|
1
|
Sugai K, Nakamura M, Okano H, Nagoshi N. Stem cell therapies for spinal cord injury in humans: A review of recent clinical research. BRAIN & SPINE 2025; 5:104207. [PMID: 40027291 PMCID: PMC11870206 DOI: 10.1016/j.bas.2025.104207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/09/2025] [Accepted: 02/04/2025] [Indexed: 03/05/2025]
Abstract
Recently, cell transplantation has emerged as a promising treatment for spinal cord injury (SCI). Over the past decade, numerous clinical studies of SCI have been conducted using various types of cells, including fetal neural stem/progenitor cells (NS/PCs), pluripotent stem cell-derived NS/PCs, mesenchymal stem/stromal cells (MSCs), olfactory ensheathing cells, and Schwann cells. Promising results have been reported for patients with subacute SCI, especially in studies involving MSCs, such as those conducted with Stemirac, although no universally recognized breakthroughs have been achieved. Allogenic NS/PCs may offer advantages over autologous MSCs because they have the potential for cell engraftment within the spinal cord and can be prepared in advance, facilitating their administration during the hyperacute phase. Recent advances achieved with induced pluripotent stem cells indicate their promise potential to be used in future therapies. This review provides an overview of recent clinical studies and discusses potential advancements anticipated in the future.
Collapse
Affiliation(s)
- Keiko Sugai
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Keio University Regenerative Medicine Research Center, Kanagawa, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
2
|
Honda Pazili T. A Severe Alzheimer's Disease Patient Improved by Intravenous Mesenchymal Stem Cell Transplant. Case Rep Neurol Med 2024; 2024:8353492. [PMID: 39040486 PMCID: PMC11262880 DOI: 10.1155/2024/8353492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 04/13/2024] [Accepted: 07/05/2024] [Indexed: 07/24/2024] Open
Abstract
Alzheimer's disease (AD) is a progressive neurological disorder and is the most common form of dementia. The terminal stage of AD is characterized by severe cognitive and substantial functional decline, requiring extensive assistance with daily activities. As effective therapies at this stage are not fully available, development of therapeutics that can recover any symptoms would be important to improve the quality of life. Recently, stem cell therapy has gathered a lot of attention in several neurological diseases, including AD. Here, we report an AD patient at the terminal stage whose symptoms were improved by the intravenous administration of ex vivo-expanded bone marrow-derived mesenchymal stem cells (MSC). The case is a 61-year-old woman with severe Alzheimer's disease who had been admitted to the special nursing home. She could neither walk nor sit up independently. She also did neither smile nor gaze properly when talked to. Rigidity including neck motion was observed. She was on dysphagia diets. We cultured her bone-marrow-derived MSCs and intravenously administered 1,5 × 108 cells. After the treatment, smile loss, eye movement dysfunction, and neck immobility were improved. This is the first case report that showed the therapeutic effects of MSCs on terminal symptoms of AD.
Collapse
Affiliation(s)
- Takahiro Honda Pazili
- Regenerative MedicineDepartment of Cell TherapyJapan Tokyo Stem Cell Transplant Research Institute Ginza Clinic, Ginza 4-3-9, Chuo-ku, Tokyo 104-0067, Japan
| |
Collapse
|
|
3
|
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.
Collapse
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
| |
Collapse
|
|
4
|
Patel GD, Liu L, Li A, Yang YH, Shen CC, Brand-Saberi B, Yang X. Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: a systematic review. Front Med (Lausanne) 2024; 11:1361723. [PMID: 38601118 PMCID: PMC11004389 DOI: 10.3389/fmed.2024.1361723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 03/13/2024] [Indexed: 04/12/2024] Open
Abstract
Background Millions of people across the globe are affected by conditions like Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD), Multiple Sclerosis (MS), Spinal Cord Injury (SCI), and Traumatic Brain Injury (TBI), although most occurrences are common in the elderly population. This systematic review aims to highlight the safety of the procedures, their tolerability, and efficacy of the available therapies conducted over the years using mesenchymal stem cells (MSCs) in treating the neurological conditions mentioned above. Methods PubMed was used to search for published data from clinical trials performed using mesenchymal stem cells. Studies that provided the necessary information that mentioned the efficacy and adverse effects of the treatment in patients were considered for this review. Results In total, 43 manuscripts were selected after a strategic search, and these studies have been included in this systematic review. Most included studies reported the safety of the procedures used and the treatment's good tolerability, with mild adverse events such as fever, headache, mild pain at the injection site, or nausea being common. A few studies also reported death of some patients, attributed to the progression of the disease to severe stages before the treatment. Other severe events, such as respiratory or urinary infections reported in some studies, were not related to the treatment. Different parameters were used to evaluate the efficacy of the treatment based on the clinical condition of the patient. Conclusion Mesenchymal stem cells transplantation has so far proven to be safe and tolerable in select studies and patient types. This systematic review includes the results from the 43 selected studies in terms of safety and tolerability of the procedures, and several adverse events and therapeutic benefits during the follow-up period after administration of MSCs.
Collapse
Affiliation(s)
- Gaurav Deepak Patel
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
| | - Lichao Liu
- Division of Histology and Embryology, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
| | - Ailian Li
- School of Stomatology, Southwest Medical University, Guangzhou, China
| | - Yun-Hsuan Yang
- School of Stomatology, Jinan University, Guangzhou, China
| | - Chia-Chi Shen
- School of Stomatology, Jinan University, Guangzhou, China
| | - Beate Brand-Saberi
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr University Bochum, Bochum, Germany
| | - Xuesong Yang
- Division of Histology and Embryology, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
- Clinical Research Center, Clifford Hospital, Guangzhou, China
| |
Collapse
|
|
5
|
Zipser CM, Curt A. Disease-specific interventions using cell therapies for spinal cord disease/injury. HANDBOOK OF CLINICAL NEUROLOGY 2024; 205:263-282. [PMID: 39341658 DOI: 10.1016/b978-0-323-90120-8.00007-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Traumatic spinal cord injury (SCI) may occur across the lifespan and is of global relevance. Damage of the spinal cord results in para- or tetraplegia and is associated with neuropathic pain, spasticity, respiratory, and autonomic dysfunction (i.e., control of bladder-bowel function). While the acute surgical treatment aims at stabilizing the spine and decompressing the damaged spinal cord, SCI patients require neurorehabilitation to restore neural function and to compensate for any impairments including motor disability, pain treatment, and bladder/bowel management. However, the spinal cord has a limited capacity to regenerate and much of the disability may persist, depending on the initial lesion severity and level of injury. For this reason, and the lack of effective drug treatments, there is an emerging interest and urgent need in promoting axonal regeneration and remyelination after SCI through cell- and stem-cell based therapies. This review briefly summarizes the state-of the art management of acute SCI and its neurorehabilitation to critically appraise phase I/II trials from the last two decades that have investigated cell-based therapies (i.e., Schwann cells, macrophages, and olfactory ensheathing cells) and stem cell-based therapies (i.e., neural stem cells, mesenchymal, and hematopoietic stem cells). Recently, two large multicenter trials provided evidence for the safety and feasibility of neural stem cell transplantation into the injured cord, whilst two monocenter trials also showed this to be the case for the transplantation of Schwann cells into the posttraumatic cord cavity. These are milestone studies that will facilitate further interventional trials. However, the clinical adoption of such approaches remains unproven, as there is only limited encouraging data, often in single patients, and no proven trial evidence to support regulatory approval.
Collapse
Affiliation(s)
- Carl Moritz Zipser
- Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland
| | - Armin Curt
- Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland.
| |
Collapse
|
|
6
|
Zeng CW. Advancing Spinal Cord Injury Treatment through Stem Cell Therapy: A Comprehensive Review of Cell Types, Challenges, and Emerging Technologies in Regenerative Medicine. Int J Mol Sci 2023; 24:14349. [PMID: 37762654 PMCID: PMC10532158 DOI: 10.3390/ijms241814349] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/17/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Spinal cord injuries (SCIs) can lead to significant neurological deficits and lifelong disability, with far-reaching physical, psychological, and economic consequences for affected individuals and their families. Current treatments for SCIs are limited in their ability to restore function, and there is a pressing need for innovative therapeutic approaches. Stem cell therapy has emerged as a promising strategy to promote the regeneration and repair of damaged neural tissue following SCIs. This review article comprehensively discusses the potential of different stem cell types, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), and neural stem/progenitor cells (NSPCs), in SCI treatment. We provide an in-depth analysis of the unique advantages and challenges associated with each stem cell type, as well as the latest advancements in the field. Furthermore, we address the critical challenges faced in stem cell therapy for SCIs, including safety concerns, ethical considerations, standardization of protocols, optimization of transplantation parameters, and the development of effective outcome measures. We also discuss the integration of novel technologies such as gene editing, biomaterials, and tissue engineering to enhance the therapeutic potential of stem cells. The article concludes by emphasizing the importance of collaborative efforts among various stakeholders in the scientific community, including researchers, clinicians, bioengineers, industry partners, and patients, to overcome these challenges and realize the full potential of stem cell therapy for SCI patients. By fostering such collaborations and advancing our understanding of stem cell biology and regenerative medicine, we can pave the way for the development of groundbreaking therapies that improve the lives of those affected by SCIs.
Collapse
Affiliation(s)
- Chih-Wei Zeng
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| |
Collapse
|
|
7
|
Montoto-Meijide R, Meijide-Faílde R, Díaz-Prado SM, Montoto-Marqués A. Mesenchymal Stem Cell Therapy in Traumatic Spinal Cord Injury: A Systematic Review. Int J Mol Sci 2023; 24:11719. [PMID: 37511478 PMCID: PMC10380897 DOI: 10.3390/ijms241411719] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Recovery from a traumatic spinal cord injury (TSCI) is challenging due to the limited regenerative capacity of the central nervous system to restore cells, myelin, and neural connections. Cell therapy, particularly with mesenchymal stem cells (MSCs), holds significant promise for TSCI treatment. This systematic review aims to analyze the efficacy, safety, and therapeutic potential of MSC-based cell therapies in TSCI. A comprehensive search of PUBMED and COCHRANE databases until February 2023 was conducted, combining terms such as "spinal cord injury," "stem cells," "stem cell therapy," "mesenchymal stem cells," and "traumatic spinal cord injury". Among the 53 studies initially identified, 22 (21 clinical trials and 1 case series) were included. Findings from these studies consistently demonstrate improvements in AIS (ASIA Impairment Scale) grades, sensory scores, and, to a lesser extent, motor scores. Meta-analyses further support these positive outcomes. MSC-based therapies have shown short- and medium-term safety, as indicated by the absence of significant adverse events within the studied timeframe. However, caution is required when drawing generalized recommendations due to the limited scientific evidence available. Further research is needed to elucidate the long-term safety and clinical implications of these advancements. Although significant progress has been made, particularly with MSC-based therapies, additional studies exploring other potential future therapies such as gene therapies, neurostimulation techniques, and tissue engineering approaches are essential for a comprehensive understanding of the evolving TSCI treatment landscape.
