|
1
|
Abbaszadeh ME, Esmaeili M, Bilabari M, Golchin A. Brain-derived neurotrophic factor (BDNF) as biomarker in stem cell-based therapies of preclinical spinal cord injury models: A systematic review. Tissue Cell 2025; 95:102875. [PMID: 40147167 DOI: 10.1016/j.tice.2025.102875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 03/12/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025]
Abstract
Stem cell-based therapies offer promising treatment for spinal cord injury (SCI) by reducing inflammation, restoring plasticity, and supporting neuroprotection and nerve regeneration. Brain-derived neurotrophic factor (BDNF) is crucial in SCI pathophysiology. This study reviews the impact of stem cells on BDNF expression in preclinical SCI models. A thorough search was performed in PubMed, Scopus, and Web of Science until June 2023, identifying studies on the effects of stem cells on BDNF in SCI. Two researchers reviewed and extracted data from relevant studies. This review is registered in the Prospective Register of Systematic Reviews (PROSPERO) with the registration number [CRD42023441466]. Out of 923 records, 51 studies met the inclusion criteria, involving rats (46 studies) and mice (5 studies). The contusion or compression model was used in 40 studies, and the transection model in 11. The most common stem cell types were bone marrow mesenchymal stem cells (BM-MSCs), neural stem cells (NSCs), and adipose-derived stem cells (ADSCs). BM-MSCs increased BDNF expression in 16 studies, NSCs in 9 studies, and ADSCs in only one study. This review highlights that BM-MSCs and NSCs are effective in enhancing BDNF expression in preclinical SCI models, while other stem cell types may not significantly affect BDNF levels. These findings suggest variability in the effectiveness of different stem cell therapies in modulating BDNF production for SCI treatment.
Collapse
Affiliation(s)
| | - Mahdi Esmaeili
- Department of Anatomy, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
| | - Maryam Bilabari
- Department of Anatomy, Faculty of Medicine, Tabriz University of Medical Sciences, Iran
| | - Ali Golchin
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Applied Cell Sciences, Medical School, Urmia University of Medical Sciences, Urmia, Iran.
| |
Collapse
|
|
2
|
Karim MS, Teranishi M, Nakagawa K, Mitsuhara T, Kurose T. High frequency exercise after human cranial bone-derived mesenchymal stem cells transplantation enhances motor functional recovery following traumatic brain injury in mice. Brain Res 2025; 1853:149527. [PMID: 39986415 DOI: 10.1016/j.brainres.2025.149527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 02/24/2025]
Abstract
Traumatic brain injury (TBI) causes a neurological impairment of the central nervous system that may induce severe motor deficits. In this study, human cranial bone-derived mesenchymal stem cells (hcMSCs) were transplanted into a mouse TBI model, and the effects of differences in exercise frequency were examined as a rehabilitation approach to improve motor function after cell transplantation. Twenty-four hours after TBI induction, phosphate-buffered saline or hcMSCs were intravenously injected into mice that were divided into a non-exercise group, a low-frequency exercise group (LF Ex), and a high-frequency exercise group (HF Ex). Beam walking tests and rotarod tests were performed over time to assess motor function. Injured brain tissues were collected for mRNA and protein expression analysis on days 8 and 35 after TBI induction. On days 28 and 35 after TBI induction, significant associations were found between hcMSC transplantation (T) and exercise factors. Notably, the T + HF Ex group exhibited a significant improvement in motor function compared with the other groups. Moreover, we found that the mRNA and protein expression levels of growth associated protein 43 (GAP-43), hepatocyte growth factor (HGF), and nerve growth factor (NGF) were significantly higher in the T + HF Ex group than in other groups. Increased expression of GAP-43 enhances synaptic regeneration and promotes functional recovery. High expression of NGF accelerates neural differentiation, and HGF ensures the efficacy of hcMSCs. These data suggest that hcMSC transplantation combined with high-frequency exercise is a promising option for TBI treatment.
