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Abolghasemi R, Davoudi-Monfared E. Guide for Cell Therapy in Human Chronic Spinal Cord Injury. Tissue Eng Part C Methods 2025; 31:174-180. [PMID: 40279279 DOI: 10.1089/ten.tec.2025.0032] [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: 04/27/2025] Open
Abstract
Based on various research, different cells are effective for improving the symptoms and paraclinical indicators of patients with chronic spinal cord injury (SCI). A big gap in front of researchers and doctors is to know the source, the number of cells required for injection, the delivery method, and the required complementary treatments. We extracted the desired data (number of cells, autologous or allogeneic source of cell extraction, delivery method, and complementary treatments) from 40 clinical trials, which checked and recorded 17 scores of symptoms and paraclinical indicators in at least two studies. The most common cells for improving 11 scores were bone marrow hematopoietic stem cell and bone marrow mesenchymal stem cell. The mean effect was more in bone marrow mesenchymal stem cell with plasma as the complementary treatment. Then the highest mean effect was in bone marrow hematopoietic stem cell therapy, with the complementary treatment being methylprednisolone. The cell number (106/kg), the source (autologous), and the delivery method (intrathecal) were similar in both cell types. No life-threatening consequences or death were recorded. This guideline helps researchers and doctors choose the appropriate cell therapy method for chronic SCI.
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Affiliation(s)
- Reyhaneh Abolghasemi
- Community Medicine Specialist, New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Esmat Davoudi-Monfared
- Health Management Research Center & Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
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2
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Ranjan S, Choudhary P, Shivalkar S, Dwivedi S, Singh S. Potential of hyaluronic acid and collagen-based scaffolds in promoting stem cell neuronal differentiation for neuroregenerative therapies: A review. Int J Biol Macromol 2025; 309:142981. [PMID: 40216130 DOI: 10.1016/j.ijbiomac.2025.142981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 03/27/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025]
Abstract
Stem cell therapy has revolutionized neurodegenerative disease treatment by presenting promising medical applications. Despite their potential, stem cell therapy remains constrained by various limitations, including low differentiation efficiency, difficulties in guiding differentiation, proliferation control, shorter half-life of growth factors, experimental reproducibility, etc. The cellular niche environment is pivotal in effective differentiation of stem cells. Neural regeneration ventures require biomaterial-based 3D scaffolds to simulate in-vivo tissue to solve the niche environment problem. Recent breakthroughs in neural regeneration have led to the development of a biomimetic scaffolds made of Hyaluronic acid (HA) and collagen (COL) that imitate the CNS's extracellular matrix (ECM) for better neural regeneration and repair. HA and COL based scaffold creates a favourable microenvironment for cellular migration, proliferation and survival of the embedded stem cells and promotes neural regeneration. HA regulates cellular activities while COL contributes in healing CNS injuries. Therefore, the utilization of HA-COL based scaffolds is appropriate for regulating cellular responses and behaviour for neural regeneration. This review investigates the synergy between HA and COL in the context of neural-specific applications for repair, regeneration, and recovery as well as augmentation of bioactivity through fabrication techniques such as 3D bioprinting, electrospinning, etc. for neural tissue regeneration.
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Affiliation(s)
- Sneha Ranjan
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Devghat, Jhalwa, Prayagraj 211015, Uttar Pradesh, India.
| | | | - Saurabh Shivalkar
- National Institute of Animal Biotechnology (NIAB), Hyderabad 500032, Telangana, India.
| | - Shrey Dwivedi
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Devghat, Jhalwa, Prayagraj 211015, Uttar Pradesh, India.
| | - Sangeeta Singh
- Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Devghat, Jhalwa, Prayagraj 211015, Uttar Pradesh, India.
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3
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Yari-Ilkhchi A, Hamidi N, Mahkam M, Ebrahimi-Kalan A. Graphene-based materials: an innovative approach for neural regeneration and spinal cord injury repair. RSC Adv 2025; 15:9829-9853. [PMID: 40165920 PMCID: PMC11956154 DOI: 10.1039/d4ra07976k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/17/2025] [Indexed: 04/02/2025] Open
Abstract
Spinal cord injury (SCI), the most serious disease affecting the central nervous system (CNS), is one of contemporary medicine's most difficult challenges, causing patients to suffer physically, emotionally, and socially. However, due to recent advances in medical science and biomaterials, graphene-based materials (GBMs) have tremendous potential in SCI therapy due to their wonderful and valuable properties, such as physicochemical properties, extraordinary electrical conductivity, distinct morphology, and high mechanical strength. This review discusses SCI pathology and GBM characteristics, as well as recent in vitro and in vivo findings on graphenic scaffolds, electrodes, and injectable achievements for SCI improvement using neuroprotective and neuroregenerative techniques to improve neural structural and functional repair. Additionally, it suggests possible ideas and desirable products for graphene-based technological advances, intending to reach therapeutic importance for SCI.
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Affiliation(s)
- Ayda Yari-Ilkhchi
- Chemistry Department, Faculty of Science, Azarbaijan Shahid Madani University 5375171379 Tabriz Iran
- Faculty of Chemical and Metallurgical Engineering, Department of Chemical Engineering, Istanbul Technical University Maslak 34469 Istanbul Turkey
- Faculty of Engineering and Natural Sciences, Sabanci University 34956 Istanbul Turkey
| | - Nazila Hamidi
- Department of Chemistry and Biochemistry, The University of Tulsa Tulsa OK 74104 USA
| | - Mehrdad Mahkam
- Chemistry Department, Faculty of Science, Azarbaijan Shahid Madani University 5375171379 Tabriz Iran
| | - Abbas Ebrahimi-Kalan
- Faculty of Advanced Medical Science, Tabriz University of Medical Sciences 5166614733 Tabriz Iran
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4
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Wang Z, Gao S, Zhu Y, Chen L. Systemic lupus erythematosus therapies: a decade of progress and prospects in clinical trials. J Transl Med 2025; 23:169. [PMID: 39930451 PMCID: PMC11808999 DOI: 10.1186/s12967-025-06184-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 02/01/2025] [Indexed: 02/14/2025] Open
Affiliation(s)
- Zhenwei Wang
- The Second Clinical Medical College of Zhejiang, Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Shiyu Gao
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Ying Zhu
- The Second Clinical Medical College of Zhejiang, Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China
| | - Liangliang Chen
- The Second Clinical Medical College of Zhejiang, Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, 310053, Zhejiang, People's Republic of China.
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5
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Martin JR, Cleary D, Abraham ME, Mendoza M, Cabrera B, Jamieson C, Marsala M, Ciacci JD. Long-term clinical and safety outcomes from a single-site phase 1 study of neural stem cell transplantation for chronic thoracic spinal cord injury. Cell Rep Med 2024; 5:101841. [PMID: 39626671 PMCID: PMC11722094 DOI: 10.1016/j.xcrm.2024.101841] [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: 06/29/2023] [Revised: 06/07/2024] [Accepted: 11/05/2024] [Indexed: 12/20/2024]
Abstract
We report the long-term results for a phase 1 study of neural stem cell transplantation for chronic spinal cord injury. The trial was registered on ClinicalTrials.gov as NCT01772810. The primary outcome of the trial was to test the feasibility and safety of human spinal cord-derived neural stem cell (NSI-566) transplantation for the treatment of chronic spinal cord injury in four subjects with thoracic two to thoracic twelve spinal cord injury. Here, we report that all four subjects tolerated the stem cell implantation procedure well, and two subjects had durable electromyography-quantifiable evidence of neurological improvement as well as increased neurological motor and sensory scores at five years post-transplantation.
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Affiliation(s)
- Joel R Martin
- Department of Neurological Surgery, University of California, San Diego, La Jolla, CA 92037, USA
| | - Daniel Cleary
- Department of Neurological Surgery, University of California, San Diego, La Jolla, CA 92037, USA
| | - Mickey E Abraham
- Department of Neurological Surgery, University of California, San Diego, La Jolla, CA 92037, USA
| | - Michelle Mendoza
- Department of Medicine, Division of Regenerative Medicine and CIRM Alpha Stem Cell Clinic, University of California, San Diego, La Jolla, CA 92037, USA
| | - Betty Cabrera
- Department of Medicine, Division of Regenerative Medicine and CIRM Alpha Stem Cell Clinic, University of California, San Diego, La Jolla, CA 92037, USA
| | - Catriona Jamieson
- Department of Medicine, Division of Regenerative Medicine and CIRM Alpha Stem Cell Clinic, University of California, San Diego, La Jolla, CA 92037, USA
| | - Martin Marsala
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92037, USA
| | - Joseph D Ciacci
- Department of Neurological Surgery, University of California, San Diego, La Jolla, CA 92037, USA.
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6
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Jung JW, Jeong JH, Ko MJ, Lee BJ, Kwon WK, Jeon SR, Lee S. Induced Neural Stem Cell Transplantation in Spinal Cord Injury: Present Status and Next Steps. Korean J Neurotrauma 2024; 20:234-245. [PMID: 39803345 PMCID: PMC11711022 DOI: 10.13004/kjnt.2024.20.e45] [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: 11/13/2024] [Revised: 12/11/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025] Open
Abstract
Spinal cord injury (SCI) remains a significant clinical challenge, with no fully effective treatment available despite advancements in various therapeutic approaches. This review examines the emerging role of induced neural stem cells (iNSCs) as promising candidates for SCI treatment, highlighting their potential for direct neural regeneration and integration with host tissue. We explore the biology of iNSCs, their mechanisms of action, and their interactions with host tissue, including modulating inflammatory responses, promoting axonal growth, and reconstructing neural circuits. Additionally, the importance of administration route, optimal timing for transplantation, and potential adverse events are discussed to address key challenges in translating these therapies to clinical applications. The review also emphasizes recent innovations, such as combining iNSC transplantation with rehabilitative training and the integration of biomaterials and growth factors to enhance therapeutic efficacy. Although preclinical studies have demonstrated positive outcomes, larger, controlled trials and standardized protocols are essential for validating the safety and effectiveness of iNSC-based therapies for SCI patients.
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Affiliation(s)
- Jae-Woo Jung
- Department of Neurosurgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Je Hoon Jeong
- Department of Neurosurgery, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Myeong Jin Ko
- Department of Neurosurgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
| | - Byung-Jou Lee
- Department of Neurosurgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Woo-Keun Kwon
- Department of Neurosurgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sang Ryong Jeon
- Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Subum Lee
- Department of Neurosurgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
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7
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Davoudi-Monfared E, Abolghasemi R, Allahyari F, Farzanegan G. Adverse events of cell therapy clinical trials in human chronic spinal cord injury, a systematic review and meta-analysis. Regen Ther 2024; 27:381-397. [PMID: 38694447 PMCID: PMC11061649 DOI: 10.1016/j.reth.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/10/2024] [Accepted: 03/15/2024] [Indexed: 05/04/2024] Open
Abstract
Spinal cord injury is a lesion with high mortality and significant morbidities. After the primary injury, during six months, a cascade of secondary cellular and molecular events makes the lesion chronic. Recently, cell-based clinical trials as a new procedure have been gradually tested to improve the symptoms of patients. Each treatment method is associated with different adverse events. Based on the PRISMA flow diagram of the identified records, and after multistep screening, finally in 76 reviewed studies with 1633 cases and 189 controls, 64 types of adverse events in 12 categories were recorded in 45 studies. The most common adverse events were transient backache and meningism (90%) and cord malacia (80%). The cell therapy method in which the treatment was associated with more adverse events was Olfactory ensheathing cell and bone marrow mesenchymal stem cell combination therapy in 55%, and the adverse events were less with the embryonic stem cell in 2.33% of patients. In a meta-analysis, the total prevalence of adverse events in cell therapy was 19% and the highest pulled effect size belonged to urinary tract and localized adverse events. Also, the total prevalence of adverse events in 14 cell therapy methods was 18% and four cell types (neural stem cell, bone marrow hematopoietic stem cell, embryonic stem cell, and umbilical cord mesenchymal stem cell) had the most effect. None of the adverse events were reported on the 4 (life-threatening consequences) and 5 (death) grading scales. We concluded that the frequency of life-threatening adverse events following cell therapy clinical trials in chronic spinal cord injury patients is very scarce and can be ignored.