Collapse
Affiliation(s)
- Rodrigo Montoto-Meijide
- Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Rosa Meijide-Faílde
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Instituto de Investigación Biomédica de A Coruña (INIBIC), Centro Interdisciplinar de Química y Biología (CICA), Universidade da Coruña, 15071 A Coruña, Spain
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
| | - Silvia María Díaz-Prado
- Grupo de Investigación en Terapia Celular y Medicina Regenerativa, Instituto de Investigación Biomédica de A Coruña (INIBIC), Centro Interdisciplinar de Química y Biología (CICA), Universidade da Coruña, 15071 A Coruña, Spain
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
| | - Antonio Montoto-Marqués
- Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Universidade da Coruña, 15071 A Coruña, Spain
- Unidad de Lesionados Medulares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
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.
Collapse
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,
| |
Collapse
|
|
10
|
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.
| |
Collapse
|
|
11
|
Milczarek O, Kwiatkowski S, Swadźba J, Swadźba P, Kwiatkowska K, Majka M. Use of Multiple Wharton Jelly Mesenchymal Stem Cell Transplants in Treatment of Incomplete Spinal Cord Injury: A Case Report. EXP CLIN TRANSPLANT 2022; 20:878-882. [DOI: 10.6002/ect.2021.0283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
12
|
Huang H, Al Zoubi ZM, Moviglia G, Sharma HS, Sarnowska A, Sanberg PR, Chen L, Xue Q, Siniscalco D, Feng S, Saberi H, Guo X, Xue M, Dimitrijevic MR, Andrews RJ, Mao G, Zhao RC, Han F. Clinical cell therapy guidelines for neurorestoration (IANR/CANR 2022). JOURNAL OF NEURORESTORATOLOGY 2022. [DOI: 10.1016/j.jnrt.2022.100015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
|
|
13
|
Effects of mesenchymal stem cell transplantation on spinal cord injury patients. Cell Tissue Res 2022; 389:373-384. [PMID: 35697943 DOI: 10.1007/s00441-022-03648-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 06/02/2022] [Indexed: 11/02/2022]
Abstract
Spinal cord injury (SCI) is a traumatic injury with sensory and motor deficits that more than 1 million patients worldwide suffer from disability due to it. Many pharmacological therapies help reduce SCI-related injury and protect CNS from more damage but no current therapy could improve the axonal repair. In this regard, stem cell therapy is considered a regenerative method for SCI patient treatment. The neurotrophic and immunomodulatory factor secretion, differentiation, neuroprotecting, and remyelinating properties have made mesenchymal stem cells (MSCs) principally useful in this field. There are studies on the role of MSCs in patients suffering from SCI. However, low number of SCI patients and the lack of control groups in these studies, the cell transplantation appropriate methods, including cell source, dose, route of delivery, and transplantation timing, are various in trials. This study reviews the beneficial effects of MSC transplantation in SCI clinical studies with a special focus on the MSC properties and limitations of MSC transplantation.
Collapse
|
|
14
|
Zhang Y, Jing Z, Cao X, Wei Q, He W, Zhang N, Liu Y, Yuan Q, Zhuang Z, Dong Y, Hong Z, Li J, Li P, Zhang L, Wang H, Li W. SOCS1, the feedback regulator of STAT1/3, inhibits the osteogenic differentiation of rat bone marrow mesenchymal stem cells. Gene 2022; 821:146190. [PMID: 35124149 DOI: 10.1016/j.gene.2022.146190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/25/2021] [Accepted: 12/06/2021] [Indexed: 11/30/2022]
Abstract
Our study showed that Signal transducer and activator of transcription (STAT)1 and STAT3 phosphorylation was firstly upregulated in the early stage of osteogenic differentiation (OD), and quickly eliminated in hours. Following with phosphorylation of STAT1/3, its downstream feedback regulator Suppressor of cytokine signaling 1 (SOCS1) protein also underwent a quick elevation. Further activation and deactivation of STAT1/3, by administrated with Colivelin and Nifuroxazide in Bone mesenchymal stem cells (BMSCs), increased and decreased SOCS1 expression, inhibited and promoted OD of BMSCs, respectively, as evidenced by Alizarin staining, alkaline phosphatase (ALP) activity, and determination of Run-related transcription factor 2 (RUNX2), Osteocalcin (OCN), ALP, and Bone sialoprotein (BSP). In addition, administration of Colivelin and Nifuroxazide caused and blocked inflammation and apoptosis of BMSCs. To further elucidate the role of STAT1/3-SOCS1 regulatory loop on OD of BMSCs, we overexpressed or silenced SOCS1 in BMSCs during OD. WB data showed that overexpression of SOCS1 repressed STAT1/3 phosphorylation, and knockdown of SOCS1 increased the phosphorylated STAT1/3. Further mechanism study showed that OD of BMSCs was elevated or reduced by SOCS1 overexpression or knockdown, respectively. The findings presenting indicated that the STAT1/3-SOCS1 axis may be exploited as an innovative strategy to enhance osteogenesis in regenerative medicine.
Collapse
Affiliation(s)
- Ying Zhang
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China; Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China.
| | - Zhenhao Jing
- Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
| | - Xiangyang Cao
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Qiushi Wei
- Institute of Orthopaedics of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China; The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China.
| | - Wei He
- Institute of Orthopaedics of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China; The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China.
| | - Ning Zhang
- Hunan University of Chinese Medicine, Zhengzhou, Henan 410208, China.
| | - Youwen Liu
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Qiang Yuan
- Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
| | - Zhikun Zhuang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China.
| | - Yipping Dong
- Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
| | - Zhinan Hong
- Institute of Orthopaedics of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China; The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510240, China.
| | - Jitian Li
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Peifeng Li
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Leilei Zhang
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| | - Haibin Wang
- Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China.
| | - Wuyin Li
- Medical Center of Hip, Luoyang Orthopedic-Traumatological Hospital (Orthopedics Hospital of Henan Province), Luoyang, Henan 471002, China.
| |
Collapse
|
|
15
|
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
|
|
16
|
Suzuki H, Imajo Y, Funaba M, Nishida N, Sakamoto T, Sakai T. Current Concepts of Neural Stem/Progenitor Cell Therapy for Chronic Spinal Cord Injury. Front Cell Neurosci 2022; 15:794692. [PMID: 35185471 PMCID: PMC8850278 DOI: 10.3389/fncel.2021.794692] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/20/2021] [Indexed: 11/13/2022] Open
Abstract
Chronic spinal cord injury (SCI) is a devastating condition that results in major neurological deficits and social burden. It continues to be managed symptomatically, and no real therapeutic strategies have been devised for its treatment. Neural stem/neural progenitor cells (NSCs/NPCs) being used for the treatment of chronic SCI in experimental SCI models can not only replace the lost cells and remyelinate axons in the injury site but also support their growth and provide neuroprotective factors. Currently, several clinical studies using NSCs/NPCs are underway worldwide. NSCs/NPCs also have the potential to differentiate into all three neuroglial lineages to regenerate neural circuits, demyelinate denuded axons, and provide trophic support to endogenous cells. This article explains the challenging pathophysiology of chronic SCI and discusses key NSC/NPC-based techniques having the greatest potential for translation over the next decade.
Collapse
|
|
17
|
Tashiro S, Tsuji O, Shinozaki M, Shibata T, Yoshida T, Tomioka Y, Unai K, Kondo T, Itakura G, Kobayashi Y, Yasuda A, Nori S, Fujiyoshi K, Nagoshi N, Kawakami M, Uemura O, Yamada S, Tsuji T, Okano H, Nakamura M. Current progress of rehabilitative strategies in stem cell therapy for spinal cord injury: a review. NPJ Regen Med 2021; 6:81. [PMID: 34824291 PMCID: PMC8616941 DOI: 10.1038/s41536-021-00191-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 10/21/2021] [Indexed: 12/21/2022] Open
Abstract
Stem cell-based regenerative therapy has opened an avenue for functional recovery of patients with spinal cord injury (SCI). Regenerative rehabilitation is attracting wide attention owing to its synergistic effects, feasibility, non-invasiveness, and diverse and systemic properties. In this review article, we summarize the features of rehabilitation, describe the mechanism of combinatorial treatment, and discuss regenerative rehabilitation in the context of SCI. Although conventional rehabilitative methods have commonly been implemented alone, especially in studies of acute-to-subacute SCI, the combinatorial effects of intensive and advanced methods, including various neurorehabilitative approaches, have also been reported. Separating the concept of combined rehabilitation from regenerative rehabilitation, we suggest that the main roles of regenerative rehabilitation can be categorized as conditioning/reconditioning, functional training, and physical exercise, all of which are indispensable for enhancing functional recovery achieved using stem cell therapies.
