversial roles of MP in SCI. However, the detailed mechanism is still unclear. In this manuscript, we investigated the LncRNA and mRNA expression profiles of NSCs treated with MP. A total of 63 differentially expressed LncRNAs and 174 differentially expressed mRNAs were identified. Gene ontology (GO) analysis showed that differentially expressed mRNAs were highly associated with terms related to regulation of external stimulation, secretion, and migration. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis results indicated that the PI3K-Akt signaling pathway contributed to the functions of MP treated NSCs. Besides, 3899 co-expression pairs were constructed among the differentially expressed LncRNA and mRNA, among which five predicted target mRNAs with the differentially expressed LncRNAs were identified. These results provide greater insight into the precise mechanisms of MP mediating NSC dysfunction in SCI.
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Affiliation(s)
- Yong Tang
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhongyu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Mengjun Ma
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Kaidi Duan
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuxi Li
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jichao Ye
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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Trends of Chitosan Based Delivery Systems in Neuroregeneration and Functional Recovery in Spinal Cord Injuries. POLYSACCHARIDES 2021. [DOI: 10.3390/polysaccharides2020031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Spinal cord injury (SCI) is one of the most complicated nervous system injuries with challenging treatment and recovery. Regenerative biomaterials such as chitosan are being reported for their wide use in filling the cavities, deliver curative drugs, and also provide adsorption sites for transplanted stem cells. Biomaterial scaffolds utilizing chitosan have shown certain therapeutic effects on spinal cord injury repair with some limitations. Chitosan-based delivery in stem cell transplantation is another strategy that has shown decent success. Stem cells can be directed to differentiate into neurons or glia in vitro. Stem cell-based therapy, biopolymer chitosan delivery strategies, and scaffold-based therapeutic strategies have been advancing as a combinatorial approach for spinal cord injury repair. In this review, we summarize the recent progress in the treatment strategies of SCI due to the use of bioactivity of chitosan-based drug delivery systems. An emphasis on the role of chitosan in neural regeneration has also been highlighted.
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