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Affiliation(s)
- Esmat Davoudi-Monfared
- Health Management Research Center & Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Reyhaneh Abolghasemi
- New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Fakhri Allahyari
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Gholamreza Farzanegan
- Trauma Research Center & Department of Neurosurgery, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Ralph PC, Choi SW, Baek MJ, Lee SJ. Regenerative medicine approaches for the treatment of spinal cord injuries: Progress and challenges. Acta Biomater 2024; 189:57-72. [PMID: 39424019 DOI: 10.1016/j.actbio.2024.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/03/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Spinal cord injury (SCI) is a profound medical condition that significantly hampers motor function, imposing substantial limitations on daily activities and exerting a considerable financial burden on patients and their families. The constrained regenerative capacity of endogenous spinal cord tissue, exacerbated by the inflammatory response following the initial trauma, poses a formidable obstacle to effective therapy. Recent advancements in the field, stem cells, biomaterials, and molecular therapy, show promising outcomes. This review provides a comprehensive analysis of tissue engineering and regenerative medicine approaches for SCI treatment, including cell transplantation, tissue-engineered construct implantation, and other potential therapeutic strategies. Additionally, it sheds light on preclinical animal studies and recent clinical trials incorporating these modalities, providing a glimpse into the evolving landscape of SCI management. STATEMENT OF SIGNIFICANCE: The investigation into spinal cord injury (SCI) treatments focuses on reducing long-term impacts by targeting scar inhibition and enhancing regeneration through stem cells, with or without growth factors. Induced pluripotent stem cells (iPSCs) show promise for autologous use, with clinical trials confirming their safety. Challenges include low cell viability and difficulty in targeted differentiation. Biomaterial scaffolds hold potential for improving cell viability and integration, and extracellular vesicles (EVs) are emerging as a novel therapy. While EV research is in its early stages, stem cell trials demonstrate safety and potential recovery. Advancing tissue engineering approaches with biomaterial scaffolds is crucial for human trials.
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Affiliation(s)
- Patrick C Ralph
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States
| | - Sung-Woo Choi
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States; Department of Orthopedic Surgery, Soonchunhyang University Hospital Seoul, Seoul 04401, Republic of Korea
| | - Min Jung Baek
- Department of Obstetrics and Gynecology, CHA University Bundang Medical Center, Seongnam, Gyeonggi-do 13496, Republic of Korea
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States.
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9
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Svendsen SP, Svendsen CN. Cell therapy for neurological disorders. Nat Med 2024; 30:2756-2770. [PMID: 39407034 DOI: 10.1038/s41591-024-03281-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/30/2024] [Indexed: 10/18/2024]
Abstract
Cell therapies for neurological disorders are entering the clinic and present unique challenges and opportunities compared with conventional medicines. They have the potential to replace damaged nervous tissue and integrate into the brain or spinal cord to produce functional effects for the lifetime of the patient, which could revolutionize the way clinicians treat debilitating neurological disorders. The major challenge has been cell sourcing, which historically relied mainly on fetal brain tissue. This has largely been overcome with the advent of pluripotent stem cell technology and the ability to make almost any cell of the nervous system at scale. Furthermore, advances in gene editing now allow the generation of genetically modified cells that could perform better and evade the immune system. With all the remarkable new approaches to treat neurological disorders, we take a critical look at the state of current clinical trials and how challenges may be overcome with the evolving technology and innovation occurring in the stem cell field.
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Affiliation(s)
- Soshana P Svendsen
- Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA
| | - Clive N Svendsen
- Cedars-Sinai Board of Governors Regenerative Medicine Institute, Los Angeles, CA, USA.
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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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11
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Deng K, Hu DX, Zhang WJ. Application of cell transplantation in the treatment of neuropathic pain. Neuroscience 2024; 554:43-51. [PMID: 38986736 DOI: 10.1016/j.neuroscience.2024.06.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/15/2024] [Accepted: 06/30/2024] [Indexed: 07/12/2024]
Abstract
Nerve injury can not only lead to sensory and motor dysfunction, but also be complicated with neuropathic pain (NPP), which brings great psychosomatic injury to patients. At present, there is no effective treatment for NPP. Based on the functional characteristics of cell transplantation in nerve regeneration and injury repair, cell therapy has been used in the exploratory treatment of NPP and has become a promising treatment of NPP. In this article, we discuss the current mainstream cell types for the treatment of NPP, including Schwann cells, olfactory ensheathing cells, neural stem cells and mesenchymal stem cells in the treatment of NPP. These bioactive cells transplanted into the host have pharmacological properties of decreasing pain threshold and relieving NPP by exerting nutritional support, neuroprotection, immune regulation, promoting axonal regeneration, and remyelination. Cell transplantation can also change the microenvironment around the nerve injury, which is conducive to the survival of neurons. It can effectively relieve pain by repairing the injured nerve and rebuilding the nerve function. At present, some preclinical and clinical studies have shown that some encouraging results have been achieved in NPP treatment based on cell transplantation. Therefore, we discussed the feasible strategy of cell transplantation as a treatment of NPP and the problems and challenges that need to be solved in the current application of cell transplantation in NPP therapy.
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Affiliation(s)
- Kan Deng
- Rehabilitation Medicine Department, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China; Ji an College, Ji an City, Jiangxi Province, China
| | - Dong-Xia Hu
- Rehabilitation Medicine Department, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China
| | - Wen-Jun Zhang
- Rehabilitation Medicine Department, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, China.
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Li C, Luo Y, Li S. The roles of neural stem cells in myelin regeneration and repair therapy after spinal cord injury. Stem Cell Res Ther 2024; 15:204. [PMID: 38978125 PMCID: PMC11232222 DOI: 10.1186/s13287-024-03825-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024] Open
Abstract
Spinal cord injury (SCI) is a complex tissue injury that results in a wide range of physical deficits, including permanent or progressive disabilities of sensory, motor and autonomic functions. To date, limitations in current clinical treatment options can leave SCI patients with lifelong disabilities. There is an urgent need to develop new therapies for reconstructing the damaged spinal cord neuron-glia network and restoring connectivity with the supraspinal pathways. Neural stem cells (NSCs) possess the ability to self-renew and differentiate into neurons and neuroglia, including oligodendrocytes, which are cells responsible for the formation and maintenance of the myelin sheath and the regeneration of demyelinated axons. For these properties, NSCs are considered to be a promising cell source for rebuilding damaged neural circuits and promoting myelin regeneration. Over the past decade, transplantation of NSCs has been extensively tested in a variety of preclinical models of SCI. This review aims to highlight the pathophysiology of SCI and promote the understanding of the role of NSCs in SCI repair therapy and the current advances in pathological mechanism, pre-clinical studies, as well as clinical trials of SCI via NSC transplantation therapeutic strategy. Understanding and mastering these frontier updates will pave the way for establishing novel therapeutic strategies to improve the quality of recovery from SCI.
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Affiliation(s)
- Chun Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, Shanghai, 200092, China
| | - Yuping Luo
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
| | - Siguang Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Neurology, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
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Abolghasemi R, Davoudi-Monfared E, Allahyari F, Farzanegan G. Systematic Review of Cell Therapy Efficacy in Human Chronic Spinal Cord Injury. TISSUE ENGINEERING. PART B, REVIEWS 2024; 30:254-269. [PMID: 37917104 DOI: 10.1089/ten.teb.2023.0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Spinal cord injury (SCI) is one of the most debilitating problems for humans. About 6 months after the initial injury, a cascade of secondary cellular and molecular events occurs and the primary damage enters the chronic phase. Current treatments are not curative. One of the new treatment methods is the use of cell therapy, which is gradually being tested in clinical trials to improve the symptoms of SCI patients. In this review article, we investigated the effect of different cell therapy trials in improving patients' symptoms and their paraclinical indicators. In the 72 final reviewed studies with 1144 cases and 186 controls, 20 scores were recorded as outcomes. We categorized the scores into seven groups. In upper extremity motor score, daily living function, trunk stability, postural hypotension, somatosensory evoked potential, and motor evoked potential scores, the bone marrow hematopoietic stem cell therapy had a more healing effect. In the International Association of Neurorestoratology SCI Functional Rating Scale, light touch score, bowel function, decreased spasticity, Visual Analog Scale, and electromyography scores, the bone marrow mesenchymal stem cell had more impact. The olfactory ensheathing cell had a greater effect on lower extremity motor score and pinprick scores than other cells. The embryonic stem cell had the greatest effect in improving the important score of the American Spinal Injury Association scale. Based on the obtained results, it seems that a special cell should be used to improve each symptom of patients with chronic SCI, and if the improvement of several harms is involved, the combination of cells may be effective. Impact statement Compared to similar review articles published so far, we reviewed the largest number of published articles, and so the largest number of cases and controls, and the variety of cells we examined was more than other published articles. We concluded that different cells are effective for improving the symptoms and paraclinical indicators of patients with chronic spinal cord injury. Bone marrow hematopoietic stem cell and bone marrow mesenchymal stem cell have had the higher overall mean effect in more scores (each in six scores). If the improvement of several harms is involved, the combination of cells may be effective.
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Affiliation(s)
- Reyhaneh Abolghasemi
- New Hearing Technologies Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Esmat Davoudi-Monfared
- Health Management Research Center and Department of Community Medicine, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Fakhri Allahyari
- Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Gholamreza Farzanegan
- Trauma Research Center and Department of Neurosurgery, Faculty of Medicine, Baqiyatallah University of Medical Sciences, Tehran, Iran
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14
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Agosti E, Zeppieri M, Pagnoni A, Fontanella MM, Fiorindi A, Ius T, Panciani PP. Current status and future perspectives on stem cell transplantation for spinal cord injury. World J Transplant 2024; 14:89674. [PMID: 38576751 PMCID: PMC10989472 DOI: 10.5500/wjt.v14.i1.89674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/04/2023] [Accepted: 12/29/2023] [Indexed: 03/15/2024] Open
Abstract
BACKGROUND Previous assessments of stem cell therapy for spinal cord injuries (SCI) have encountered challenges and constraints. Current research primarily emphasizes safety in early-phase clinical trials, while systematic reviews prioritize effectiveness, often overlooking safety and translational feasibility. This situation prompts inquiries regarding the readiness for clinical adoption. AIM To offer an up-to-date systematic literature review of clinical trial results con cerning stem cell therapy for SCI. METHODS A systematic search was conducted across major medical databases [PubMed, Embase, Reference Citation Analysis (RCA), and Cochrane Library] up to October 14, 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "spinal cord", "injury", "clinical trials", "stem cells", "functional outcomes", and "adverse events". Studies included in this review consisted of randomized controlled trials and non-randomized controlled trials reporting on the use of stem cell therapies for the treatment of SCI. RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI, 496 papers were initially identified, with 237 chosen for full-text analysis. Among them, 236 were deemed eligible after excluding 170 for various reasons. These studies encompassed 1086 patients with varying SCI levels, with cervical injuries being the most common (42.2%). Bone marrow stem cells were the predominant stem cell type used (71.1%), with various administration methods. Follow-up durations averaged around 84.4 months. The 32.7% of patients showed functional impro vement from American spinal injury association Impairment Scale (AIS) A to B, 40.8% from AIS A to C, 5.3% from AIS A to D, and 2.1% from AIS B to C. Sensory improvements were observed in 30.9% of patients. A relatively small number of adverse events were recorded, including fever (15.1%), headaches (4.3%), muscle tension (3.1%), and dizziness (2.6%), highlighting the potential for SCI recovery with stem cell therapy. CONCLUSION In the realm of SCI treatment, stem cell-based therapies show promise, but clinical trials reveal potential adverse events and limitations, underscoring the need for meticulous optimization of transplantation conditions and parameters, caution against swift clinical implementation, a deeper understanding of SCI pathophysiology, and addressing ethical, tumorigenicity, immunogenicity, and immunotoxicity concerns before gradual and careful adoption in clinical practice.