Collapse
Affiliation(s)
- Syoichi Tashiro
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Tokyo, Japan. .,Department of Rehabilitation Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
| | - Osahiko Tsuji
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Takahiro Shibata
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Takashi Yoshida
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Yohei Tomioka
- Department of Rehabilitation, Murayama Medical Center, Musashi-Murayama, Tokyo, Japan
| | - Kei Unai
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Takahiro Kondo
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Go Itakura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Yoshiomi Kobayashi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan.,Department of Orthopaedic Surgery, Murayama Medical Center, Musashi-Murayama, Tokyo, Japan
| | - Akimasa Yasuda
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan.,Department of Orthopaedic surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Satoshi Nori
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Kanehiro Fujiyoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan.,Department of Orthopaedic Surgery, Murayama Medical Center, Musashi-Murayama, Tokyo, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Michiyuki Kawakami
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Osamu Uemura
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Tokyo, Japan.,Department of Rehabilitation, Murayama Medical Center, Musashi-Murayama, Tokyo, Japan
| | - Shin Yamada
- Department of Rehabilitation Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
| | - Tetsuya Tsuji
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| |
Collapse
|
|
18
|
Aithal AP, Bairy LK, Seetharam RN. Safety and therapeutic potential of human bone marrow-derived mesenchymal stromal cells in regenerative medicine. Stem Cell Investig 2021; 8:10. [PMID: 34124233 DOI: 10.21037/sci-2020-036] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 03/24/2021] [Indexed: 12/20/2022]
Abstract
Regenerative medicine is considered as an alternative approach to healthcare. Owing to their pluripotent abilities and their relative lack of ethical and legal issues, adult stem cells are considered as optimal candidates for use in the treatment of various diseases. Bone marrow-derived mesenchymal stem cells are among the most promising candidates for clinical applications as they have expressed a higher degree of plasticity in vitro. Many investigators have begun to examine how bone marrow stem cells might be used to rebuild damaged tissues. The systemic administration of cells for therapeutic applications requires efficient migration and homing of cells to the target site. Cell adhesion molecules and their ligands, chemokines, extracellular matrix components and specialized bone marrow niches all participate in the proper regulation of this process. MSCs suppress the pathophysiological process that is mediated by chronic inflammation and contributes to a modification of the microenvironment and tissue regeneration. Due to the intricacy of the mesenchymal stem cell, there is ever-increasing amount of data emerging about their migration and regenerative mechanisms. Many factors influence MSC mobilization and their homing to injured tissues. This review summarizes the current clinical and pre-clinical data available in literature regarding the use of MSC in tissue repair and their prospective therapeutic role in various diseases and the underlying repair mechanisms will be discussed.
Collapse
Affiliation(s)
- Ashwini P Aithal
- Department of Anatomy, Melaka Manipal Medical College (Manipal Campus), Manipal Academy of Higher Education, Manipal, India
| | - Laxminarayana K Bairy
- Department of Pharmacology, RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
| | | |
Collapse
|
|
19
|
Muthu S, Jeyaraman M, Gulati A, Arora A. Current evidence on mesenchymal stem cell therapy for traumatic spinal cord injury: systematic review and meta-analysis. Cytotherapy 2021; 23:186-197. [PMID: 33183980 DOI: 10.1016/j.jcyt.2020.09.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND AIMS The authors aim to analyze the evidence in the literature regarding the efficacy and safety of mesenchymal stem cell (MSC) therapy in human subjects with traumatic spinal cord injury (SCI) and identify its potential role in the management of SCI. METHODS The authors conducted independent and duplicate searches of electronic databases, including PubMed, Embase and the Cochrane Library, until May 2020 for studies analyzing the efficacy and safety of stem cell therapy for SCI. American Spine Injury Association (ASIA) impairment scale (AIS) grade improvement, ASIA sensorimotor score, activities of daily living score, residual urine volume, bladder function improvement, somatosensory evoked potential (SSEP) improvement and adverse reactions were the outcomes analyzed. Analysis was performed in R platform using OpenMeta[Analyst] software. RESULTS Nineteen studies involving 670 patients were included for analysis. On analysis, the intervention group showed statistically significant improvement in AIS grade (P < 0.001), ASIA sensory score (P < 0.017), light touch (P < 0.001), pinprick (P = 0.046), bladder function (P = 0.012), residual urine volume (P = 0.023) and SSEP (P = 0.002). However, no significant difference was noted in motor score (P = 0.193) or activities of daily living score (P = 0.161). Although the intervention group had a significant increase in complications (P < 0.001), no serious or permanent adverse events were reported. On subgroup analysis, low concentration of MSCs (<5 × 107 cells) and initial AIS grade A presentation showed significantly better outcomes than their counterparts. CONCLUSIONS The authors' analysis establishes the efficacy and safety of MSC transplantation in terms of improvement in AIS grade, ASIA sensory score, bladder function and electrophysiological parameters like SSEP compared with controls, without major adverse events. However, further research is needed to standardize dose, timing, route and source of MSCs used for transplantation.
Collapse
Affiliation(s)
- Sathish Muthu
- Government Hospital, Velayuthampalayam, Karur, Tamil Nadu, India; Orthopaedic Research Group, Coimbatore, Tamil Nadu, India; Indian Stem Cells Study Group, Lucknow, India.
| | - Madhan Jeyaraman
- Orthopaedic Research Group, Coimbatore, Tamil Nadu, India; Indian Stem Cells Study Group, Lucknow, India; Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, India
| | - Arun Gulati
- Department of Orthopaedics, Kalpana Chawla Government Medical College & Hospital, Karnal, India
| | - Arunabh Arora
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, India
| |
Collapse
|
|
20
|
Cheng Z, Wang R, Cao K, Wang G, Qin J, Li H, Li J, Wang D, He X. Ten years of clinical observation of olfactory ensheathing cell transplantation in patients with spinal cord injury. JOURNAL OF NEURORESTORATOLOGY 2021. [DOI: 10.26599/jnr.2021.9040009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Objective: To evaluate the long-term curative efficacy and safety of olfactory ensheathing cell (OEC) transplantation by 10 years of follow-up investigation. Methods: A follow-up observation was done on 13 patients with allograft olfactory bulb-derived OEC transplantation from September 2005 to September 2007 at the Second Affiliated Hospital of Xi’an Jiaotong University. After cell purification, amplification, and identification, a 2 × 107/mL cell suspension was prepared for transplantation. In the posterior horn of the spinal cord 0.5 cm distal and proximal to the spinal cord injury zone, 4 needle points were selected to avoid the blood vessels. The needle depth was 3 mm, and the injection volume per point was 10 μL. Postoperatively and at 1 week, 4 weeks, 12 weeks, 24 weeks, 1 year, 3 years, 5 years, and 10 years after the surgery, the patient’s American Spinal Injury Association (ASIA) score, adverse reactions, and other minor observations were assessed. Results: All the patients did not have serious complications. No gliomas or other new organisms formed during the 10-year observation period. Eight of 13 patients had improvement in sensory function, and 5 patients showed improvement in motor function. The ASIA acupuncture, light touch, and exercise scores improved significantly 1 year after the surgery, and this improvement continued until the 10-year follow-up period. Three of 13 patients had improvement in defecation and urination, and 1 patient had improved neuralgia after spinal cord injury. Conclusion: OEC transplantation is safe and effective in treating spinal cord injury. The observation period of OEC transplantation is 1 to 3 years.
Collapse
|
|
21
|
Guo X, Feng Y, Sun T, Feng S, Tang J, Chen L, Cao X, Lin H, He X, Li M, Zhang Z, Yin G, Mei X, Huang H. Clinical guidelines for neurorestorative therapies in spinal cord injury (2021 China version). JOURNAL OF NEURORESTORATOLOGY 2021. [DOI: 10.26599/jnr.2021.9040003] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Treatment of spinal cord injury (SCI) remains challenging. Considering the rapid developments in neurorestorative therapies for SCI, we have revised and updated the Clinical Therapeutic Guidelines for Neurorestoration in Spinal Cord Injury (2016 Chinese version) of the Chinese Association of Neurorestoratology (Preparatory) and China Committee of International Association of Neurorestoratology. Treatment of SCI is a systematic multimodal process that aims to improve survival and restore neurological function. These guidelines cover real-world comprehensive neurorestorative management of acute, subacute, and chronic SCI and include assessment and diagnosis, pre-hospital first aid, treatment, rehabilitation, and complication management.
Collapse
|
|
22
|
Salehi-Pourmehr H, Hajebrahimi S, Rahbarghazi R, Pashazadeh F, Mahmoudi J, Maasoumi N, Sadigh-Eteghad S. Stem Cell Therapy for Neurogenic Bladder Dysfunction in Rodent Models: A Systematic Review. Int Neurourol J 2020; 24:241-257. [PMID: 33017895 PMCID: PMC7538284 DOI: 10.5213/inj.2040058.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/23/2020] [Indexed: 12/28/2022] Open
Abstract
PURPOSE Neurogenic bladder dysfunction (NGB) has an impact on the quality of life, which made it an important research subject in preclinical studies. The present review investigates the effect of stem cell (SC) therapy on bladder functional recovery after the onset of spinal cord injury (SCI), multiple sclerosis (MS), Parkinson disease (PD), and stroke in rodent models. METHODS All experiments evaluated the regenerative potential of SC on the management of NGB in rodent models up to June 2019, were included. From 1,189 relevant publications, 20 studies met our inclusion criteria of which 15 were conducted on SCI, 2 on PD, 2 on stroke, and 1 on MS in the rodent models. We conducted a meta-analysis on SCI experiments and for other neurological diseases, detailed urodynamic findings were reported. RESULTS The common SC sources used for therapeutical purposes were neural progenitor cells, bone marrow mesenchymal SCs, human amniotic fluid SCs, and human umbilical cord blood SCs. There was a significant improvement of micturition pressure in both contusion and transaction SCI models 4 and 8 weeks post-SC transplantation. Residual urine volume, micturition volume, and bladder capacity were improved 28 days after SC transplantation only in the transaction model of SCI. Nonvoiding contraction recovered only in 56 days post-cell transplantation in the contusion model. CONCLUSION Partial bladder recovery has been evident after SC therapy in SCI models. Due to limitations in the number of studies in other neurological diseases, additional studies are necessary to confirm the detailed mechanism for bladder recovery.