Collapse
Affiliation(s)
- Md Salimul Karim
- Department of Bio-Environmental Adaptation Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masataka Teranishi
- Department of Bio-Environmental Adaptation Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Nakagawa
- Department of Biomechanics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takafumi Mitsuhara
- Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Kurose
- Department of Anatomy and Histology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
| |
Collapse
|
|
3
|
Moriarty N, Fraser TD, Hunt CPJ, Eleftheriou G, Kauhausen JA, Thompson LH, Parish CL. Exercise promotes the functional integration of human stem cell-derived neural grafts in a rodent model of Parkinson's disease. Stem Cell Reports 2025:102480. [PMID: 40280136 DOI: 10.1016/j.stemcr.2025.102480] [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: 08/19/2024] [Revised: 03/25/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
Human pluripotent stem cell (hPSC)-derived dopamine neurons can functionally integrate and reverse motor symptoms in Parkinson's disease models, motivating current clinical trials. However, dopamine neuron proportions remain low and their plasticity inferior to fetal tissue grafts. Evidence shows exercise can enhance neuron survival and plasticity, warranting investigation for hPSC-derived neural grafts. We show voluntary exercise (wheel running) significantly increases graft plasticity, accelerating motor recovery in animals receiving ectopic, but not homotopic, placed grafts, suggestive of threshold requirements. Plasticity was accompanied by increased phosphorylated extracellular signal-regulated kinase (ERK+) cells in the graft (and host), reflective of mitogen-activated protein kinase (MAPK)-ERK signaling, a downstream target of glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), proteins that were also elevated. Verifying improved graft integration was the increase in cFos+ postsynaptic striatal neurons. These findings have direct implications for the adoption of physical therapy-based approaches to enhance neural transplantation outcomes in future Parkinson's disease clinical trials.
Collapse
Affiliation(s)
- Niamh Moriarty
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Tyra D Fraser
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Cameron P J Hunt
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Georgia Eleftheriou
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Jessica A Kauhausen
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Lachlan H Thompson
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; Charles Perkins Institute, The University of Sydney, Sydney, NSW, Australia.
| | - Clare L Parish
- The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
| |
Collapse
|
|
4
|
Tucker A, Baltazar A, Eisdorfer JT, Thackray JK, Vo K, Thomas H, Tandon A, Moses J, Singletary B, Gillespie T, Smith A, Pauken A, Nadella S, Pitonak M, Letchuman S, Jang J, Totty M, Jalufka FL, Aceves M, Adler AF, Maren S, Blackmon H, McCreedy DA, Abraira V, Dulin JN. Functional synaptic connectivity of engrafted spinal cord neurons with locomotor circuitry in the injured spinal cord. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.05.644402. [PMID: 40236108 PMCID: PMC11996546 DOI: 10.1101/2025.04.05.644402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Spinal cord injury (SCI) results in significant neurological deficits, with no currently available curative therapies. Neural progenitor cell (NPC) transplantation has emerged as a promising approach for neural repair, as graft-derived neurons (GDNs) can integrate into the host spinal cord and support axon regeneration. However, the mechanisms underlying functional recovery remain poorly understood. In this study, we investigate the synaptic integration of NPC-derived neurons into locomotor circuits, the projection patterns of distinct neuronal subtypes, and their potential to modulate motor circuit activity. Using transsynaptic tracing in a mouse thoracic contusion SCI model, we found that NPC-derived neurons form synaptic connections with host locomotor circuits, albeit at low frequencies. Furthermore, we mapped the axon projections of V0C and V2a interneurons, revealing distinct termination patterns within host spinal cord laminae. To assess functional integration, we employed chemogenetic activation of GDNs, which induced muscle activity in a subset of transplanted animals. However, NPC transplantation alone did not significantly improve locomotor recovery, highlighting a key challenge in the field. Our findings suggest that while GDNs can integrate into host circuits and modulate motor activity, synaptic connectivity remains a limiting factor in functional recovery. Future studies should focus on enhancing graft-host connectivity and optimizing transplantation strategies to maximize therapeutic benefits for SCI.