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Affiliation(s)
- Edoardo Agosti
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Zeppieri
- Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
| | - Andrea Pagnoni
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Marco Maria Fontanella
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia 25123, BS, Italy
| | - Alessandro Fiorindi
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
| | - Tamara Ius
- Neurosurgery Unit, Head-Neck and NeuroScience Department, University Hospital of Udine, Udine 33100, Italy
| | - Pier Paolo Panciani
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
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15
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Hosseini SM, Borys B, Karimi-Abdolrezaee S. Neural stem cell therapies for spinal cord injury repair: an update on recent preclinical and clinical advances. Brain 2024; 147:766-793. [PMID: 37975820 DOI: 10.1093/brain/awad392] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/22/2023] [Accepted: 11/02/2023] [Indexed: 11/19/2023] Open
Abstract
Traumatic spinal cord injury (SCI) is a leading cause of lifelong disabilities. Permanent sensory, motor and autonomic impairments after SCI are substantially attributed to degeneration of spinal cord neurons and axons, and disintegration of neural network. To date, minimal regenerative treatments are available for SCI with an unmet need for new therapies to reconstruct the damaged spinal cord neuron-glia network and restore connectivity with the supraspinal pathways. Multipotent neural precursor cells (NPCs) have a unique capacity to generate neurons, oligodendrocytes and astrocytes. Due to this capacity, NPCs have been an attractive cell source for cellular therapies for SCI. Transplantation of NPCs has been extensively tested in preclinical models of SCI in the past two decades. These studies have identified opportunities and challenges associated with NPC therapies. While NPCs have the potential to promote neuroregeneration through various mechanisms, their low long-term survival and integration within the host injured spinal cord limit the functional benefits of NPC-based therapies for SCI. To address this challenge, combinatorial strategies have been developed to optimize the outcomes of NPC therapies by enriching SCI microenvironment through biomaterials, genetic and pharmacological therapies. In this review, we will provide an in-depth discussion on recent advances in preclinical NPC-based therapies for SCI. We will discuss modes of actions and mechanism by which engrafted NPCs contribute to the repair process and functional recovery. We will also provide an update on current clinical trials and new technologies that have facilitated preparation of medical-grade human NPCs suitable for transplantation in clinical studies.
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Affiliation(s)
- Seyed Mojtaba Hosseini
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
- Manitoba Multiple Sclerosis Research Center, Winnipeg, Manitoba R3E 0J9, Canada
| | - Ben Borys
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
- Manitoba Multiple Sclerosis Research Center, Winnipeg, Manitoba R3E 0J9, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada
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16
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Anggraini D, Zhang T, Liu X, Okano K, Tanaka Y, Inagaki N, Li M, Hosokawa Y, Yamada S, Yalikun Y. Guided axon outgrowth of neurons by molecular gradients generated from femtosecond laser-fabricated micro-holes. Talanta 2024; 267:125200. [PMID: 37738745 DOI: 10.1016/j.talanta.2023.125200] [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: 06/12/2023] [Revised: 09/04/2023] [Accepted: 09/11/2023] [Indexed: 09/24/2023]
Abstract
OBJECTIVE Transplantation of scaffold-embedded guided neurons has been reported to increase neuronal regeneration following brain injury. However, precise axonal integration between host and transplant neurons to form functional synapses remains a major problem. Thus, a high-precision tool to actuate neuronal axon outgrowth in real-time conditions is required to attain robust axon regeneration. This study aims to establish a microfluidic platform for precise and real-time axon outgrowth guidance. METHODS A microfluidic device with a 4 μm thick thin-glass sheet as the neuron culture substrate is fabricated. Surface of the glass sheet is chemically modified to facilitate neuron attachment. Femtosecond (fs) laser is used to engrave the glass sheet to achieve micro-holes, where netrin-1 is released for directing the movement of the neuronal axon. RESULTS Numerical simulation and experimental data demonstrate that netrin-1 gradient is formed after it passes through the micro-hole. The neuronal response results show the outgrowth rate of the axon is significantly increased by netrin-1 gradient. Furthermore, a majority of neuronal axons exhibit guided outgrowth characterized by positive turning angles of axon displacement in the direction of netrin-1 gradients. CONCLUSION Integrating fs laser and microfluidic device facilitates controlled and instantaneous axon outgrowth in a non-invasive manner. SIGNIFICANCE The developed real-time microfluidic platform shows potential in the application for on-site neuronal transplantation, which is significant for the treatment of a range of neurological disorders and injuries.
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Affiliation(s)
- Dian Anggraini
- Division of Materials Science, Nara Institute of Science and Technology, Ikoma, 630-0192, Japan
| | - Tianlong Zhang
- College of Mechanical Engineering, Jiangsu University of Science and Technology, Zhenjiang, 212100, China
| | - Xun Liu
- Division of Materials Science, Nara Institute of Science and Technology, Ikoma, 630-0192, Japan
| | - Kazunori Okano
- Division of Materials Science, Nara Institute of Science and Technology, Ikoma, 630-0192, Japan
| | - Yo Tanaka
- Center for Biosystems Dynamics Research (BDR), RIKEN, Osaka, 565-0871, Japan
| | - Naoyuki Inagaki
- Division of Biological Science, Nara Institute of Science and Technology, Ikoma, 630-0192, Japan
| | - Ming Li
- School of Engineering, Macquarie University, Sydney, 2122, Australia
| | - Yoichiroh Hosokawa
- Division of Materials Science, Nara Institute of Science and Technology, Ikoma, 630-0192, Japan
| | - Sohei Yamada
- Division of Materials Science, Nara Institute of Science and Technology, Ikoma, 630-0192, Japan.
| | - Yaxiaer Yalikun
- Division of Materials Science, Nara Institute of Science and Technology, Ikoma, 630-0192, Japan; Center for Biosystems Dynamics Research (BDR), RIKEN, Osaka, 565-0871, Japan.
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17
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Roman A, Huntemer-Silveira A, Waldron MA, Khalid Z, Blake J, Parr AM, Low WC. Cell Transplantation for Repair of the Spinal Cord and Prospects for Generating Region-Specific Exogenic Neuronal Cells. Cell Transplant 2024; 33:9636897241241998. [PMID: 38590295 PMCID: PMC11005494 DOI: 10.1177/09636897241241998] [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: 09/25/2023] [Revised: 03/05/2024] [Accepted: 03/11/2024] [Indexed: 04/10/2024] Open
Abstract
Spinal cord injury (SCI) is associated with currently irreversible consequences in several functional components of the central nervous system. Despite the severity of injury, there remains no approved treatment to restore function. However, with a growing number of preclinical studies and clinical trials, cell transplantation has gained significant potential as a treatment for SCI. Researchers have identified several cell types as potential candidates for transplantation. To optimize successful functional outcomes after transplantation, one key factor concerns generating neuronal cells with regional and subtype specificity, thus calling on the developmental transcriptome patterning of spinal cord cells. A potential source of spinal cord cells for transplantation is the generation of exogenic neuronal progenitor cells via the emerging technologies of gene editing and blastocyst complementation. This review highlights the use of cell transplantation to treat SCI in the context of relevant developmental gene expression patterns useful for producing regionally specific exogenic spinal cells via in vitro differentiation and blastocyst complementation.
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Affiliation(s)
- Alex Roman
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Department of Neurosurgery, Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Anne Huntemer-Silveira
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - Madison A. Waldron
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
| | - Zainab Khalid
- Department of Neurosurgery, Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Jeffrey Blake
- Department of Neurosurgery, Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Ann M. Parr
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Department of Neurosurgery, Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Walter C. Low
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA
- Department of Neurosurgery, Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
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18
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Grijalva-Otero I, Doncel-Pérez E. Traumatic Human Spinal Cord Injury: Are Single Treatments Enough to Solve the Problem? Arch Med Res 2024; 55:102935. [PMID: 38157747 DOI: 10.1016/j.arcmed.2023.102935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/17/2023] [Accepted: 12/11/2023] [Indexed: 01/03/2024]
Abstract
Traumatic spinal cord injury (SCI) results in partial or complete motor deficits, such as paraplegia, tetraplegia, and sphincter control, as well as sensory disturbances and autonomic dysregulation such as arterial hypotension, lack of sweating, and alterations in skin lability. All this has a strong psychological impact on the affected person and his/her family, as well as costs to healthcare institutions with an economic burden in the short, medium, and long terms. Despite at least forty years of experimental animal studies and several clinical trials with different therapeutic strategies, effective therapy is not universally accepted. Most of the published works on acute and chronic injury use a single treatment, such as medication, trophic factor, transplant of a cell type, and so on, to block some secondary injury mechanisms or promote some mechanisms of structural/functional restoration. However, despite significant results in experimental models, the outcome is a moderate improvement in muscle strength, sensation, or eventually in sphincter control, which has been considered non-significant in human clinical trials. Here we present a brief compilation of successful individual treatments that have been applied to secondary mechanisms of action. These studies show limited neuroprotective or neurorestorative approaches in animal models and clinical trials. Thus, the few benefits achieved so far represent a rationale to further explore other strategies that seek better structural and functional restoration of the injured spinal cord.
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Affiliation(s)
- Israel Grijalva-Otero
- Medical Research Unit for Neurological Diseases, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.
| | - Ernesto Doncel-Pérez
- Neural Regeneration Group, Hospital Nacional de Parapléjicos de Toledo, Servicios de Salud de Castilla-La Mancha, Toledo, Spain
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19
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Khan SI, Ahmed N, Ahsan K, Abbasi M, Maugeri R, Chowdhury D, Bonosi L, Brunasso L, Costanzo R, Iacopino DG, Umana GE, Chaurasia B. An Insight into the Prospects and Drawbacks of Stem Cell Therapy for Spinal Cord Injuries: Ongoing Trials and Future Directions. Brain Sci 2023; 13:1697. [PMID: 38137145 PMCID: PMC10741986 DOI: 10.3390/brainsci13121697] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating neurological disorder that has a substantial detrimental impact on a person's quality of life. The estimated global incidence of SCI is 40 to 80 cases per million people and around 90% of cases are traumatic. Various etiologies can be recognized for SCI, and post-traumatic SCI represents the most common of these. Patients worldwide with SCI suffer from a persistent loss of motor and sensory function, which affects every aspect of their personal and social lives. Given the lack of effective treatments, many efforts have been made to seek a cure for this condition. In recent years, thanks to their ability to regenerate tissue and repair lost or damaged cells, much attention has been directed toward the use of stem cells (embryonic, induced pluripotent, mesenchymal, hematopoietic), aimed at restoring the functional integrity of the damaged spinal cord and improving a functional recovery including sensory and motor function. In this paper, we offer an overview of the benefits and drawbacks of stem cell therapy for SCI based on clinical evidence. This report also addresses the characteristics of various stem cell treatments, as well as the field's likely future. Each cell type targets specific pathological characteristics associated with SCI and demonstrates therapeutic effects via cell replacement, nutritional support, scaffolds, and immunomodulation pathways. SCI accompanied by complex pathological processes cannot be resolved by single treatment measures. Stem cells are associated with the adjustment of the expression of neurotrophic factors that help to achieve better nutrition to damaged tissue. Single-cell treatments have been shown in some studies to provide very minor benefits for SCI in multiple preclinical studies and a growing number of clinical trials. However, SCI damage is complex, and many studies are increasingly recognizing a combination approach such as physical therapy, electrical stimulation, or medication therapy to treatment.