Collapse
Affiliation(s)
- Hanieh Salehi-Pourmehr
- Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sakineh Hajebrahimi
- Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
- Urology Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Pashazadeh
- Research Center for Evidence-Based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narjes Maasoumi
- University Hospital Southampton, Southampton, United Kingdom
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- East-Azerbaijan Comprehensive Stroke Program, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Persian Medicine, Faculty of Persian Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
23
|
Yamazaki K, Kawabori M, Seki T, Houkin K. Clinical Trials of Stem Cell Treatment for Spinal Cord Injury. Int J Mol Sci 2020; 21:ijms21113994. [PMID: 32498423 PMCID: PMC7313002 DOI: 10.3390/ijms21113994] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/22/2020] [Accepted: 05/29/2020] [Indexed: 12/12/2022] Open
Abstract
There are more than one million patients worldwide suffering paralysis caused by spinal cord injury (SCI). SCI causes severe socioeconomic problems not only to the patients and their caregivers but also to society; therefore, the development of innovative treatments is crucial. Many pharmacological therapies have been attempted in an effort to reduce SCI-related damage; however, no single therapy that could dramatically improve the serious long-term sequelae of SCI has emerged. Stem cell transplantation therapy, which can ameliorate damage or regenerate neurological networks, has been proposed as a promising candidate for SCI treatment, and many basic and clinical experiments using stem cells for SCI treatment have been launched, with promising results. However, the cell transplantation methods, including cell type, dose, transplantation route, and transplantation timing, vary widely between trials, and there is no consensus regarding the most effective treatment strategy. This study reviews the current knowledge on this issue, with a special focus on the clinical trials that have used stem cells for treating SCI, and highlights the problems that remain to be solved before the widespread clinical use of stem cells can be adopted.
Collapse
|
|
24
|
Quality Standards of Stem Cell Sources for Clinical Treatment of Neurodegenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1266:9-19. [PMID: 33105492 DOI: 10.1007/978-981-15-4370-8_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
A large number of experimental and clinical studies have shown that cell transplantation has therapeutic effects for PD, AD and other neurodegenerative diseases or damages. Good Manufacturing Practice (GMP) guidance must be defined to produce clinical-grade cells for transplantation to the patients. Standardized quality and clinical preparation procedures of the transplanted cells will ensure the therapeutic efficacy and reduce the side-effect risk of cell therapy. Here we review the cell quality standards governing the clinical transplantation of stem cells for neurodegenerative diseases to clinical practitioners. These quality standards include cell quality control, minimal suggested cell doses for undergoing cell transplantation, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, not charging the patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.
Collapse
|
|
25
|
Huang H, Chen L, Mao G, Sharma HS. Clinical neurorestorative cell therapies: Developmental process, current state and future prospective. JOURNAL OF NEURORESTORATOLOGY 2020. [DOI: 10.26599/jnr.2020.9040009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.
Collapse
|
|
26
|
Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, Garbossa D. Mesenchymal Stem Cells for Spinal Cord Injury: Current Options, Limitations, and Future of Cell Therapy. Int J Mol Sci 2019; 20:ijms20112698. [PMID: 31159345 PMCID: PMC6600381 DOI: 10.3390/ijms20112698] [Citation(s) in RCA: 230] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/29/2019] [Accepted: 05/30/2019] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) constitutes an inestimable public health issue. The most crucial phase in the pathophysiological process of SCI concerns the well-known secondary injury, which is the uncontrolled and destructive cascade occurring later with aberrant molecular signaling, inflammation, vascular changes, and secondary cellular dysfunctions. The use of mesenchymal stem cells (MSCs) represents one of the most important and promising tested strategies. Their appeal, among the other sources and types of stem cells, increased because of their ease of isolation/preservation and their properties. Nevertheless, encouraging promise from preclinical studies was followed by weak and conflicting results in clinical trials. In this review, the therapeutic role of MSCs is discussed, together with their properties, application, limitations, and future perspectives.
Collapse
Affiliation(s)
- Fabio Cofano
- Department of Neuroscience "Rita Levi Montalcini", Neurosurgery Unit, University of Turin, 10126 Turin, Italy.
| | - Marina Boido
- Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute "Cavalieri Ottolenghi", University of Turin, Consorzio Istituto Nazionale di Neuroscienze, 10043 Orbassano, Italy.
| | - Matteo Monticelli
- Department of Neuroscience "Rita Levi Montalcini", Neurosurgery Unit, University of Turin, 10126 Turin, Italy.
| | - Francesco Zenga
- Department of Neuroscience "Rita Levi Montalcini", Neurosurgery Unit, University of Turin, 10126 Turin, Italy.
| | - Alessandro Ducati
- Department of Neuroscience "Rita Levi Montalcini", Neurosurgery Unit, University of Turin, 10126 Turin, Italy.
| | - Alessandro Vercelli
- Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute "Cavalieri Ottolenghi", University of Turin, Consorzio Istituto Nazionale di Neuroscienze, 10043 Orbassano, Italy.
| | - Diego Garbossa
- Department of Neuroscience "Rita Levi Montalcini", Neurosurgery Unit, University of Turin, 10126 Turin, Italy.
| |
Collapse
|
|
27
|
Mazini L, Rochette L, Amine M, Malka G. Regenerative Capacity of Adipose Derived Stem Cells (ADSCs), Comparison with Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2019; 20:ijms20102523. [PMID: 31121953 PMCID: PMC6566837 DOI: 10.3390/ijms20102523] [Citation(s) in RCA: 262] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/03/2019] [Accepted: 05/06/2019] [Indexed: 12/13/2022] Open
Abstract
Adipose tissue is now on the top one of stem cell sources regarding its accessibility, abundance, and less painful collection procedure when compared to other sources. The adipose derived stem cells (ADSCs) that it contains can be maintained and expanded in culture for long periods of time without losing their differentiation capacity, leading to large cell quantities being increasingly used in cell therapy purposes. Many reports showed that ADSCs-based cell therapy products demonstrated optimal efficacy and efficiency in some clinical indications for both autologous and allogeneic purposes, hence becoming considered as potential tools for replacing, repairing, and regenerating dead or damaged cells. In this review, we analyzed the therapeutic advancement of ADSCs in comparison to bone marrow (BM) and umbilical cord (UC)-mesenchymal stem cells (MSCs) and designed the specific requirements to their best clinical practices and safety. Our analysis was focused on the ADSCs, rather than the whole stromal vascular fraction (SVF) cell populations, to facilitate characterization that is related to their source of origins. Clinical outcomes improvement suggested that these cells hold great promise in stem cell-based therapies in neurodegenerative, cardiovascular, and auto-immunes diseases.
Collapse
Affiliation(s)
- Loubna Mazini
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
| | - Luc Rochette
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne Franche Comté, Faculté des Sciences de Santé, 7 Bd Jeanne d'Arc, 21000 Dijon, France.
| | - Mohamed Amine
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Département de Santé Publique et de Médecine Communautaire, Faculté de Médecine et de Pharmacie, Université Cadi Ayyad, Marrakech 40000, Morocco.
| | - Gabriel Malka
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
| |
Collapse
|
|
28
|
Mazini L, Rochette L, Amine M, Malka G. Regenerative Capacity of Adipose Derived Stem Cells (ADSCs), Comparison with Mesenchymal Stem Cells (MSCs). Int J Mol Sci 2019. [PMID: 31121953 DOI: 10.3390/ijms20102523.pmid:31121953;pmcid:pmc6566837] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023] Open
Abstract
Adipose tissue is now on the top one of stem cell sources regarding its accessibility, abundance, and less painful collection procedure when compared to other sources. The adipose derived stem cells (ADSCs) that it contains can be maintained and expanded in culture for long periods of time without losing their differentiation capacity, leading to large cell quantities being increasingly used in cell therapy purposes. Many reports showed that ADSCs-based cell therapy products demonstrated optimal efficacy and efficiency in some clinical indications for both autologous and allogeneic purposes, hence becoming considered as potential tools for replacing, repairing, and regenerating dead or damaged cells. In this review, we analyzed the therapeutic advancement of ADSCs in comparison to bone marrow (BM) and umbilical cord (UC)-mesenchymal stem cells (MSCs) and designed the specific requirements to their best clinical practices and safety. Our analysis was focused on the ADSCs, rather than the whole stromal vascular fraction (SVF) cell populations, to facilitate characterization that is related to their source of origins. Clinical outcomes improvement suggested that these cells hold great promise in stem cell-based therapies in neurodegenerative, cardiovascular, and auto-immunes diseases.
Collapse
Affiliation(s)
- Loubna Mazini
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
| | - Luc Rochette
- Equipe d'Accueil (EA 7460), Physiopathologie et Epidémiologie Cérébro-Cardiovasculaires (PEC2), Université de Bourgogne Franche Comté, Faculté des Sciences de Santé, 7 Bd Jeanne d'Arc, 21000 Dijon, France.
| | - Mohamed Amine
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Département de Santé Publique et de Médecine Communautaire, Faculté de Médecine et de Pharmacie, Université Cadi Ayyad, Marrakech 40000, Morocco.
| | - Gabriel Malka
- Laboratoire Cellules Souches et Ingénierie Tissulaire, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
- Laboratoire d'Epidémiologie et de Biostatique, Centre Interface Applications Médicales CIAM, Université Mohammed VI polytechnique, Ben Guérir 43150, Morocco.
| |
Collapse
|
|
29
|
Kabataş S, Civelek E, İnci Ç, Yalçınkaya EY, Günel G, Kır G, Albayrak E, Öztürk E, Adaş G, Karaöz E. Wharton's Jelly-Derived Mesenchymal Stem Cell Transplantation in a Patient with Hypoxic-Ischemic Encephalopathy: A Pilot Study. Cell Transplant 2018; 27:1425-1433. [PMID: 30203688 PMCID: PMC6180731 DOI: 10.1177/0963689718786692] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) have been introduced as a possible therapy in hypoxic-ischemic encephalopathy (HIE). We report a 16-year-old boy who was treated with WJ-MSCs in the course of HIE due to post-cardiopulmonary resuscitation. He received a long period of mechanical ventilation and tracheostomy with spastic quadriparesis. He underwent the intrathecal (1×106/kg in 3 mL), intramuscular (1×106/kg in 20 mL) and intravenous (1×106/kg in 30 mL) administrations of WJ-MSCs for each application route (twice a month for 2 months). After stem cell infusions, progressive improvements were shown in his neurological examination, neuroradiological, and neurophysiological findings. To our best knowledge, this is a pioneer project to clinically study the neural repair effect of WJ-MSCs in a patient with HIE.