Collapse
|
|
5
|
Zhang L, Yamada S, Nagoshi N, Shinozaki M, Tsuji T, Nakamura M, Okano H, Tashiro S. Combining therapeutic strategies with rehabilitation improves motor recovery in animal models of spinal cord injury: A systematic review and meta-analysis. Ann Phys Rehabil Med 2025; 68:101911. [PMID: 39798215 DOI: 10.1016/j.rehab.2024.101911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 07/25/2024] [Accepted: 08/18/2024] [Indexed: 01/15/2025]
Abstract
BACKGROUND Despite the lack of clinically validated strategies for treating spinal cord injury (SCI), combining therapeutic strategies with rehabilitation is believed to promote recovery of motor function; however, current research findings are inconsistent. OBJECTIVES To explore whether combination therapy involving therapy and rehabilitative training (CIRT) has a synergistic effect on motor function recovery in animal models of SCI. METHODS We conducted a systematic review and meta-analysis of studies identified in a keyword search of 6 databases and extracted open-field motor scores from the Basso Mouse Scale (BMS) and the Basso, Beattie, and Bresnahan Locomotor Rating Scale (BBB) for meta-analysis using a weighted mean difference (WMD) and 95 % CI. We also performed qualitative synthesis and analysis of secondary outcome measures related to histological improvements and adverse effects. RESULTS Eighty-seven preclinical studies were included. Combination treatment with treadmill training resulted in a significant improvement in motor function (1.40, 95 % CI 0.82 to 1.98, P < 0.01, I2 = 49 %), especially when initiated 1-2 weeks post-injury (1.77, 95 % CI 1.10 to 2.45, P < 0.01, I2 = 33 %) in rats. In mice, CIRT lasting <6 weeks may enhance recovery (0.95, 95 % CI 0.49 to 1.40, P < 0.01, I2 = 33 %). Although there is a trend toward better outcomes in the chronic phase, insufficient sample sizes prevent definitive conclusions from being drawn. Combined therapy also enhances the reorganization of inhibitory synaptic structures and functions, without aggravating allodynia or spasticity. CONCLUSIONS This systematic review and meta-analysis suggest that CIRT can lead to superior motor function recovery compared to single-modality therapy (SMT) in animal models of SCI, with no significant adverse effects on allodynia or spasticity. However, the efficacy of CIRT depends on various factors, and further research is needed to establish optimal treatment strategies and understand the underlying mechanisms of recovery.
Collapse
Affiliation(s)
- Liang Zhang
- Department of Rehabilitation Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
| | - Shin Yamada
- Department of Rehabilitation Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
| | - Narihito Nagoshi
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582
| | - Tetsuya Tsuji
- Department of Rehabilitation Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582
| | - Syoichi Tashiro
- Department of Rehabilitation Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan; Department of Rehabilitation Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| |
Collapse
|
|
6
|
Daadi MM, Snyder EY. Exercise your graft - An important lesson for cell replacement therapy for Parkinson's disease. Exp Neurol 2025; 385:115085. [PMID: 39631719 DOI: 10.1016/j.expneurol.2024.115085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 08/24/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024]
Abstract
Parkinson's disease (PD) is a complex multisystem, chronic and so far, incurable disease affecting millions of people worldwide. With the continuing need for better therapeutic options for PD, there is a global renewed interest in cell replacement therapy due to progress in using pluripotent stem cells as an unlimited source of dopaminergic (DA) neurons for cell transplantation. Despite the significant progress made, obstacles remain that interfere with the restoration of functional circuits by DA grafts. The functional connectivity between DA grafts and host cells may be enhanced by adjunctive therapies, such as physical activity. Exercise modalities, such as use of treadmill, enhance neuroplasticity and improve motor and cognitive functions in PD patients. The patients are able to re-learn movement and adjust their posture, which, in turn, results in short term-reduced rigidity and improved stride length and cadence. By stabilizing selected active inputs and eliminating inactive ones, activity-dependent mechanisms fine-tune new neural circuits for optimal connection and physiological function. This communication will review the mechanisms and synergies between cell replacement therapy and physical and cognitive training to enhance induced pluripotent stem cell-mediated functional reinnervation of the striatum in PD.
Collapse
Affiliation(s)
- Marcel M Daadi
- Department of Cell Systems & Anatomy, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA; Department of Radiology, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA.