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Affiliation(s)
- Shahidul Islam Khan
- Spine Surgery Unit, Department of Orthopaedic Surgery, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000, Bangladesh; (S.I.K.); (K.A.)
| | - Nazmin Ahmed
- Department of Neurosurgery, Ibrahim Cardiac Hospital and Research Institute, Shahbag, Dhaka 1000, Bangladesh;
| | - Kamrul Ahsan
- Spine Surgery Unit, Department of Orthopaedic Surgery, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000, Bangladesh; (S.I.K.); (K.A.)
| | - Mahmud Abbasi
- Department of General Anaesthesiology, Ibrahim Cardiac Hospital and Research Institute, Shahbag, Dhaka 1000, Bangladesh;
| | - Rosario Maugeri
- Neurosurgical Clinic, AOUP “Paolo Giaccone”, Post Graduate Residency Program in Neurologic Surgery, Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, 90133 Palermo, Italy; (L.B.); (L.B.); (R.C.); (D.G.I.)
| | - Dhiman Chowdhury
- Department of Neurosurgery, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 1000, Bangladesh;
| | - Lapo Bonosi
- Neurosurgical Clinic, AOUP “Paolo Giaccone”, Post Graduate Residency Program in Neurologic Surgery, Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, 90133 Palermo, Italy; (L.B.); (L.B.); (R.C.); (D.G.I.)
| | - Lara Brunasso
- Neurosurgical Clinic, AOUP “Paolo Giaccone”, Post Graduate Residency Program in Neurologic Surgery, Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, 90133 Palermo, Italy; (L.B.); (L.B.); (R.C.); (D.G.I.)
| | - Roberta Costanzo
- Neurosurgical Clinic, AOUP “Paolo Giaccone”, Post Graduate Residency Program in Neurologic Surgery, Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, 90133 Palermo, Italy; (L.B.); (L.B.); (R.C.); (D.G.I.)
| | - Domenico Gerardo Iacopino
- Neurosurgical Clinic, AOUP “Paolo Giaccone”, Post Graduate Residency Program in Neurologic Surgery, Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, 90133 Palermo, Italy; (L.B.); (L.B.); (R.C.); (D.G.I.)
| | - Giuseppe Emmanuele Umana
- Department of Neurosurgery, Trauma Center, Gamma Knife Center, Cannizzaro Hospital, 95126 Catania, Italy;
| | - Bipin Chaurasia
- Department of Neurosurgery, Neurosurgery Clinic, Birgunj 44300, Nepal;
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20
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Evans D, Barcons AM, Basit RH, Adams C, Chari DM. Evaluating the Feasibility of Hydrogel-Based Neural Cell Sprays. J Funct Biomater 2023; 14:527. [PMID: 37888192 PMCID: PMC10607175 DOI: 10.3390/jfb14100527] [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: 09/02/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
Neurological injuries have poor prognoses with serious clinical sequelae. Stem cell transplantation enhances neural repair but is hampered by low graft survival (ca. 80%) and marker expression/proliferative potential of hydrogel-sprayed astrocytes was retained. Combining a cell spray format with polymer encapsulation technologies could form the basis of a non-invasive graft delivery method, offering potential advantages over current cell delivery approaches.
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Affiliation(s)
- Daisy Evans
- Keele University School of Medicine, Keele University, Staffordshire ST5 5BG, UK;
| | - Aina Mogas Barcons
- Department of Physiology, Anatomy and Genetics, Oxford Parkinson’s Disease Centre, University of Oxford, Oxford OX1 3AZ, UK;
| | - Raja Haseeb Basit
- Department of General Surgery, Queen Elizabeth Hospital, Birmingham B15 2GW, UK;
| | - Christopher Adams
- Neural Tissue Engineering, School of Life Sciences, Keele University, Staffordshire ST5 5BG, UK;
| | - Divya Maitreyi Chari
- Neural Tissue Engineering, School of Life Sciences, Keele University, Staffordshire ST5 5BG, UK;
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21
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Kwokdinata C, Ramanujam V, Chen J, de Oliveira PN, Nai MH, Chooi WH, Lim CT, Ng SY, David L, Chew SY. Encapsulation of Human Spinal Cord Progenitor Cells in Hyaluronan-Gelatin Hydrogel for Spinal Cord Injury Treatment. ACS APPLIED MATERIALS & INTERFACES 2023; 15:50679-50692. [PMID: 37751213 DOI: 10.1021/acsami.3c07419] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Transplanting human induced pluripotent stem cells (iPSCs)-derived spinal cord progenitor cells (SCPCs) is a promising approach to treat spinal cord injuries. However, stem cell therapies face challenges in cell survival, cell localization to the targeted site, and the control of cell differentiation. Here, we encapsulated SCPCs in thiol-modified hyaluronan-gelatin hydrogels and optimized scaffold mechanical properties and cell encapsulation density to promote cell viability and neuronal differentiation in vitro and in vivo. Different compositions of hyaluronan-gelatin hydrogels formulated by varying concentrations of poly(ethylene glycol) diacrylate were mechanically characterized by using atomic force microscopy. In vitro SCPC encapsulation study showed higher cell viability and proliferation with lower substrate Young's modulus (200 Pa vs 580 Pa) and cell density. Moreover, the soft hydrogels facilitated a higher degree of neuronal differentiation with extended filament structures in contrast to clumped cellular morphologies obtained in stiff hydrogels (p < 0.01). When transplanted in vivo, the optimized SCPC-encapsulated hydrogels resulted in higher cell survival and localization at the transplanted region as compared to cell delivery without hydrogel encapsulation at 2 weeks postimplantation within the rat spinal cord (p < 0.01). Notably, immunostaining demonstrated that the hydrogel-encapsulated SCPCs differentiated along the neuronal and oligodendroglial lineages in vivo. The lack of pluripotency and proliferation also supported the safety of the SCPC transplantation approach. Overall, the injectable hyaluronan-gelatin hydrogel shows promise in supporting the survival and neural differentiation of human SCPCs after transplantation into the spinal cord.
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Affiliation(s)
- Christy Kwokdinata
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637459, Singapore
| | - Vaibavi Ramanujam
- CNRS@CREATE, Create Tower #08-01, 1 Create Way, Singapore 138602, Singapore
| | - Jiahui Chen
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637459, Singapore
| | | | - Mui Hoon Nai
- Department of Biomedical Engineering, National University of Singapore, Singapore 117576, Singapore
| | - Wai Hon Chooi
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Chwee Teck Lim
- Department of Biomedical Engineering, National University of Singapore, Singapore 117576, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore 117411, Singapore
| | - Shi Yan Ng
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Laurent David
- CNRS@CREATE, Create Tower #08-01, 1 Create Way, Singapore 138602, Singapore
- Ingénierie des Matériaux Polymères IMP UMR 5223, CNRS, Université Claude Bernard Lyon 1, INSA de Lyon, Université Jean Monnet, Université de Lyon, Villeurbanne F69622, France
| | - Sing Yian Chew
- School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore 637459, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore
- School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore
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22
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Garcia E, Buzoianu-Anguiano V, Silva-Garcia R, Esparza-Salazar F, Arriero-Cabañero A, Escandon A, Doncel-Pérez E, Ibarra A. Use of Cells, Supplements, and Peptides as Therapeutic Strategies for Modulating Inflammation after Spinal Cord Injury: An Update. Int J Mol Sci 2023; 24:13946. [PMID: 37762251 PMCID: PMC10531377 DOI: 10.3390/ijms241813946] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/02/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Spinal cord injury is a traumatic lesion that causes a catastrophic condition in patients, resulting in neuronal deficit and loss of motor and sensory function. That loss is caused by secondary injury events following mechanical damage, which results in cell death. One of the most important events is inflammation, which activates molecules like proinflammatory cytokines (IL-1β, IFN-γ, and TNF-α) that provoke a toxic environment, inhibiting axonal growth and exacerbating CNS damage. As there is no effective treatment, one of the developed therapies is neuroprotection of the tissue to preserve healthy tissue. Among the strategies that have been developed are the use of cell therapy, the use of peptides, and molecules or supplements that have been shown to favor an anti-inflammatory environment that helps to preserve tissue and cells at the site of injury, thus favoring axonal growth and improved locomotor function. In this review, we will explain some of these strategies used in different animal models of spinal cord injury, their activity as modulators of the immune system, and the benefits they have shown.
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Affiliation(s)
- Elisa Garcia
- Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico; (E.G.); (F.E.-S.); (A.E.)
| | - Vinnitsa Buzoianu-Anguiano
- Grupo Regeneración Neural, Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain; (V.B.-A.); (A.A.-C.)
| | - Raúl Silva-Garcia
- Unidad de Investigación Médica en Inmunología Hospital de Pediatría, CMN-SXXI, IMSS, Mexico City 06720, Mexico;
| | - Felipe Esparza-Salazar
- Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico; (E.G.); (F.E.-S.); (A.E.)
| | - Alejandro Arriero-Cabañero
- Grupo Regeneración Neural, Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain; (V.B.-A.); (A.A.-C.)
| | - Adela Escandon
- Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico; (E.G.); (F.E.-S.); (A.E.)
| | - Ernesto Doncel-Pérez
- Grupo Regeneración Neural, Hospital Nacional de Parapléjicos, SESCAM, 45071 Toledo, Spain; (V.B.-A.); (A.A.-C.)
| | - Antonio Ibarra
- Centro de Investigación en Ciencias de la Salud (CICSA), FCS, Universidad Anáhuac México Campus Norte, Huixquilucan 52786, Mexico; (E.G.); (F.E.-S.); (A.E.)
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23
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Ribeiro BF, da Cruz BC, de Sousa BM, Correia PD, David N, Rocha C, Almeida RD, Ribeiro da Cunha M, Marques Baptista AA, Vieira SI. Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential. Brain 2023; 146:2672-2693. [PMID: 36848323 DOI: 10.1093/brain/awad047] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 12/23/2022] [Accepted: 01/29/2023] [Indexed: 03/01/2023] Open
Abstract
Spinal cord injury (SCI) is an as yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential, but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and which cell types result in higher neurological and functional recovery remains under debate. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analysed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages and various types of stem cells have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale, motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic aetiology and did not display a randomized comparative control arm. Bone marrow stem cells and OECs were the most commonly tested cells, while open surgery and injection were the main methods of delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest ASIA Impairment Scale (AIS) grade conversion rates (improvements in ∼40% of transplanted patients), which surpassed the spontaneous improvement rate expected for complete chronic SCI patients within 1 year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated and neural stem cells, offer potential for improving patient recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may contribute highly to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials and how these are reported. It is therefore crucial to standardize these trials when aiming for higher value clinical evidence-based conclusions.
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Affiliation(s)
- Beatriz F Ribeiro
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bruna C da Cruz
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bárbara M de Sousa
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Patrícia D Correia
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Nuno David
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Camila Rocha
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Ramiro D Almeida
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Maria Ribeiro da Cunha
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
- Spinal Cord Injury Rehabilitation Unit, Centro de Reabilitação do Norte (CRN), Centro Hospitalar de Vila Nova de Gaia e Espinho (CHVNG/E), 4400-129 Vila Nova de Gaia, Portugal
| | - António A Marques Baptista
- Department of Neurosurgery, Centro Hospitalar de Vila Nova de Gaia e Espinho (CHVNG/E), 4400-129 Vila Nova de Gaia, Portugal
| | - Sandra I Vieira
- Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
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Hu X, Xu W, Ren Y, Wang Z, He X, Huang R, Ma B, Zhao J, Zhu R, Cheng L. Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther 2023; 8:245. [PMID: 37357239 DOI: 10.1038/s41392-023-01477-6] [Citation(s) in RCA: 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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25
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Huang H, Sanberg PR, Moviglia GA, Sharma A, Chen L, Chen D. Clinical results of neurorestorative cell therapies and therapeutic indications according to cellular bio-proprieties. Regen Ther 2023; 23:52-59. [PMID: 37122360 PMCID: PMC10130496 DOI: 10.1016/j.reth.2023.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/09/2023] [Accepted: 03/21/2023] [Indexed: 05/02/2023] Open
Abstract
Cell therapies have been explored to treat patients with nervous diseases for over 20 years. Even though most kinds of cell therapies demonstrated neurorestorative effects in non-randomized clinical trials; the effects of the majority type cells could not be confirmed by randomized controlled trials. In this review, clinical therapeutic results of neurorestorative cell therapies according to cellular bio-proprieties or cellular functions were introduced. Currently it was demonstrated from analysis of this review that some indications of cell therapies were not appropriate, they might be reasons why their neurorestorative effects could not be proved by multicenter, randomized, double blind, placebo-controlled clinical trials. Theoretically if one kind of cell therapy has neurorestorative effects according to its cellular bio-proprieties, it should have appropriate indications. The cell therapies with special bio-properties is promising if the indication selections are appropriate, such as olfactory ensheathing cells for chronic ischemic stroke, and their neurorestorative effects can be confirmed by higher level clinical trials of evidence-based medicine.