Collapse
Affiliation(s)
- Serdar Kabataş
- Department of Neurosurgery, Gaziosmanpaşa Taksim Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
- Serdar Kabataş, University of Health Sciences, Gaziosmanpaşa Taksim Training and Research Hospital, Department of Neurosurgery, Karayolları Mahallesi, Osmanbey Caddesi 616. Sokak No:10, 34255 Gaziosmanpaşa, Istanbul, Turkey. Emails: ,
| | - Erdinç Civelek
- Department of Neurosurgery, Gaziosmanpaşa Taksim Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Çiğdem İnci
- Liv Hospital, Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Istanbul, Turkey
| | - Ebru Yılmaz Yalçınkaya
- Department of Physical Medicine and Rehabilitation, Gaziosmanpaşa Taksim Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Gülşen Günel
- Liv Hospital, Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Istanbul, Turkey
| | - Gülay Kır
- Department of Anestesiology and Reanimation, Gaziosmanpaşa Taksim Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Esra Albayrak
- Liv Hospital, Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Istanbul, Turkey
| | - Erek Öztürk
- Department of Neurosurgery, Gaziosmanpaşa Taksim Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Gökhan Adaş
- Department of General Surgery, Gaziosmanpaşa Taksim Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Erdal Karaöz
- Liv Hospital, Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Istanbul, Turkey
- Istinye University, Vice President, Istanbul, Turkey
| |
Collapse
|
|
30
|
Dalamagkas K, Tsintou M, Seifalian A, Seifalian AM. Translational Regenerative Therapies for Chronic Spinal Cord Injury. Int J Mol Sci 2018; 19:1776. [PMID: 29914060 PMCID: PMC6032191 DOI: 10.3390/ijms19061776] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/05/2018] [Accepted: 06/06/2018] [Indexed: 12/22/2022] Open
Abstract
Spinal cord injury is a chronic and debilitating neurological condition that is currently being managed symptomatically with no real therapeutic strategies available. Even though there is no consensus on the best time to start interventions, the chronic phase is definitely the most stable target in order to determine whether a therapy can effectively restore neurological function. The advancements of nanoscience and stem cell technology, combined with the powerful, novel neuroimaging modalities that have arisen can now accelerate the path of promising novel therapeutic strategies from bench to bedside. Several types of stem cells have reached up to clinical trials phase II, including adult neural stem cells, human spinal cord stem cells, olfactory ensheathing cells, autologous Schwann cells, umbilical cord blood-derived mononuclear cells, adult mesenchymal cells, and autologous bone-marrow-derived stem cells. There also have been combinations of different molecular therapies; these have been either alone or combined with supportive scaffolds with nanostructures to facilitate favorable cell⁻material interactions. The results already show promise but it will take some coordinated actions in order to develop a proper step-by-step approach to solve impactful problems with neural repair.
Collapse
Affiliation(s)
- Kyriakos Dalamagkas
- The Institute for Rehabilitation and Research, Memorial Hermann Texas Medical Centre, Houston, TX 77030, USA.
- Centre for Nanotechnology & Regenerative Medicine, Division of Surgery and Interventional Science, University College of London (UCL), London NW3 2QG, UK.
| | - Magdalini Tsintou
- Centre for Nanotechnology & Regenerative Medicine, Division of Surgery and Interventional Science, University College of London (UCL), London NW3 2QG, UK.
- Center for Neural Systems Investigations, Massachusetts General Hospital/HST Athinoula A., Martinos Centre for Biomedical Imaging, Harvard Medical School, Boston, MA 02129, USA.
| | - Amelia Seifalian
- Faculty of Medical Sciences, UCL Medical School, London WC1E 6BT, UK.
| | - Alexander M Seifalian
- NanoRegMed Ltd. (Nanotechnology & Regenerative Medicine Commercialization Centre), The London BioScience Innovation Centre, London NW1 0NH, UK.
| |
Collapse
|
|
31
|
Sediq AS, Klem R, Nejadnik MR, Meij P, Jiskoot W. Label-Free, Flow-Imaging Methods for Determination of Cell Concentration and Viability. Pharm Res 2018; 35:150. [PMID: 29846807 PMCID: PMC5976703 DOI: 10.1007/s11095-018-2422-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 05/01/2018] [Indexed: 11/29/2022]
Abstract
Purpose To investigate the potential of two flow imaging microscopy (FIM) techniques (Micro-Flow Imaging (MFI) and FlowCAM) to determine total cell concentration and cell viability. Methods B-lineage acute lymphoblastic leukemia (B-ALL) cells of 2 different donors were exposed to ambient conditions. Samples were taken at different days and measured with MFI, FlowCAM, hemocytometry and automated cell counting. Dead and live cells from a fresh B-ALL cell suspension were fractionated by flow cytometry in order to derive software filters based on morphological parameters of separate cell populations with MFI and FlowCAM. The filter sets were used to assess cell viability in the measured samples. Results All techniques gave fairly similar cell concentration values over the whole incubation period. MFI showed to be superior with respect to precision, whereas FlowCAM provided particle images with a higher resolution. Moreover, both FIM methods were able to provide similar results for cell viability as the conventional methods (hemocytometry and automated cell counting). Conclusion FIM-based methods may be advantageous over conventional cell methods for determining total cell concentration and cell viability, as FIM measures much larger sample volumes, does not require labeling, is less laborious and provides images of individual cells. Electronic supplementary material The online version of this article (10.1007/s11095-018-2422-5) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- A S Sediq
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
| | - R Klem
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
| | - M R Nejadnik
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
| | - P Meij
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Wim Jiskoot
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.
| |
Collapse
|
|
32
|
Huang H, Young W, Chen L, Feng S, Zoubi ZMA, Sharma HS, Saberi H, Moviglia GA, He X, Muresanu DF, Sharma A, Otom A, Andrews RJ, Al-Zoubi A, Bryukhovetskiy AS, Chernykh ER, Domańska-Janik K, Jafar E, Johnson WE, Li Y, Li D, Luan Z, Mao G, Shetty AK, Siniscalco D, Skaper S, Sun T, Wang Y, Wiklund L, Xue Q, You SW, Zheng Z, Dimitrijevic MR, Masri WSE, Sanberg PR, Xu Q, Luan G, Chopp M, Cho KS, Zhou XF, Wu P, Liu K, Mobasheri H, Ohtori S, Tanaka H, Han F, Feng Y, Zhang S, Lu Y, Zhang Z, Rao Y, Tang Z, Xi H, Wu L, Shen S, Xue M, Xiang G, Guo X, Yang X, Hao Y, Hu Y, Li J, AO Q, Wang B, Zhang Z, Lu M, Li T. Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017). Cell Transplant 2018; 27:310-324. [PMID: 29637817 PMCID: PMC5898693 DOI: 10.1177/0963689717746999] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 07/22/2017] [Accepted: 11/13/2017] [Indexed: 12/11/2022] Open
Abstract
Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version "Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)". The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.
Collapse
Affiliation(s)
- Hongyun Huang
- Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing, People’s Republic of China
| | - Wise Young
- W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA
| | - Lin Chen
- Department of Neurosurgery, Tsinghua University Yuquan Hospital, Beijing, People’s Republic of China
| | - Shiqing Feng
- Department of Orthopaedics, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China
| | - Ziad M. Al Zoubi
- Jordan Ortho and Spinal Centre, Al-Saif Medical Center, Amman, Jordan
| | - Hari Shanker Sharma
- Intensive Experimental CNS Injury and Repair, University Hospital, Uppsala University, Uppsala, Sweden
| | - Hooshang Saberi
- Department of Neurosurgery, Brain and Spinal Injury Research center, Tehran University of Medical Sciences, Tehran, Iran
| | - Gustavo A. Moviglia
- Center of Research and Engineer of Tissues and Cellular Therapy, Maimonides University, Buenos Aires, Argentina
| | - Xijing He
- Department of Orthopaedics, Second Affiliated Hospital of Xi’an Jiaotong University, Xian, People’s Republic of China
| | - Dafin F. Muresanu
- Department of Neurosciences “Iuliu Hatieganu,” University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Alok Sharma
- Department of Neurosurgery, LTM Medical College, LTMG Hospital, Mumbai, Mumbai, India
| | - Ali Otom
- Royal Rehabilitation Center, King Hussein Medical Centre-RJRC Amman, Jordan
| | - Russell J. Andrews
- Nanotechnology & Smart Systems, NASA Ames Research Center, Silicon Valley, CA, USA
| | - Adeeb Al-Zoubi
- The University of Illinois College of Medicine in Peoria, Peoria, IL, USA
| | - Andrey S. Bryukhovetskiy
- NeuroVita Clinic of Interventional and Restorative Neurology and Therapy, Kashirskoye shosse, Moscow, Russia
| | - Elena R. Chernykh
- Lab of Cellular Immunotherapy, Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
| | | | - Emad Jafar
- Jordan Ortho and Spinal Centre, Al-Saif Medical Center, Amman, Jordan
| | - W. Eustace Johnson
- Stem Cells and Regenerative Biology, Faculty of Medicine Dentistry and Life Sciences, University of Chester, Chester, United Kingdom
| | - Ying Li
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom
| | - Daqing Li
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, London, United Kingdom
| | - Zuo Luan
- Department of Pediatrics, Navy General Hospital of PLA, Beijing, People’s Republic of China
| | - Gengsheng Mao
- Institute of Neurorestoratology, General Hospital of Armed Police Forces, Beijing, People’s Republic of China
| | - Ashok K. Shetty
- Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA
| | - Dario Siniscalco
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli,” Naples, Italy
| | - Stephen Skaper
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy
| | - Tiansheng Sun
- Department of orthopedics, PLA Army General Hospital, Beijing, People’s Republic of China
| | - Yunliang Wang
- Department of Neurology, 148th Hospital, Zibo, Shandong, People’s Republic of China
| | - Lars Wiklund
- Unit of Neurology, Department of Pharmacology and Clinical Neuroscience, Umea University, Ostersund, Sweden
| | - Qun Xue
- Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou Jiangsu, People’s Republic of China
| | - Si-Wei You
- Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China
| | - Zuncheng Zheng
- Department of Rehabilitation Medicine, The Central Hospital of Taian, Taian, Shandong, People’s Republic of China
| | | | - W. S. El Masri
- Spinal Injuries Unit, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, United Kingdom
| | - Paul R. Sanberg
- Center of Excellence for Aging & Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Qunyuan Xu
- Institute of Neuroscience, Capital Medical University, Beijing, People’s Republic of China
| | - Guoming Luan
- Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Michael Chopp
- Henry Ford Hospital, Henry Ford Health System, Neurology Research, Detroit, MI, USA
| | - Kyoung-Suok Cho
- Department of Neurosurgery, Uijongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijongbu, South Korea
| | - Xin-Fu Zhou
- Division of Health Sciences, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia
| | - Ping Wu
- Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA
| | - Kai Liu
- Division of Life Science, The Hong Kong University of Science and Technology, Kowloon, Hong Kong
| | - Hamid Mobasheri
- Biomaterials Research Center, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Seiji Ohtori
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroyuki Tanaka
- Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Fabin Han
- Centre for Stem Cells and Regenerative Medicine, Liaocheng University/Liaocheng People’s Hospital, Liaocheng, Shandong, People’s Republic of China
| | - Yaping Feng
- Department of Neurosurgery, Kunming General Hospital of Chengdu Military Command of Chinese PLA, Kunming, Yunnan, People’s Republic of China
| | - Shaocheng Zhang
- Department of Orthopedics, Changhai Hospital, The Second Military Medical University, Shanghai, People’s Republic of China
| | - Yingjie Lu
- Department of Neurosurgery, Chengde Dadu Hospital, Weichang, Hebei, People’s Republic of China
| | - Zhicheng Zhang
- Department of orthopedics, PLA Army General Hospital, Beijing, People’s Republic of China
| | - Yaojian Rao
- Department of Spinal Surgery, Luoyang Orthopedic Hospital of Henan Province, Luoyang, Henan, People’s Republic of China
| | - Zhouping Tang
- Department of Neurology, Tongji Medical College of HUST, Tongji Hospital, Wuhan, People’s Republic of China
| | - Haitao Xi
- Department of Neurology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, People’s Republic of China
| | - Liang Wu
- Center of Rehabilitation, Beijing Xiaotangshan Rehabilitation Hospital, Beijing, People’s Republic of China
| | - Shunji Shen
- Department of Rehabilitation, Weihai Municipal Hospital, Weihai, Shandong, People’s Republic of China
| | - Mengzhou Xue
- Department of Neurorehabilitation, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China
| | - Guanghong Xiang
- Brain Hospital of Hunan Province, Changsha, Hunan, People’s Republic of China
| | - Xiaoling Guo
- Department of Neurology, PLA Army 266 Hospital, Chengde, Hebei, People’s Republic of China
| | - Xiaofeng Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhejiang University Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Yujun Hao
- Department of Neurosurgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Yong Hu
- Department of Orthopaedic and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong
| | - Jinfeng Li
- Unit of Neurology, Department of Pharmacology and Clinical Neuroscience, Umea University, Ostersund, Sweden
| | - Qiang AO
- Department of tissue engineering, China Medical University, Shenyang, Liaoning, People’s Republic of China
| | - Bin Wang
- Department of Traumatology, The Second Affiliated Hospital of Guangzhou Medical University, Haizhu District, Guangzhou, People’s Republic of China
| | - Zhiwen Zhang
- Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Ming Lu
- Department of Neurosurgery, Second Affiliated Hospital of Hunan Normal University (163 Hospital of PLA), Changsha, Hunan, People’s Republic of China
| | - Tong Li
- Department of Neurology, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, People’s Republic of China
| |
Collapse
|
|
33
|
Huang H, Sharma HS, Chen L, Otom A, Al Zoubi ZM, Saberi H, Muresanu DF, He X. Review of clinical neurorestorative strategies for spinal cord injury: Exploring history and latest progresses. JOURNAL OF NEURORESTORATOLOGY 2018. [DOI: 10.26599/jnr.2018.9040013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Clinical neurorestorative therapies recently made great progress for patients with spinal cord injury (SCI). This paper systemically reviews historical perspectives, recent advancements and achievements in SCI through key neurorestorative strategies. In this study, a search was performed in the PubMed, Scopus, and Scholar Google search engines using the keywords “neurorestorative strategies”, “spinal cord injury”, “cell therapy”, “neuromodulation”, and “nerve bridges”. Clinical studies published in the English language were included. It is paramount for academic community involved in this field to take the initiative of a multicenter randomized, double-blind, and placebo-control clinical study with high level of evidence-based treatments for most SCI neurorestorative strategies in patient management. It is of utmost need to establish standard therapeutic methods for patients with SCI as early as possible.
Collapse
|
|
34
|
Moviglia GA, Moviglia Brandolino MT, Couto D, Piccone S. Local immunomodulation and muscle progenitor cells induce recovery in atrophied muscles in spinal cord injury patients. JOURNAL OF NEURORESTORATOLOGY 2018. [DOI: 10.26599/jnr.2018.9040011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Objectives: Restore muscular trophism and voluntary contractile capacity through cell therapy in atrophied muscles in SCI patients. Setting: Out Patient Treatment, Universidad Maimonides, Buenos Aires, Argentina. Methods: After receiving spinal cord cell therapy and intensive rehabilitation, 7 chronic complete spinal cord injury (SCI) patients (4 people with paraplegia and 3 people with quadriplegia) regained muscular electrical activity in previously denervated territories. However, signs of severe muscular atrophy persisted. Looking to reverse chronic muscular atrophy, atrophied muscles with electrical activity were implanted with autologous type 1 macrophages (Mo1) and autologous tissue-specific T helper 1 Cells (Th1) associated with autologous muscular progenitor cells (MPC). The Mo1 and Th1 used cells were named Effector Cells (EC). Each muscle received between 6 to 8 implants, one every 6 weeks. Cellular therapy was combined with intensive rehabilitation program. Results: Sonogram and histological signs of recovery started eight weeks after the first implant. Sonograms showed progressively muscle volume increasing and gradually replacement of hyperechogenic muscle tissue by hypoechogenic muscle bands (resembling normal muscular structure). New bands were distributed parallel to the main muscle axis, along the entire muscular length. Histological samples of hypoechogenic bands showed new and normal muscular tissue. Changes were seen in 7/7 patients. Non-significant side events were detected in any patient over the 24 months of follow up. Conclusions: The results presented here suggest that the combination of immune and regenerative cell therapy may play an important therapeutic role in clinical and histological recovery of chronic muscular atrophy.
Collapse
|
|
35
|
Wang W, Li P, Li W, Jiang J, Cui Y, Li S, Wang Z. Osteopontin activates mesenchymal stem cells to repair skin wound. PLoS One 2017; 12:e0185346. [PMID: 28957406 PMCID: PMC5619734 DOI: 10.1371/journal.pone.0185346] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 09/11/2017] [Indexed: 01/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are promising candidates for skin wound repair due to their capabilities of accumulating at wounds and differentiating into multiple types of skin cells. However, the underlying mechanisms responsible for these processes remain unclear. In this study, we found that osteopontin (OPN) stimulated the migration of MSCs in vitro, and observed the recruitment of endogenous MSCs to a skin wound and their differentiation into keratinocytes and endothelial cells. In OPN knock-out mice, the recruitment of MSCs to the skin wound was significantly inhibited, and wound closure was hampered after an intradermal injection of exogenous MSCs compared to wild-type mice. Consistent with these observations, the expressions of adhesion molecule CD44 and its receptor E-selectin were significantly decreased in the lesions of OPN knock-out mice compared with wild-type mice suggesting that OPN may regulate the migration of MSCs through its interactions with CD44 during skin wound recovery. In summary, our data demonstrated that OPN played a critical role in activating the migration of MSCs to injured sites and their differentiation into specific skin cell types during skin wound healing.
Collapse
Affiliation(s)
- Wenping Wang
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Pei Li
- Department of Orthopedics, No.89 Hospital of People’s Liberation Army, Weifang, Shandong, China
| | - Wei Li
- Department of Plastic and Burn Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Junzi Jiang
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yanyan Cui
- Department of Genetics and Cell Biology, Chongqing Medical University, Chongqing, China
| | - Shirong Li
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- * E-mail: (ZW); (SL)
| | - Zhenxiang Wang
- Department of Plastic and Aesthetic Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- * E-mail: (ZW); (SL)
| |
Collapse
|
|
36
|
Magnetic resonance imaging tracking and assessing repair function of the bone marrow mesenchymal stem cells transplantation in a rat model of spinal cord injury. Oncotarget 2017; 8:58985-58999. [PMID: 28938612 PMCID: PMC5601708 DOI: 10.18632/oncotarget.19775] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022] Open
Abstract
The transplantation of bone marrow mesenchymal stem cells (BMSCs) to repair spinal cord injury (SCI) has become a promising therapy. However, there is still a lack of visual evidence directly implicating the transplanted cells as the source of the improvement of spinal cord function. In this study, BMSCs were labeled with NF-200 promoter and lipase-activated gadolinium-containing nanoparticles (Gd-DTPA-FA). Double labeled BMSCs were implanted into spinal cord transaction injury in rat models in situ, the function recovery was evaluated on 1st, 7th, 14th, 28 th days by MRI, Diffusion Tensor Imaing, CT imaging and post-processing, and histological observations. BBB scores were used for assessing function recovery. After transplantation of BMSCs, the hypersignal emerged in spinal cord in T1WI starting at day 7 that was focused at the injection site, which then increased and extended until day 14. Subsequently, the increased signal intensity area rapidly spread from the injection site to entire injured segment lasting four weeks. The diffusion tensor tractography and histological analysis both showed the nerve fibre from dividing to connecting partly. Immunofluorescence showed higher expression of NF-200 in Repaired group than Injury group. Electron microscopy showed detachment and loose of myelin lamellar getting better in Repaired group compared with the Injury group. BBB scores in Repaired group were significantly higher than those of injury animals. Our study suggests that the migration and distribution of Gd-DTPA-FA labeled BMSCs can be tracked using MRI. Transplantation of BMSCs represents a promising potential strategy for the repair of SCI.