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Affiliation(s)
- Hongyun Huang
- Beijing Hongtianji Neuroscience Academy, Beijing 100143, China
- Corresponding author.
| | - Paul R. Sanberg
- Center of Excellence for Aging & Brain Repair, Department of Neurosurgery & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa 33612, Florida, USA
| | | | - Alok Sharma
- Department of Neurosurgery, LTM Medical College, LTMG Hospital, Mumbai, India
| | - Lin Chen
- Department of Neurosurgery, Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100700, China
| | - Di Chen
- Beijing Hongtianji Neuroscience Academy, Beijing 100143, China
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26
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Aceves M, Tucker A, Chen J, Vo K, Moses J, Amar Kumar P, Thomas H, Miranda D, Dampf G, Dietz V, Chang M, Lukose A, Jang J, Nadella S, Gillespie T, Trevino C, Buxton A, Pritchard AL, Green P, McCreedy DA, Dulin JN. Developmental stage of transplanted neural progenitor cells influences anatomical and functional outcomes after spinal cord injury in mice. Commun Biol 2023; 6:544. [PMID: 37208439 PMCID: PMC10199026 DOI: 10.1038/s42003-023-04893-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/02/2023] [Indexed: 05/21/2023] Open
Abstract
Neural progenitor cell (NPC) transplantation is a promising therapeutic strategy for replacing lost neurons following spinal cord injury (SCI). However, how graft cellular composition influences regeneration and synaptogenesis of host axon populations, or recovery of motor and sensory functions after SCI, is poorly understood. We transplanted developmentally-restricted spinal cord NPCs, isolated from E11.5-E13.5 mouse embryos, into sites of adult mouse SCI and analyzed graft axon outgrowth, cellular composition, host axon regeneration, and behavior. Earlier-stage grafts exhibited greater axon outgrowth, enrichment for ventral spinal cord interneurons and Group-Z spinal interneurons, and enhanced host 5-HT+ axon regeneration. Later-stage grafts were enriched for late-born dorsal horn interneuronal subtypes and Group-N spinal interneurons, supported more extensive host CGRP+ axon ingrowth, and exacerbated thermal hypersensitivity. Locomotor function was not affected by any type of NPC graft. These findings showcase the role of spinal cord graft cellular composition in determining anatomical and functional outcomes following SCI.
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Affiliation(s)
- Miriam Aceves
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA
| | - Ashley Tucker
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA
| | - Joseph Chen
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Katie Vo
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Joshua Moses
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | | | - Hannah Thomas
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Diego Miranda
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Gabrielle Dampf
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Valerie Dietz
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Matthew Chang
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Aleena Lukose
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Julius Jang
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Sneha Nadella
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Tucker Gillespie
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Christian Trevino
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Andrew Buxton
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Anna L Pritchard
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | | | - Dylan A McCreedy
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Jennifer N Dulin
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA.
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA.
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27
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Song S, Li Y, Huang J, Cheng S, Zhang Z. Inhibited astrocytic differentiation in neural stem cell-laden 3D bioprinted conductive composite hydrogel scaffolds for repair of spinal cord injury. BIOMATERIALS ADVANCES 2023; 148:213385. [PMID: 36934714 DOI: 10.1016/j.bioadv.2023.213385] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 01/15/2023] [Accepted: 03/10/2023] [Indexed: 03/18/2023]
Abstract
The emergence of three-dimensional (3D) bioprinting technology has attracted ever-increasing attention in engineered tissue fabrication for stem cell-based tissue repair. However, the in vivo performance of transplanted stem cells in the tissue engineering scaffolds is still a major concern for regenerative medicine researches. Especially for neural stem cell (NSC) transplantation, the uncontrollable differentiation of the NSCs in host often leads to a poor therapeutic effect in nerve tissue repair, such as spinal cord injury (SCI) repair. To address this issue, we have fabricated a conductive composite hydrogel (CCH) scaffold loading with NSCs by 3D bioprinting, for delivering the NSCs to injured spinal cord and repairing the propriospinal nerve circuit. In our strategy, a novel conductive polymer (PEDOT:CSMA,TA) was synthesized and introduced into a photocrosslinkable gelatin/polyethylene glycol physical-gel matrix, thereby forming a composite bioink with well shear-thinning and self-healing properties. The composite bioink we prepared was then printed into the NSC-laden CCH scaffold with high shape fidelity and similar physicochemical properties to native spinal cord tissues. The NSCs encapsulated in the bioprinted CCH scaffold extended their neurites to form superior physical contact with the neighboring cells as well as the electroconductive matrix, and maintained a predominant in vivo neuronal differentiation, accompanying with few astrocytic production in the lesion area after transplantation into the SCI sites. As a result, the removal of glial scar tissues and the regeneration of well-developed nerve fibres sequentially happened, which not only facilitated nerve tissue development, but also accelerated locomotor function recovery in the SCI rats. By exploring the application of conductive biomaterials in stem cell-based SCI therapy, this work represents a feasible, new approach to precisely construct tissue engineering scaffolds for stem cell-based therapy in traumatic SCI and other nervous system diseases.
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Affiliation(s)
- Shaoshuai Song
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), 96 Jinzhai Road, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, 398 Ruoshui Road, Suzhou 215123, China
| | - Yuxuan Li
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), 96 Jinzhai Road, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, 398 Ruoshui Road, Suzhou 215123, China
| | - Jie Huang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), 96 Jinzhai Road, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, 398 Ruoshui Road, Suzhou 215123, China.
| | - Shengnan Cheng
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), 96 Jinzhai Road, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, 398 Ruoshui Road, Suzhou 215123, China
| | - Zhijun Zhang
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China (USTC), 96 Jinzhai Road, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics (SINANO), Chinese Academy of Sciences, 398 Ruoshui Road, Suzhou 215123, China.
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28
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Li X, Zhu Y, Wang Y, Xia X, Zheng JC. Neural stem/progenitor cell-derived extracellular vesicles: A novel therapy for neurological diseases and beyond. MedComm (Beijing) 2023; 4:e214. [PMID: 36776763 PMCID: PMC9905070 DOI: 10.1002/mco2.214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 02/10/2023] Open
Abstract
As bilayer lipid membrane vesicles secreted by neural stem/progenitor cells (NSCs), NSC-derived extracellular vesicles (NSC-EVs) have attracted growing attention for their promising potential to serve as novel therapeutic agents in treatment of neurological diseases due to their unique physicochemical characteristics and biological functions. NSC-EVs exhibit advantages such as stable physical and chemical properties, low immunogenicity, and high penetration capacity to cross blood-brain barrier to avoid predicaments of the clinical applications of NSCs that include autoimmune responses, ethical/religious concerns, and the problematic logistics of acquiring fetal tissues. More importantly, NSC-EVs inherit excellent neuroprotective and neuroregenerative potential and immunomodulatory capabilities from parent cells, and display outstanding therapeutic effects on mitigating behavioral alterations and pathological phenotypes of patients or animals with neurological diseases. In this review, we first comprehensively summarize the progress in functional research and application of NSC-EVs in different neurological diseases, including neurodegenerative diseases, acute neurological diseases, dementia/cognitive dysfunction, and peripheral diseases. Next, we provide our thoughts on current limitations/concerns as well as tremendous potential of NSC-EVs in clinical applications. Last, we discuss future directions of further investigations on NSC-EVs and their probable applications in both basic and clinical research.
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Affiliation(s)
- Xiangyu Li
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
| | - Yingbo Zhu
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
| | - Yi Wang
- Center for Translational Neurodegeneration and Regenerative TherapyYangzhi Rehabilitation Hospital, Tongji UniversityShanghaiChina
| | - Xiaohuan Xia
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
- Shanghai Frontiers Science Center of Nanocatalytic MedicineTongji University School of MedicineShanghaiChina
- Translational Research Institute of Brain and Brain‐Like IntelligenceShanghai Fourth People's Hospital, Tongji University School of MedicineShanghaiChina
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Tongji UniversityMinistry of EducationShanghaiChina
| | - Jialin C. Zheng
- Center for Translational Neurodegeneration and Regenerative TherapyTongji Hospital, Tongji University School of MedicineShanghaiChina
- Shanghai Frontiers Science Center of Nanocatalytic MedicineTongji University School of MedicineShanghaiChina
- Translational Research Institute of Brain and Brain‐Like IntelligenceShanghai Fourth People's Hospital, Tongji University School of MedicineShanghaiChina
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Tongji UniversityMinistry of EducationShanghaiChina
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29
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Sterner RC, Sterner RM. Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Front Immunol 2023; 13:1084101. [PMID: 36685598 PMCID: PMC9853461 DOI: 10.3389/fimmu.2022.1084101] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/19/2022] [Indexed: 01/09/2023] Open
Abstract
Traumatic spinal cord injury (SCI) is a devastating condition that is often associated with significant loss of function and/or permanent disability. The pathophysiology of SCI is complex and occurs in two phases. First, the mechanical damage from the trauma causes immediate acute cell dysfunction and cell death. Then, secondary mechanisms of injury further propagate the cell dysfunction and cell death over the course of days, weeks, or even months. Among the secondary injury mechanisms, inflammation has been shown to be a key determinant of the secondary injury severity and significantly worsens cell death and functional outcomes. Thus, in addition to surgical management of SCI, selectively targeting the immune response following SCI could substantially decrease the progression of secondary injury and improve patient outcomes. In order to develop such therapies, a detailed molecular understanding of the timing of the immune response following SCI is necessary. Recently, several studies have mapped the cytokine/chemokine and cell proliferation patterns following SCI. In this review, we examine the immune response underlying the pathophysiology of SCI and assess both current and future therapies including pharmaceutical therapies, stem cell therapy, and the exciting potential of extracellular vesicle therapy.
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Affiliation(s)
- Robert C. Sterner
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Rosalie M. Sterner
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States,*Correspondence: Rosalie M. Sterner,
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30
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Huang T, Wu J, Mu J, Gao J. Advanced Therapies for Traumatic Central Nervous System Injury: Delivery Strategy Reinforced Efficient Microglial Manipulation. Mol Pharm 2023; 20:41-56. [PMID: 36469398 DOI: 10.1021/acs.molpharmaceut.2c00605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Traumatic central nervous system (CNS) injuries, including spinal cord injury and traumatic brain injury, are challenging enemies of human health. Microglia, the main component of the innate immune system in CNS, can be activated postinjury and are key participants in the pathological procedure and development of CNS trauma. Activated microglia can be typically classified into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Reducing M1 polarization while promoting M2 polarization is thought to be promising for CNS injury treatment. However, obstacles such as the low permeability of the blood-brain barrier and short retention time in circulation limit the therapeutic outcomes of administrated drugs, and rational delivery strategies are necessary for efficient microglial regulation. To this end, proper administration methods and delivery systems like nano/microcarriers and scaffolds are investigated to augment the therapeutic effects of drugs, while some of these delivery systems have self-efficacies in microglial manipulation. Besides, systems based on cell and cell-derived exosomes also show impressive effects, and some underlying targeting mechanisms of these delivery systems have been discovered. In this review, we introduce the roles of microglia play in traumatic CNS injuries, discuss the potential targets for the polarization regulation of microglial phenotype, and summarize recent studies and clinical trials about delivery strategies on enhancing the effect of microglial regulation and therapeutic outcome, as well as targeting mechanisms post CNS trauma.
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Affiliation(s)
- Tianchen Huang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jiahe Wu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer, Pharmacology and Toxicology Research of Zhejiang Province, Affiliated, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Jiafu Mu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jianqing Gao
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Jinhua Institute of Zhejiang University, Jinhua 321002, China
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31
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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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Hall A, Fortino T, Spruance V, Niceforo A, Harrop JS, Phelps PE, Priest CA, Zholudeva LV, Lane MA. Cell transplantation to repair the injured spinal cord. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2022; 166:79-158. [PMID: 36424097 PMCID: PMC10008620 DOI: 10.1016/bs.irn.2022.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Adam Hall
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Tara Fortino
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - Victoria Spruance
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Division of Kidney, Urologic, & Hematologic Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Alessia Niceforo
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States
| | - James S Harrop
- Department of Neurological and Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA, United States
| | - Patricia E Phelps
- Department of Integrative Biology & Physiology, UCLA, Los Angeles, CA, United States
| | | | - Lyandysha V Zholudeva
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States; Gladstone Institutes, San Francisco, CA, United States
| | - Michael A Lane
- Drexel University, Philadelphia, PA, United States; Marion Murray Spinal Cord Research Center, Drexel University, Philadelphia, PA, United States.
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Giraldo E, Bonilla P, Mellado M, Garcia-Manau P, Rodo C, Alastrue A, Lopez E, Moratonas EC, Pellise F, Đorđević S, Vicent MJ, Moreno Manzano V. Transplantation of Human-Fetal-Spinal-Cord-Derived NPCs Primed with a Polyglutamate-Conjugated Rho/Rock Inhibitor in Acute Spinal Cord Injury. Cells 2022; 11:cells11203304. [PMID: 36291170 PMCID: PMC9600863 DOI: 10.3390/cells11203304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/11/2022] [Accepted: 10/19/2022] [Indexed: 12/31/2022] Open
Abstract
Neural precursor cell (NPC) transplantation represents a promising therapy for treating spinal cord injuries (SCIs); however, despite successful results obtained in preclinical models, the clinical translation of this approach remains challenging due, in part, to the lack of consensus on an optimal cell source for human neuronal cells. Depending on the cell source, additional limitations to NPC-based therapies include high tumorigenic potential, alongside poor graft survival and engraftment into host spinal tissue. We previously demonstrated that NPCs derived from rat fetal spinal cords primed with a polyglutamate (PGA)-conjugated form of the Rho/Rock inhibitor fasudil (PGA-SS-FAS) displayed enhanced neuronal differentiation and graft survival when compared to non-primed NPCs. We now conducted a similar study of human-fetal-spinal-cord-derived NPCs (hfNPCs) from legal gestational interruptions at the late gestational stage, at 19-21.6 weeks. In vitro, expanded hfNPCs retained neural features, multipotency, and self-renewal, which supported the development of a cell banking strategy. Before transplantation, we established a simple procedure to prime hfNPCs by overnight incubation with PGA-SS-FAS (at 50 μM FAS equiv.), which improved neuronal differentiation and overcame neurite-like retraction after lysophosphatidic-acid-induced Rho/Rock activation. The transplantation of primed hfNPCs into immune-deficient mice (NU(NCr)-Foxn1nu) immediately after the eighth thoracic segment compression prompted enhanced migration of grafted cells from the dorsal to the ventral spinal cord, increased preservation of GABAergic inhibitory Lbx1-expressing and glutamatergic excitatory Tlx3-expressing somatosensory interneurons, and elevated the numbers of preserved, c-Fos-expressing, activated neurons surrounding the injury epicenter, all in a low percentage. Overall, the priming procedure using PGA-SS-FAS could represent an alternative methodology to improve the capabilities of the hfNPC lines for a translational approach for acute SCI treatment.
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Affiliation(s)
- Esther Giraldo
- Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
- Department of Biotechnology. Universitat Politècnica de València, E-46022 Valencia, Spain
- UPV-CIPF Joint Research Unit Disease Mechanisms and Nanomedicine, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
| | - Pablo Bonilla
- Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
| | - Mara Mellado
- Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
| | - Pablo Garcia-Manau
- Maternal-Foetal Medicine Unit, Vall d’Hebron Hospital Campus, E-08035 Barcelona, Spain
| | - Carlota Rodo
- Maternal-Foetal Medicine Unit, Vall d’Hebron Hospital Campus, E-08035 Barcelona, Spain
| | - Ana Alastrue
- Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
| | - Eric Lopez
- Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
| | | | - Ferran Pellise
- Spine Surgery Unit, Hospital Universitari Vall d’Hebron, E-08035 Barcelona, Spain
| | - Snežana Đorđević
- Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, E-46012, Valencia, Spain
| | - María J. Vicent
- Polymer Therapeutics Laboratory, Centro de Investigación Príncipe Felipe, E-46012, Valencia, Spain
| | - Victoria Moreno Manzano
- Neuronal and Tissue Regeneration Laboratory, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain
- Correspondence:
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Shang Z, Wang M, Zhang B, Wang X, Wanyan P. Clinical translation of stem cell therapy for spinal cord injury still premature: results from a single-arm meta-analysis based on 62 clinical trials. BMC Med 2022; 20:284. [PMID: 36058903 PMCID: PMC9442938 DOI: 10.1186/s12916-022-02482-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/14/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND How much scientific evidence is there to show that stem cell therapy is sufficient in preclinical and clinical studies of spinal cord injury before it is translated into clinical practice? This is a complicated problem. A single, small-sample clinical trial is difficult to answer, and accurate insights into this question can only be given by systematically evaluating all the existing evidence. METHODS The PubMed, Ovid-Embase, Web of Science, and Cochrane databases were searched from inception to February 10, 2022. Two independent reviewers performed the literature search, identified and screened the studies, and performed a quality assessment and data extraction. RESULTS In total, 62 studies involving 2439 patients were included in the analysis. Of these, 42 were single-arm studies, and 20 were controlled studies. The meta-analysis showed that stem cells improved the ASIA impairment scale score by at least one grade in 48.9% [40.8%, 56.9%] of patients with spinal cord injury. Moreover, the rate of improvement in urinary and gastrointestinal system function was 42.1% [27.6%, 57.2%] and 52.0% [23.6%, 79.8%], respectively. However, 28 types of adverse effects were observed to occur due to stem cells and transplantation procedures. Of these, neuropathic pain, abnormal feeling, muscle spasms, vomiting, and urinary tract infection were the most common, with an incidence of > 20%. While no serious adverse effects such as tumorigenesis were reported, this could be due to the insufficient follow-up period. CONCLUSIONS Overall, the results demonstrated that although the efficacy of stem cell therapy is encouraging, the subsequent adverse effects remain concerning. In addition, the clinical trials had problems such as small sample sizes, poor design, and lack of prospective registration, control, and blinding. Therefore, the current evidence is not sufficiently strong to support the clinical translation of stem cell therapy for spinal cord injury, and several problems remain. Additional well-designed animal experiments and high-quality clinical studies are warranted to address these issues.
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Affiliation(s)
- Zhizhong Shang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Mingchuan Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Baolin Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China
| | - Xin Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, China.
- Chengren Institute of Traditional Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
- Department of Spine, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
| | - Pingping Wanyan
- Gansu University of Chinese Medicine, Lanzhou, 730000, China
- The Second Hospital of Lanzhou University, Lanzhou, 730000, China
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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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Darrow DP, Balser DY, Freeman D, Pelrine E, Krassioukov A, Phillips A, Netoff T, Parr A, Samadani U. Effect of epidural spinal cord stimulation after chronic spinal cord injury on volitional movement and cardiovascular function: study protocol for the phase II open label controlled E-STAND trial. BMJ Open 2022; 12:e059126. [PMID: 35851008 PMCID: PMC9297213 DOI: 10.1136/bmjopen-2021-059126] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 06/17/2022] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION Spinal cord injury (SCI) leads to significant changes in morbidity, mortality and quality of life (QOL). Currently, there are no effective therapies to restore function after chronic SCI. Preliminary studies have indicated that epidural spinal cord stimulation (eSCS) is a promising therapy to improve motor control and autonomic function for patients with chronic SCI. The aim of this study is to assess the effects of tonic eSCS after chronic SCI on quantitative outcomes of volitional movement and cardiovascular function. Our secondary objective is to optimise spinal cord stimulation parameters for volitional movement. METHODS AND ANALYSIS The Epidural Stimulation After Neurologic Damage (ESTAND) trial is a phase II single-site self-controlled trial of epidural stimulation with the goal of restoring volitional movement and autonomic function after motor complete SCI. Participants undergo epidural stimulator implantation and are followed up over 15 months while completing at-home, mobile application-based movement testing. The primary outcome measure integrates quantity of volitional movement and similarity to normal controls using the volitional response index (VRI) and the modified Brain Motor Control Assessment. The mobile application is a custom-designed platform to support participant response and a kinematic task to optimise the settings for each participant. The application optimises stimulation settings by evaluating the parameter space using movement data collected from the tablet application and accelerometers. A subgroup of participants with cardiovascular dysautonomia are included for optimisation of blood pressure stabilisation. Indirect effects of stimulation on cardiovascular function, pain, sexual function, bowel/bladder, QOL and psychiatric measures are analysed to assess generalisability of this targeted intervention. ETHICS AND DISSEMINATION This study has been approved after full review by the Minneapolis Medical Research Foundation Institutional Review Board and by the Minneapolis VA Health Care System. This project has received Food and Drug Administration investigational device exemption approval. Trial results will be disseminated through peer-reviewed publications, conference presentations and seminars. TRIAL REGISTRATION NUMBER NCT03026816.
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Affiliation(s)
- David P Darrow
- Neurosurgery, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA
- Division of Neurosurgery, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - David Young Balser
- Rehabilitation Medicine, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA
| | - David Freeman
- Neurosurgery, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA
| | - Eliza Pelrine
- Orthopaedic Surgery, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Andrei Krassioukov
- Physical Medicine and Rehabilitation, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Aaron Phillips
- Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
| | - Theoden Netoff
- Biomedical Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Ann Parr
- Neurosurgery, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA
| | - Uzma Samadani
- Surgery, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota, USA
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Zhang ZR, Wu Y, Wang WJ, Wang FY. The Effect of GABAergic Cells Transplantation on Allodynia and Hyperalgesia in Neuropathic Animals: A Systematic Review With Meta-Analysis. Front Neurol 2022; 13:900436. [PMID: 35860495 PMCID: PMC9289294 DOI: 10.3389/fneur.2022.900436] [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: 03/20/2022] [Accepted: 06/13/2022] [Indexed: 12/09/2022] Open
Abstract
The role of GABAergic cell transplantation in improving neuropathic pain is controversial. We comprehensively searched the relevant literature to identify animal studies of GABAergic cell transplantation that recorded pain behaviors as an outcome according to the Cochrane Handbook 5.0.2. Controlled studies assessing the administration of GABAergic neurons or GABAergic neuronal progenitor cells to rat or mouse neuropathic pain animal models were included. Basic design information and mechanical allodynia thresholds and heat hyperalgesia thresholds data were collected. The risk of bias for the animal experiments was assessed according to the SYRCLE's tool. This study included 10 full-text articles. GABAergic cells transplantation leads to a statistically significant improvement of allodynia (SMD = 5.26; 95% confidence interval: 3.02-7.51; P < 0.001) and hyperalgesia (SMD: 4.10; 95% confidence interval: 1.84-6.35; P < 0.001). Differentiated GABAergic cells and without antibiotics using may have a better effect for improving neuropathic pain. GABAergic cell transplantation is a promising treatment for improving neuropathic pain. This systematic review and meta-analysis evaluated the effects of GABAergic cell transplantation on neuropathic pain, which can guide future clinical trials and possible clinical treatments, and better attenuate neuropathic pain caused by abnormal circuit hyperexcitability.