Collapse
|
|
37
|
Spinal Cord Cellular Therapeutics Delivery: Device Design Considerations. REGENERATIVE MEDICINE FOR DEGENERATIVE MUSCLE DISEASES 2016. [DOI: 10.1007/978-1-4939-3228-3_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
|
38
|
Clinical Trial of Human Fetal Brain-Derived Neural Stem/Progenitor Cell Transplantation in Patients with Traumatic Cervical Spinal Cord Injury. Neural Plast 2015; 2015:630932. [PMID: 26568892 PMCID: PMC4619963 DOI: 10.1155/2015/630932] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Accepted: 07/01/2015] [Indexed: 12/15/2022] Open
Abstract
In a phase I/IIa open-label and nonrandomized controlled clinical trial, we sought to assess the safety and neurological effects of human neural stem/progenitor cells (hNSPCs) transplanted into the injured cord after traumatic cervical spinal cord injury (SCI). Of 19 treated subjects, 17 were sensorimotor complete and 2 were motor complete and sensory incomplete. hNSPCs derived from the fetal telencephalon were grown as neurospheres and transplanted into the cord. In the control group, who did not receive cell implantation but were otherwise closely matched with the transplantation group, 15 patients with traumatic cervical SCI were included. At 1 year after cell transplantation, there was no evidence of cord damage, syrinx or tumor formation, neurological deterioration, and exacerbating neuropathic pain or spasticity. The American Spinal Injury Association Impairment Scale (AIS) grade improved in 5 of 19 transplanted patients, 2 (A → C), 1 (A → B), and 2 (B → D), whereas only one patient in the control group showed improvement (A → B). Improvements included increased motor scores, recovery of motor levels, and responses to electrophysiological studies in the transplantation group. Therefore, the transplantation of hNSPCs into cervical SCI is safe and well-tolerated and is of modest neurological benefit up to 1 year after transplants. This trial is registered with Clinical Research Information Service (CRIS), Registration Number: KCT0000879.
Collapse
|
|
39
|
Lei J, Firdaus W, Rosenzweig JM, Alrebh S, Bakhshwin A, Borbiev T, Fatemi A, Blakemore K, Johnston MV, Burd I. Murine model: maternal administration of stem cells for prevention of prematurity. Am J Obstet Gynecol 2015; 212:639.e1-10. [PMID: 25555657 DOI: 10.1016/j.ajog.2014.12.032] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 11/01/2014] [Accepted: 12/21/2014] [Indexed: 01/14/2023]
Abstract
OBJECTIVE Using a mouse model of intrauterine inflammation, we have demonstrated that exposure to inflammation induces preterm birth and perinatal brain injury. Mesenchymal stem cells (MSCs) have been shown to exhibit immunomodulatory effects in many inflammatory conditions. We hypothesized that treatment with human adipose tissue-derived MSCs may decrease the rate of preterm birth and perinatal brain injury through changes in antiinflammatory and regulatory milieu. STUDY DESIGN A mouse model of intrauterine inflammation was used with the following groups: (1) control; (2) intrauterine inflammation (lipopolysaccharide); and (3) intrauterine lipopolysaccharide+intraperitoneal (MSCs). Preterm birth was investigated. Luminex multiplex enzyme-linked immunosorbent assays were performed for protein levels of cytokines in maternal and fetal compartments. Immunofluorescent staining was used to identify and localize MSCs and to examine microglial morphologic condition and neurotoxicity in perinatal brain. Behavioral testing was performed at postnatal day 5. RESULTS Pretreatment with MSCs significantly decreased the rate of preterm birth by 21% compared with the lipopolysaccharide group (P<.01). Pretreatment was associated with increased interleukin-10 in maternal serum, increased interleukin-4 in placenta, decreased interleukin-6 in fetal brain (P<.05), decreased microglial activation (P<.05), and decreased fetal neurotoxicity (P<.05). These findings were associated with improved neurobehavioral testing at postnatal day 5 (P<.05). Injected MSCs were localized to placenta. CONCLUSION Maternally administered MSCs appear to modulate maternal and fetal immune response to intrauterine inflammation in the model and decrease preterm birth, perinatal brain injury, and motor deficits in offspring mice.
Collapse
Affiliation(s)
- Jun Lei
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Wance Firdaus
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jason M Rosenzweig
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Shorouq Alrebh
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ahmed Bakhshwin
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Talaibek Borbiev
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ali Fatemi
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; The Kennedy Krieger Institute, Baltimore, MD
| | - Karin Blakemore
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael V Johnston
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; The Kennedy Krieger Institute, Baltimore, MD
| | - Irina Burd
- Integrated Research Center for Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; The Kennedy Krieger Institute, Baltimore, MD.
| |
Collapse
|
|
40
|
Mariano ED, Teixeira MJ, Marie SKN, Lepski G. Adult stem cells in neural repair: Current options, limitations and perspectives. World J Stem Cells 2015; 7:477-482. [PMID: 25815131 PMCID: PMC4369503 DOI: 10.4252/wjsc.v7.i2.477] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/22/2014] [Accepted: 11/03/2014] [Indexed: 02/06/2023] Open
Abstract
Stem cells represent a promising step for the future of regenerative medicine. As they are able to differentiate into any cell type, tissue or organ, these cells are great candidates for treatments against the worst diseases that defy doctors and researchers around the world. Stem cells can be divided into three main groups: (1) embryonic stem cells; (2) fetal stem cells; and (3) adult stem cells. In terms of their capacity for proliferation, stem cells are also classified as totipotent, pluripotent or multipotent. Adult stem cells, also known as somatic cells, are found in various regions of the adult organism, such as bone marrow, skin, eyes, viscera and brain. They can differentiate into unipotent cells of the residing tissue, generally for the purpose of repair. These cells represent an excellent choice in regenerative medicine, every patient can be a donor of adult stem cells to provide a more customized and efficient therapy against various diseases, in other words, they allow the opportunity of autologous transplantation. But in order to start clinical trials and achieve great results, we need to understand how these cells interact with the host tissue, how they can manipulate or be manipulated by the microenvironment where they will be transplanted and for how long they can maintain their multipotent state to provide a full regeneration.
Collapse
|
|
41
|
Nicaise C, Mitrecic D, Falnikar A, Lepore AC. Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury. World J Stem Cells 2015; 7:380-398. [PMID: 25815122 PMCID: PMC4369494 DOI: 10.4252/wjsc.v7.i2.380] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/07/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Neglected for years, astrocytes are now recognized to fulfill and support many, if not all, homeostatic functions of the healthy central nervous system (CNS). During neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), astrocytes in the vicinity of degenerating areas undergo both morphological and functional changes that might compromise their intrinsic properties. Evidence from human and animal studies show that deficient astrocyte functions or loss-of-astrocytes largely contribute to increased susceptibility to cell death for neurons, oligodendrocytes and axons during ALS and SCI disease progression. Despite exciting advances in experimental CNS repair, most of current approaches that are translated into clinical trials focus on the replacement or support of spinal neurons through stem cell transplantation, while none focus on the specific replacement of astroglial populations. Knowing the important functions carried out by astrocytes in the CNS, astrocyte replacement-based therapies might be a promising approach to alleviate overall astrocyte dysfunction, deliver neurotrophic support to degenerating spinal tissue and stimulate endogenous CNS repair abilities. Enclosed in this review, we gathered experimental evidence that argue in favor of astrocyte transplantation during ALS and SCI. Based on their intrinsic properties and according to the cell type transplanted, astrocyte precursors or stem cell-derived astrocytes promote axonal growth, support mechanisms and cells involved in myelination, are able to modulate the host immune response, deliver neurotrophic factors and provide protective molecules against oxidative or excitotoxic insults, amongst many possible benefits. Embryonic or adult stem cells can even be genetically engineered in order to deliver missing gene products and therefore maximize the chance of neuroprotection and functional recovery. However, before broad clinical translation, further preclinical data on safety, reliability and therapeutic efficiency should be collected. Although several technical challenges need to be overcome, we discuss the major hurdles that have already been met or solved by targeting the astrocyte population in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology.
Collapse
|
|
42
|
Jarocha D, Milczarek O, Wedrychowicz A, Kwiatkowski S, Majka M. Continuous improvement after multiple mesenchymal stem cell transplantations in a patient with complete spinal cord injury. Cell Transplant 2015; 24:661-72. [PMID: 25807231 DOI: 10.3727/096368915x687796] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Interruption of spinal cord (SC) continuity leads to functional loss below the lesion level. The purpose of this study was to evaluate the safety and efficacy of bone marrow nucleated cell (BMNC) and multiple mesenchymal stem cell (MSC) transplantations in spinal cord injury (SCI). A patient with total SC interruption at the Th2-3 level underwent experimental therapy with BMNC and MSC transplantations followed with intensive neurorehabilitation treatment. At admission, 6 h after SCI, the patient was scored ASIA A, had a Th1 sensation level, paraplegia with sphincter palsy, and was without the ability to control trunk movement. Neurophysiology examination showed bilateral axonal damage to the motor and sensory neural fibers with no motor unit potentials or peripheral motor nerve conduction in the lower extremities. The standard therapy had been applied and had not produced any positive results. The patient was treated with autologous BMNCs injected intravenously (3.2×10(9)) and intrathecally (0.5×10(9)) 10 weeks after the SCI and with five rounds of MSCs every 3-4 months (1.3-3.65×10(7)) administered via lumbar puncture. Total number of transplanted MSC cells during the course of treatment was 1.54×10(8). There were no complications related to transplantations and no side effects related to the therapy during 2 years of treatment. The ASIA score improved from A to C/D (from 112 to 231 points). The sensation level expanded from Th1 to L3-4, and the patient's ability to control the body trunk was fully restored. Bladder filling sensation, bladder control, and anal sensation were also restored. Muscle strength in the left lower extremities improved from plegia to deep paresis (1 on the Lovett scale). The patient's ability to move lower extremities against gravity supported by the movements in quadriceps was restored. The patient gained the ability to stand in a standing frame and was able to walk with the support of hip and knee ortheses. Magnetic resonance imaging (MRI) revealed that at the Th2/Th3 level, where the hemorrhagic necrosis was initially observed, small tissue structures appeared. Our results suggest that repeated intrathecal infusions of MSCs might have the potential to produce clinically meaningful improvements for SCI patients.