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Affiliation(s)
- Zhen-Rong Zhang
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Spine Surgery, China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, China
| | - Yao Wu
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Spine Surgery, China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, China
| | - Wen-Jing Wang
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Occupational Therapy, China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, China
| | - Fang-Yong Wang
- School of Rehabilitation, Capital Medical University, Beijing, China
- Department of Spine Surgery, China Rehabilitation Research Center, Beijing Bo'ai Hospital, Beijing, China
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Gadot R, Smith DN, Prablek M, Grochmal JK, Fuentes A, Ropper AE. Established and Emerging Therapies in Acute Spinal Cord Injury. Neurospine 2022; 19:283-296. [PMID: 35793931 PMCID: PMC9260540 DOI: 10.14245/ns.2244176.088] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/05/2022] [Indexed: 12/11/2022] Open
Abstract
Acute spinal cord injury (SCI) is devastating for patients and their caretakers and has an annual incidence of 20–50 per million people. Following initial assessment with appropriate physical examination and imaging, patients who are deemed surgical candidates should undergo decompression with stabilization. Earlier intervention can improve neurological recovery in the post-operative period while allowing earlier mobilization. Optimized medical management is paramount to improve outcomes. Emerging strategies for managing SCI in the acute period stem from an evolving understanding of the pathophysiology of the injury. General areas of focus include ischemia prevention, reduction of secondary injury due to inflammation, modulation of the cytotoxic and immune response, and promotion of cellular regeneration. In this article, we review established, emerging, and novel experimental therapies. Continued translational research on these methods will improve the feasibility of bench-to-bedside innovations in treating patients with acute SCI.
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Affiliation(s)
- Ron Gadot
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - David N. Smith
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Marc Prablek
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Joey K. Grochmal
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Alfonso Fuentes
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Alexander E. Ropper
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
- Corresponding Author Alexander E. Ropper Department of Neurosurgery, Baylor College of Medicine, 7200 Cambridge St. Suite 9A, Houston, TX, USA
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Qu J, Liu Z, Li L, Zou Z, He Z, Zhou L, Luo Y, Zhang M, Ye J. Efficacy and Safety of Stem Cell Therapy in Children With Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. Front Pediatr 2022; 10:897398. [PMID: 35601435 PMCID: PMC9114801 DOI: 10.3389/fped.2022.897398] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/01/2022] [Indexed: 01/08/2023] Open
Abstract
AIM There is insufficient evidence regarding the efficacy and safety of stem cell therapy for autism spectrum disorders. We performed the first meta-analysis of stem cell therapy for autism spectrum disorders in children to provide evidence for clinical rehabilitation. METHODS The data source includes PubMed/Medline, Web of Science, EMBASE, Cochrane Library and China Academic Journal, from inception to 24th JULY 2021. After sifting through the literature, the Cochrane tool was applied to assess the risk of bias. Finally, we extracted data from these studies and calculated pooled efficacy and safety. RESULTS 5 studies that met the inclusion criteria were included in current analysis. Meta-analysis was performed using rehabilitation therapy as the reference standard. Data showed that the Childhood Autism Rating Scale score of stem cell group was striking lower than the control group (WMD: -5.96; 95%CI [-8.87, -3.06]; p < 0.0001). The Clinical Global Impression score consolidated effect size RR = 1.01, 95%CI [0.87, 1.18], Z = 0.14 (p = 0.89), the effective rate for The Clinical Global Impression was 62% and 60% in the stem cell group and the control group, respectively. The occurrence events of adverse reactions in each group (RR = 1.55; 95%CI = 0.60 to 3.98; p = 0.36), there was no significant difference in the incidence of adverse reactions between the stem cell group and the control group. CONCLUSIONS The results of this meta-analysis suggested that stem cell therapy for children with autism might be safe and effective. However, the evidence was compromised by the limitations in current study size, lacking standardized injection routes and doses of stem cells, as well as shortages in diagnostic tools and long period follow-up studies. Hence, it calls for more studies to systematically confirm the efficacy and safety of stem cell therapy for children with autism spectrum disorders.
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Affiliation(s)
- Jiayang Qu
- The First Clinical Medicine College of Gannan Medical University, Ganzhou, China
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- School of Rehabilitation Medicine Gannan Medical University, GanZhou, China
| | - Zicai Liu
- School of Rehabilitation Medicine Gannan Medical University, GanZhou, China
| | - Lincai Li
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, GanZhou, China
| | - Zhengwei Zou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, GanZhou, China
| | - Zhengyi He
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, GanZhou, China
- Clinical Medicine Research Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Lin Zhou
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, GanZhou, China
| | - Yaolin Luo
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, GanZhou, China
- Clinical Medicine Research Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Minhong Zhang
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, GanZhou, China
- Clinical Medicine Research Center, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Junsong Ye
- The First Clinical Medicine College of Gannan Medical University, Ganzhou, China
- Subcenter for Stem Cell Clinical Translation, First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Ganzhou Key Laboratory of Stem Cell and Regenerative Medicine, GanZhou, China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China
- Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, Gannan Medical University, Ganzhou, China
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Xu X, Liang Z, Lin Y, Rao J, Lin F, Yang Z, Wang R, Chen C. Comparing the Efficacy and Safety of Cell Transplantation for Spinal Cord Injury: A Systematic Review and Bayesian Network Meta-Analysis. Front Cell Neurosci 2022; 16:860131. [PMID: 35444516 PMCID: PMC9013778 DOI: 10.3389/fncel.2022.860131] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectiveTo compare the safety and effectiveness of transplanted cells from different sources for spinal cord injury (SCI).DesignA systematic review and Bayesian network meta-analysis.Data SourcesMedline, Embase, and the Cochrane Central Register of Controlled Trials.Study SelectionWe included randomized controlled trials, case–control studies, and case series related to cell transplantation for SCI patients, that included at least 1 of the following outcome measures: American Spinal Cord Injury Association (ASIA) Impairment Scale (AIS grade), ASIA motor score, ASIA sensory score, the Functional Independence Measure score (FIM), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), or adverse events. Follow-up data were analyzed at 6 and 12 months.ResultsForty-four eligible trials, involving 1,266 patients, investigated 6 treatments: olfactory ensheathing cells (OECs), neural stem cells/ neural progenitor cells (NSCs), mesenchymal stem cells (MSCs), Schwann cells, macrophages, and combinations of cells (MSCs plus Schwann cells). Macrophages improved the AIS grade at 12 months (mean 0.42, 95% credible interval: 0–0.91, low certainty) and FIM score at 12 months (42.83, 36.33–49.18, very low certainty). MSCs improved the AIS grade at 6 months (0.42, 0.15–0.73, moderate certainty), the motor score at 6 months (4.43, 0.91–7.78, moderate certainty), light touch at 6 (10.01, 5.81–13.88, moderate certainty) and 12 months (11.48, 6.31–16.64, moderate certainty), pinprick score at 6 (14.54, 9.76–19.46, moderate certainty) and 12 months (12.48, 7.09–18.12, moderate certainty), and the IANR-SCIFRS at 6 (3.96, 0.62–6.97, moderate certainty) and 12 months (5.54, 2.45–8.42, moderate certainty). OECs improved the FIM score at 6 months (9.35, 1.71–17.00, moderate certainty). No intervention improved the motor score significantly at 12 months. The certainty of other interventions was low or very low. Overall, the number of adverse events associated with transplanted cells was low.ConclusionsPatients with SCI who receive transplantation of macrophages, MSCs, NSCs, or OECs may have improved disease prognosis. MSCs are the primary recommendations. Further exploration of the mechanism of cell transplantation in the treatment of SCI, transplantation time window, transplantation methods, and monitoring of the number of transplanted cells and cell survival is needed.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier: CRD 42021282043.
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Huang H, Chen L, Moviglia G, Sharma A, Al Zoubi ZM, He X, Chen D. Advances and prospects of cell therapy for spinal cord injury patients. JOURNAL OF NEURORESTORATOLOGY 2022. [DOI: 10.26599/jnr.2022.9040007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Mutepfa AR, Hardy JG, Adams CF. Electroactive Scaffolds to Improve Neural Stem Cell Therapy for Spinal Cord Injury. FRONTIERS IN MEDICAL TECHNOLOGY 2022; 4:693438. [PMID: 35274106 PMCID: PMC8902299 DOI: 10.3389/fmedt.2022.693438] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) is a serious condition caused by damage to the spinal cord through trauma or disease, often with permanent debilitating effects. Globally, the prevalence of SCI is estimated between 40 to 80 cases per million people per year. Patients with SCI can experience devastating health and socioeconomic consequences from paralysis, which is a loss of motor, sensory and autonomic nerve function below the level of the injury that often accompanies SCI. SCI carries a high mortality and increased risk of premature death due to secondary complications. The health, social and economic consequences of SCI are significant, and therefore elucidation of the complex molecular processes that occur in SCI and development of novel effective treatments is critical. Despite advances in medicine for the SCI patient such as surgery and anaesthesiology, imaging, rehabilitation and drug discovery, there have been no definitive findings toward complete functional neurologic recovery. However, the advent of neural stem cell therapy and the engineering of functionalized biomaterials to facilitate cell transplantation and promote regeneration of damaged spinal cord tissue presents a potential avenue to advance SCI research. This review will explore this emerging field and identify new lines of research.
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Affiliation(s)
- Anthea R. Mutepfa
- Neural Tissue Engineering Keele, School of Life Sciences, Keele University, Keele, United Kingdom
| | - John G. Hardy
- Department of Chemistry, Lancaster University, Lancaster, United Kingdom
- Materials Science Institute, Lancaster University, Lancaster, United Kingdom
| | - Christopher F. Adams
- Neural Tissue Engineering Keele, School of Life Sciences, Keele University, Keele, United Kingdom
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Van den Bos J, Ouaamari YE, Wouters K, Cools N, Wens I. Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis. Biomolecules 2022; 12:340. [PMID: 35204840 PMCID: PMC8869169 DOI: 10.3390/biom12020340] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/14/2022] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson's disease (PD) and Alzheimer's disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01-0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes.
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Affiliation(s)
- Jasper Van den Bos
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
| | - Yousra El Ouaamari
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
| | - Kristien Wouters
- Clinical Trial Center (CTC), CRC Antwerp, Antwerp University Hospital, University of Antwerp, Drie Eikenstraat 655, B-2650 Edegem, Belgium;
| | - Nathalie Cools
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
- Center for Cell Therapy and Regenerative Medicine (CCRG), Antwerp University Hospital, Drie Eikenstraat 655, B-2650 Edegem, Belgium
| | - Inez Wens
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium; (Y.E.O.); (N.C.); (I.W.)
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Cieśla J, Tomsia M. Cadaveric Stem Cells: Their Research Potential and Limitations. Front Genet 2022; 12:798161. [PMID: 35003228 PMCID: PMC8727551 DOI: 10.3389/fgene.2021.798161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 11/30/2021] [Indexed: 12/28/2022] Open
Abstract
In the era of growing interest in stem cells, the availability of donors for transplantation has become a problem. The isolation of embryonic and fetal cells raises ethical controversies, and the number of adult donors is deficient. Stem cells isolated from deceased donors, known as cadaveric stem cells (CaSCs), may alleviate this problem. So far, it was possible to isolate from deceased donors mesenchymal stem cells (MSCs), adipose delivered stem cells (ADSCs), neural stem cells (NSCs), retinal progenitor cells (RPCs), induced pluripotent stem cells (iPSCs), and hematopoietic stem cells (HSCs). Recent studies have shown that it is possible to collect and use CaSCs from cadavers, even these with an extended postmortem interval (PMI) provided proper storage conditions (like cadaver heparinization or liquid nitrogen storage) are maintained. The presented review summarizes the latest research on CaSCs and their current therapeutic applications. It describes the developments in thanatotranscriptome and scaffolding for cadaver cells, summarizes their potential applications in regenerative medicine, and lists their limitations, such as donor’s unknown medical condition in criminal cases, limited differentiation potential, higher risk of carcinogenesis, or changing DNA quality. Finally, the review underlines the need to develop procedures determining the safe CaSCs harvesting and use.
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Affiliation(s)
- Julia Cieśla
- School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Marcin Tomsia
- Department of Forensic Medicine and Forensic Toxicology, Medical University of Silesia, Katowice, Poland
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Tang QR, Xue H, Zhang Q, Guo Y, Xu H, Liu Y, Liu JM. Evaluation of the Clinical Efficacy of Stem Cell Transplantation in the Treatment of Spinal Cord Injury: A Systematic Review and Meta-analysis. Cell Transplant 2021; 30:9636897211067804. [PMID: 34939443 PMCID: PMC8725233 DOI: 10.1177/09636897211067804] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Stem cell transplantation has been applied to treat spinal cord injury (SCI) in
clinical trials for many years. However, the clinical efficacies of stem cell
transplantation in SCI have been quite diverse. The purpose of our study was to
systematically investigate the efficacy of stem cell transplantation in patients
with SCI. The PubMed, Web of Science, Ovid-Medline, Cochrane Library, China
National Knowledge Infrastructure, VIP, Wanfang, and SinoMed databases were
searched until October 27, 2020. Quantitative and qualitative data were analyzed
by Review Manager 5.3 and R. Nine studies (n = 328) were
included, and the overall risk of bias was moderate. The ASIA Impairment Scale
(AIS) grading improvement rate was analyzed in favor of stem cell
transplantation group [odds ratio (OR) = 6.06, 95% confidence interval (CI):
3.16–11.62, P < 0.00001]. Urodynamic indices also showed
improvement in bladder function. In subgroup analyses, the results indicated
that in patients with complete (AIS A) SCI, with the application of cell numbers
between n*(107–108), two cell types
(i.e., bone marrow–derived mesenchymal stem cells and bone marrow mononuclears),
and treatment time of more than 6 months, stem cell transplantation was more
beneficial for sensorimotor function (P < 0.05 for all
groups). The risk of fever incidence in the stem cell transplantation group was
4.22 (95% CI: 1.7–10.22, P = 0.001), and principal component
analysis (PCA) suggested it was more related to transplanted cell numbers. Thus,
stem cell transplantation can promote functional recovery in SCI patients.
Moreover, the type and quantity of transplanted stem cells and treatment time
are important factors affecting the therapeutic effect of stem cell
transplantation in SCI. Further studies are needed to evaluate the effects and
elucidate the mechanisms of these factors on stem cell therapy in SCI.
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Affiliation(s)
- Qiao-Rui Tang
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Hui Xue
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Qiao Zhang
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Ying Guo
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Hao Xu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Ying Liu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
| | - Jia-Mei Liu
- Department of Histology and Embryology,
College of Basic Medical Sciences, Jilin University, Changchun, P.R. China
- Ying Liu, Department of Histology and
Embryology, College of Basic Medical Sciences, Jilin University, Changchun
130021, Jilin Province, P.R. China.
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Liu D, Bobrovskaya L, Zhou XF. Cell Therapy for Neurological Disorders: The Perspective of Promising Cells. BIOLOGY 2021; 10:1142. [PMID: 34827135 PMCID: PMC8614777 DOI: 10.3390/biology10111142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/13/2022]
Abstract
Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.
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Affiliation(s)
| | | | - Xin-Fu Zhou
- School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia; (D.L.); (L.B.)
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Gala D, Gurusamy V, Patel K, Damodar S, Swaminath G, Ullal G. Stem Cell Therapy for Post-Traumatic Stress Disorder: A Novel Therapeutic Approach. Diseases 2021; 9:diseases9040077. [PMID: 34842629 PMCID: PMC8628773 DOI: 10.3390/diseases9040077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/11/2021] [Accepted: 10/25/2021] [Indexed: 12/04/2022] Open
Abstract
Stem cell therapy is a rapidly evolving field of regenerative medicine being employed for the management of various central nervous system disorders. The ability to self-renew, differentiate into specialized cells, and integrate into neuronal networks has positioned stem cells as an ideal mechanism for the treatment of epilepsy. Epilepsy is characterized by repetitive seizures caused by imbalance in the GABA and glutamate neurotransmission following neuronal damage. Stem cells provide benefit by reducing the glutamate excitotoxicity and strengthening the GABAergic inter-neuron connections. Similar to the abnormal neuroanatomic location in epilepsy, post-traumatic stress disorder (PTSD) is caused by hyperarousal in the amygdala and decreased activity of the hippocampus and medial prefrontal cortex. Thus, stem cells could be used to modulate neuronal interconnectivity. In this review, we provide a rationale for the use of stem cell therapy in the treatment of PTSD.
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Moinuddin FM, Yolcu YU, Wahood W, Zreik J, Goncalves S, Windebank AJ, Qu W, Bydon M. Time-to-enrollment in clinical trials investigating neurological recovery in chronic spinal cord injury: observations from a systematic review and ClinicalTrials.gov database. Neural Regen Res 2021; 17:953-958. [PMID: 34558507 PMCID: PMC8552853 DOI: 10.4103/1673-5374.324826] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Currently, large numbers of clinical trials are performed to investigate different forms of experimental therapy for patients suffering from chronic spinal cord injury (SCI). However, for the enrollment process, there are different views on how the time period between injury and interventions should be determined. Herein, we sought to evaluate the impact of time-to-enrollment in chronic SCI clinical trials. A data set comprising 957 clinical studies from clinicalTrials.gov was downloaded and analyzed focusing on the eligibility criteria for post-injury time-to-enrollment. We also aggregated individual patient data from nine clinical trials of regenerative interventions for chronic SCI selected by a systematic literature search from 1990 to 2018. Characteristics of the studies were assessed and compared by dividing into three groups based on time-to-enrollment (group 1 ≤ 12 months, group 2 = 12–23 months and group 3 ≥ 24 months). In ClinicalTrials.gov registry, 445 trials were identified for chronic SCI where 87% (385) were unrestricted in the maximum post-injury time for trial eligibility. From systematic literature search, nine studies and 156 patients (group 1 = 30, group 2 = 55 and group 3 = 71) were included. The range of time-to-enrollment was 0.5 to 321 months in those studies. We also observed various degrees of motor and sensory improvement in between three time-to-enrollment groups. Our results indicate that enrolling wide ranges of time-to-enrollment in a group may present imprecise outcomes. Clinical trial designs should consider appropriate post-injury time frames to evaluate therapeutic benefit.
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Affiliation(s)
- F M Moinuddin
- Mayo Clinic Neuro-Informatics Laboratory; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Yagiz Ugur Yolcu
- Mayo Clinic Neuro-Informatics Laboratory; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Waseem Wahood
- Mayo Clinic Neuro-Informatics Laboratory; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN; Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL, USA
| | - Jad Zreik
- Mayo Clinic Neuro-Informatics Laboratory; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Sandy Goncalves
- Mayo Clinic Neuro-Informatics Laboratory; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | - Wenchun Qu
- Department of Physical Medicine & Rehabilitation, Mayo Clinic, Rochester, MN, USA
| | - Mohamad Bydon
- Mayo Clinic Neuro-Informatics Laboratory; Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
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Fernandez-Muñoz B, Garcia-Delgado AB, Arribas-Arribas B, Sanchez-Pernaute R. Human Neural Stem Cells for Cell-Based Medicinal Products. Cells 2021; 10:2377. [PMID: 34572024 PMCID: PMC8469920 DOI: 10.3390/cells10092377] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/01/2021] [Accepted: 09/03/2021] [Indexed: 12/15/2022] Open
Abstract
Neural stem cells represent an attractive tool for the development of regenerative therapies and are being tested in clinical trials for several neurological disorders. Human neural stem cells can be isolated from the central nervous system or can be derived in vitro from pluripotent stem cells. Embryonic sources are ethically controversial and other sources are less well characterized and/or inefficient. Recently, isolation of NSC from the cerebrospinal fluid of patients with spina bifida and with intracerebroventricular hemorrhage has been reported. Direct reprogramming may become another alternative if genetic and phenotypic stability of the reprogrammed cells is ensured. Here, we discuss the advantages and disadvantages of available sources of neural stem cells for the production of cell-based therapies for clinical applications. We review available safety and efficacy clinical data and discuss scalability and quality control considerations for manufacturing clinical grade cell products for successful clinical application.
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Affiliation(s)
- Beatriz Fernandez-Muñoz
- Cellular Reprogramming and Production Unit, Andalusian Network for the Design and Translation of Advanced Therapies, 41092 Sevilla, Spain; (A.B.G.-D.); (B.A.-A.)
| | - Ana Belen Garcia-Delgado
- Cellular Reprogramming and Production Unit, Andalusian Network for the Design and Translation of Advanced Therapies, 41092 Sevilla, Spain; (A.B.G.-D.); (B.A.-A.)
| | - Blanca Arribas-Arribas
- Cellular Reprogramming and Production Unit, Andalusian Network for the Design and Translation of Advanced Therapies, 41092 Sevilla, Spain; (A.B.G.-D.); (B.A.-A.)
- Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Sevilla, 41012 Sevilla, Spain
| | - Rosario Sanchez-Pernaute
- Cellular Reprogramming and Production Unit, Andalusian Network for the Design and Translation of Advanced Therapies, 41092 Sevilla, Spain; (A.B.G.-D.); (B.A.-A.)
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Zhang B, Hu L, Zhang J, Wu H, Li W, Gou L, Liu H. Insulin growth factor-1 enhances proliferation and inhibits apoptosis of neural progenitor cells by phosphorylation of Akt/mTOR/p70S6K molecules and triggering intrinsic apoptosis signaling pathway. Cell Tissue Bank 2021; 23:459-472. [PMID: 34494222 DOI: 10.1007/s10561-021-09956-2] [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] [Received: 07/30/2021] [Accepted: 09/02/2021] [Indexed: 02/05/2023]
Abstract
Neural progenitor cells (NPCs) transplantation is known as a potential strategy for treating spinal cord injury (SCI). This study aimed to investigate effects of insulin growth factor-1 (IGF-I) on NPCs proliferation and clarify associated mechanisms. NPCs isolated from T8-T10 segmental spinal cord tissues of rats were cultured and identification. Then, lentivirus packing plasmids containing IGF-I was constructed and used for NPCs infection. Cell proliferation was evaluated by detecting 5-Bromodeoxyuridine (BrdU) expression in NPCs, cell differentiation was detected using double-labeling immunofluorescence staining while cell apoptosis was detected using TUNEL assay. In addition, the signal expression of Akt/mTOR/p70S6K in NPCs cells were investigated using immunofluorescence staining and western blot assay. The experimental group was defined as pCMV-IGF-I group, while the negative control group was defined as pCMV-LacZ group. Cells infected with pCMV-IGF-I lentivirus followed by addition of 100 mg/ml rapamycin were defined as pCMV-IGF-I + Rapa group. NPCs were successfully isolated, identified and cultured. IGF-I overexpression significantly inhibited cell apoptosis and enhanced cell migration. Akt/mTOR/ p70S6K signaling cascade was proved to be present in NPCs, IGF-I overexpression significantly activated Akt/mTOR/p70S6K signaling cascade, while rapamycin addition inhibited its expression. Also, the activated Akt/mTOR/p70S6K signal cascade induced by IGF-I significantly enhanced BrdU expression and inhibited cell apoptosis, and promoted the differentiation of NPC into the neuronal system. However, the rapamycin addition inhibited the cell response induced by IGF-I overexpression. IGF-I overexpression could enhance cell proliferation, inhibit cell apoptosis and promote their differentiation into neuronal systems by activating Akt/mTOR/p70S6K signaling cascade in vitro, indicating that the Akt/mTOR/p70S6K signaling cascade may be the potentially mechanism for the endogenous repair and remodeling of spinal cord after injury.
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Affiliation(s)
- Bo Zhang
- Department of Orthopaedic Surgery, Nanchong Central Hospital, the Second Clinical Medical College of North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Lingyun Hu
- Department of Orthopaedic Surgery, Nanchong Central Hospital, the Second Clinical Medical College of North Sichuan Medical College, Nanchong, 637000, Sichuan, China.,Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jianying Zhang
- Department of Radiology, Nanchong Central Hospital, the Second Clinical Medical College of North Sichuan Medical College, Nanchong, Sichuan, 637000, China
| | - Hui Wu
- Department of Orthopaedic Surgery, Nanchong Central Hospital, the Second Clinical Medical College of North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Wei Li
- Department of Orthopaedic Surgery, Nanchong Central Hospital, the Second Clinical Medical College of North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Lin Gou
- Department of Orthopaedic Surgery, Nanchong Central Hospital, the Second Clinical Medical College of North Sichuan Medical College, Nanchong, 637000, Sichuan, China
| | - Hao Liu
- Department of Orthopedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
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