Collapse
Affiliation(s)
- Danuta Jarocha
- Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Cracow, Poland
| | | | | | | | | |
Collapse
|
|
43
|
Schroeder J, Kueper J, Leon K, Liebergall M. Stem cells for spine surgery. World J Stem Cells 2015; 7:186-194. [PMID: 25621119 PMCID: PMC4300930 DOI: 10.4252/wjsc.v7.i1.186] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 10/08/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
In the past few years, stem cells have become the focus of research by regenerative medicine professionals and tissue engineers. Embryonic stem cells, although capable of differentiating into cell lineages of all three germ layers, are limited in their utilization due to ethical issues. In contrast, the autologous harvest and subsequent transplantation of adult stem cells from bone marrow, adipose tissue or blood have been experimentally utilized in the treatment of a wide variety of diseases ranging from myocardial infarction to Alzheimer’s disease. The physiologic consequences of stem cell transplantation and its impact on functional recovery have been studied in countless animal models and select clinical trials. Unfortunately, the bench to bedside translation of this research has been slow. Nonetheless, stem cell therapy has received the attention of spinal surgeons due to its potential benefits in the treatment of neural damage, muscle trauma, disk degeneration and its potential contribution to bone fusion.
Collapse
|
|
44
|
Mariano ED, Batista CM, Barbosa BJAP, Marie SKN, Teixeira MJ, Morgalla M, Tatagiba M, Li J, Lepski G. Current perspectives in stem cell therapy for spinal cord repair in humans: a review of work from the past 10 years. ARQUIVOS DE NEURO-PSIQUIATRIA 2014; 72:451-6. [PMID: 24964113 DOI: 10.1590/0004-282x20140051] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 04/16/2014] [Indexed: 12/14/2022]
Abstract
UNLABELLED Spinal cord injury (SCI) and amyotrophic laterals sclerosis (ALS) are devastating neurological conditions that affect individuals worldwide, significantly reducing quality of life, both for patients and their relatives. OBJECTIVE The present review aims to summarize the multiple restorative approaches being developed for spinal cord repair, the use of different stem cell types and the current knowledge regarding stem cell therapy. METHOD Review of the literature from the past 10 years of human studies using stem cell transplantation as the main therapy, with or without adjuvant therapies. CONCLUSION The current review offers an overview of the state of the art regarding spinal cord restoration, and serves as a starting point for future studies.
Collapse
Affiliation(s)
- Eric Domingos Mariano
- Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, SP, Brazil
| | - Chary Marquez Batista
- Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, SP, Brazil
| | | | | | - Manoel Jacobsen Teixeira
- Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, SP, Brazil
| | - Matthias Morgalla
- Department of Neurosurgery, Eberhard-Karls University, Tuebingen, Germany
| | - Marcos Tatagiba
- Department of Neurosurgery, Eberhard-Karls University, Tuebingen, Germany
| | - Jun Li
- Department of Neurosurgery, Eberhard-Karls University, Tuebingen, Germany
| | - Guilherme Lepski
- Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, SP, Brazil
| |
Collapse
|
|
45
|
Sevlever G, Miriuka S, Pitossi F. Differentiation of mesenchymal stem cells into retinal progenitor cells. Ophthalmic Res 2014; 53:28-9. [PMID: 25504311 DOI: 10.1159/000365218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 06/10/2014] [Indexed: 11/19/2022]
Affiliation(s)
- Gustavo Sevlever
- Institute of Neurological Research, FLENI, Buenos Aires, Argentina
| | | | | |
Collapse
|
|
46
|
Huang H, Sun T, Chen L, Moviglia G, Chernykh E, von Wild K, Deda H, Kang KS, Kumar A, Jeon SR, Zhang S, Brunelli G, Bohbot A, Soler MD, Li J, Cristante AF, Xi H, Onose G, Kern H, Carraro U, Saberi H, Sharma HS, Sharma A, He X, Muresanu D, Feng S, Otom A, Wang D, Iwatsu K, Lu J, Al-Zoubi A. Consensus of clinical neurorestorative progress in patients with complete chronic spinal cord injury. Cell Transplant 2014; 23 Suppl 1:S5-17. [PMID: 25302689 DOI: 10.3727/096368914x684952] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Currently, there is a lack of effective therapeutic methods to restore neurological function for chronic complete spinal cord injury (SCI) by conventional treatment. Neurorestorative strategies with positive preclinical results have been translated to the clinic, and some patients have gotten benefits and their quality of life has improved. These strategies include cell therapy, neurostimulation or neuromodulation, neuroprosthesis, neurotization or nerve bridging, and neurorehabilitation. The aim of this consensus by 31 experts from 20 countries is to show the objective evidence of clinical neurorestoration for chronic complete SCI by the mentioned neurorestorative strategies. Complete chronic SCI patients are no longer told, "nothing can be done." The clinical translation of more effective preclinical neurorestorative strategies should be encouraged as fast as possible in order to benefit patients with incurable CNS diseases. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.
Collapse
Affiliation(s)
- Hongyun Huang
- Center of Neurorestoratology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Alexandrova SA, Pinaev GP. Actin cytoskeleton reorganization in bone marrow multipotent mesenchymal stromal cells at the initial step of transendothelial migration. Biophysics (Nagoya-shi) 2014. [DOI: 10.1134/s0006350914050029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
|
|
48
|
Nakajima R, Ono M, Hara ES, Oida Y, Shinkawa S, Pham HT, Akiyama K, Sonoyama W, Maekawa K, Kuboki T. Mesenchymal stem/progenitor cell isolation from tooth extraction sockets. J Dent Res 2014; 93:1133-40. [PMID: 25170030 DOI: 10.1177/0022034514549377] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Bone marrow-derived mesenchymal stem/progenitor cells (BMSCs) are commonly used in regeneration therapy. The current primary source of BMSCs is the iliac crest; however, the procedure is associated with various burdens on the patient, including the risk of pain and infection. Hence, the possibility to collect BMSCs from other, more accessible, sources would be an attractive approach. It is well known that stem cells migrate from surrounding tissues and play important roles in wound healing. We thus hypothesized that stem/progenitor cells could be isolated from granulation tissue in the dental socket, and we subsequently collected granulation tissue from dog dental socket 3 d after tooth extraction. After enzyme digestion of the collected tissue, the cells forming colonies constituted the dental socket-derived stem/progenitor cells (dDSCs). Next, dDSCs were compared with dog BMSCs (dBMSCs) for phenotype characterization. A flow cytometric analysis showed that dDSCs were positive for CD44, CD90, and CD271 but negative for CD34 and CD45, similar to dBMSCs. dDSCs also exhibited osteogenic, adipogenic, and chondrogenic differentiation ability, similar to dBMSCs, with a higher capacity for colony formation, proliferation, and motility than dBMSCs. In addition, an in vivo ectopic bone formation assay showed that dDSCs and dBMSCs both induced hard tissue formation, although only dDSCs formed a fibrous tissue-like structure connected to the newly formed bone. Finally, we tested the ability of dDSCs to regenerate periodontal tissue in a one-wall defect model. The defects in the dDSC-transplanted group (β-TCP/PGA/dDSCs) were regenerated with cementum-like and periodontal ligament-like tissues and alveolar bone, whereas only bony tissue was observed in the control group (β-TCP/PGA). In conclusion, we identified and characterized a population of stem/progenitor cells in granulation tissue obtained from the dental socket that exhibited several characteristics similar to those of BMSCs. Dental sockets could therefore be a novel source for isolating stem/progenitor cells from bone.
Collapse
Affiliation(s)
- R Nakajima
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - M Ono
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - E S Hara
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Y Oida
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - S Shinkawa
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - H T Pham
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - K Akiyama
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - W Sonoyama
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - K Maekawa
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - T Kuboki
- Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| |
Collapse
|
|
49
|
Deer TR, Krames E, Mekhail N, Pope J, Leong M, Stanton-Hicks M, Golovac S, Kapural L, Alo K, Anderson J, Foreman RD, Caraway D, Narouze S, Linderoth B, Buvanendran A, Feler C, Poree L, Lynch P, McJunkin T, Swing T, Staats P, Liem L, Williams K. The Appropriate Use of Neurostimulation: New and Evolving Neurostimulation Therapies and Applicable Treatment for Chronic Pain and Selected Disease States. Neuromodulation 2014; 17:599-615; discussion 615. [DOI: 10.1111/ner.12204] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 01/14/2014] [Accepted: 02/07/2014] [Indexed: 12/20/2022]
Affiliation(s)
| | | | - Nagy Mekhail
- University of Kentucky-Lexington; Lexington KY USA
| | - Jason Pope
- Center for Pain Relief; Charleston WV USA
| | | | | | | | - Leo Kapural
- Carolinas Pain Institute at Brookstown; Wake Forest Baptist Health; Winston-Salem NC USA
| | - Ken Alo
- The Methodist Hospital Research Institute; Houston TX USA
- Monterey Technical Institute; Monterey Mexico
| | | | - Robert D. Foreman
- University of Oklahoma Health Sciences Center, College of Medicine; Oklahoma City OK USA
| | - David Caraway
- Center for Pain Relief, Tri-State, LLC; Huntington WV USA
| | - Samer Narouze
- Anesthesiology and Pain Medicine, Neurological Surgery; Summa Western Reserve Hospital; Cuyahoga Falls OH USA
| | - Bengt Linderoth
- Functional Neurosurgery and Applied Neuroscience Research Unit, Karolinska Institute; Karolinska University Hospital; Stockholm Sweden
| | | | - Claudio Feler
- University of Tennessee; Memphis TN USA
- Valley View Hospital; Glenwood Springs CO USA
| | - Lawrence Poree
- University of California at San Francisco; San Francisco CA USA
- Pain Clinic of Monterey Bay; Aptos CA
| | - Paul Lynch
- Arizona Pain Specialists; Scottsdale AZ USA
| | | | - Ted Swing
- Arizona Pain Specialists; Scottsdale AZ USA
| | - Peter Staats
- Premier Pain Management Centers; Shrewsbury NJ USA
- Johns Hopkins University; Baltimore MD USA
| | - Liong Liem
- St. Antonius Hospital; Nieuwegein The Netherlands
| | - Kayode Williams
- Johns Hopkins School of Medicine and Carey Business School; Baltimore MD USA
| |
Collapse
|
|
50
|
Wu Z, Zhao Z, Yu Y, Hu X, Xu W, Zeng Z, Sun YE, Cheng L. New strategies for the repair of spinal cord injury. CHINESE SCIENCE BULLETIN-CHINESE 2014. [DOI: 10.1007/s11434-014-0484-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|