| | - Evan Y Snyder
- Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Sanford Burnham Prebys Medical Discovery Institute, Center for Stem Cells & Regenerative Medicine, La Jolla, CA 92037, USA
| |
Collapse
|
|
7
|
Nagoshi N, Hashimoto S, Okano H, Nakamura M. Regenerative medicine for spinal cord injury using induced pluripotent stem cells: from animals to humans. Pain 2024; 165:S76-S81. [PMID: 39560418 DOI: 10.1097/j.pain.0000000000003306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 05/05/2024] [Indexed: 11/20/2024]
Abstract
ABSTRACT Spinal cord injury (SCI) results in permanent neurological dysfunction and neuropathic pain. To address this pathology, we recently conducted a clinical study in which we transplanted neural precursor cells (NPCs) derived from human induced pluripotent stem cells into patients during the subacute phase of SCI. One of the therapeutic mechanisms of cell transplantation is the formation of synaptic connections with the host's neural tissues, which we demonstrated using a chemogenetic tool. In addition, we have developed innovative strategies to enhance the effectiveness of cell transplantation through gene therapy. Moreover, our current study is focused on developing cell therapy for chronic SCI, a more challenging pathology characterized by the formation of cavities and scar tissue. In such situations, transplanting NPCs with neurogenic properties could effectively penetrate scar tissue and form functional synapses with the host neurons. To improve the outcomes of cell transplantation alone, we have found that incorporating rehabilitation is beneficial. In animal models of SCI, we have established an effective rehabilitative training program in which NPCs were transplanted during the chronic phase. Robotic rehabilitation has demonstrated improvements in gait ability and trunk function in clinical situations. Therefore, regenerative medicine shows promise for chronic SCI, particularly when rehabilitation strategies are incorporated.
Collapse
Affiliation(s)
| | | | - Hideyuki Okano
- Physiology, Keio University School of Medicine, Tokyo, Japan
- Keio University Regenerative Medicine Center, Kawasaki, Japan
| | | |
Collapse
|
|
8
|
Deng C, Aldali F, Luo H, Chen H. Regenerative rehabilitation: a novel multidisciplinary field to maximize patient outcomes. MEDICAL REVIEW (2021) 2024; 4:413-434. [PMID: 39444794 PMCID: PMC11495474 DOI: 10.1515/mr-2023-0060] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 05/15/2024] [Indexed: 10/25/2024]
Abstract
Regenerative rehabilitation is a novel and rapidly developing multidisciplinary field that converges regenerative medicine and rehabilitation science, aiming to maximize the functions of disabled patients and their independence. While regenerative medicine provides state-of-the-art technologies that shed light on difficult-to-treated diseases, regenerative rehabilitation offers rehabilitation interventions to improve the positive effects of regenerative medicine. However, regenerative scientists and rehabilitation professionals focus on their aspects without enough exposure to advances in each other's field. This disconnect has impeded the development of this field. Therefore, this review first introduces cutting-edge technologies such as stem cell technology, tissue engineering, biomaterial science, gene editing, and computer sciences that promote the progress pace of regenerative medicine, followed by a summary of preclinical studies and examples of clinical investigations that integrate rehabilitative methodologies into regenerative medicine. Then, challenges in this field are discussed, and possible solutions are provided for future directions. We aim to provide a platform for regenerative and rehabilitative professionals and clinicians in other areas to better understand the progress of regenerative rehabilitation, thus contributing to the clinical translation and management of innovative and reliable therapies.
Collapse
Affiliation(s)
- Chunchu Deng
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Fatima Aldali
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hongmei Luo
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hong Chen
- Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
9
|
Freria CM, Lu P. Combining neural progenitor cell transplant and rehabilitation for enhanced recovery after cervical spinal cord injury. Neural Regen Res 2024; 19:1433-1434. [PMID: 38051883 PMCID: PMC10883491 DOI: 10.4103/1673-5374.387993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 09/12/2023] [Indexed: 12/07/2023] Open
Affiliation(s)
- Camila M Freria
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
| | - Paul Lu
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
- Veterans Administration San Diego Healthcare System, San Diego, CA, USA
| |
Collapse
|
|
10
|
Fischer G, Bättig L, Stienen MN, Curt A, Fehlings MG, Hejrati N. Advancements in neuroregenerative and neuroprotective therapies for traumatic spinal cord injury. Front Neurosci 2024; 18:1372920. [PMID: 38812974 PMCID: PMC11133582 DOI: 10.3389/fnins.2024.1372920] [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: 01/18/2024] [Accepted: 04/10/2024] [Indexed: 05/31/2024] Open
Abstract
Traumatic spinal cord injuries (SCIs) continue to be a major healthcare concern, with a rising prevalence worldwide. In response to this growing medical challenge, considerable scientific attention has been devoted to developing neuroprotective and neuroregenerative strategies aimed at improving the prognosis and quality of life for individuals with SCIs. This comprehensive review aims to provide an up-to-date and thorough overview of the latest neuroregenerative and neuroprotective therapies currently under investigation. These strategies encompass a multifaceted approach that include neuropharmacological interventions, cell-based therapies, and other promising strategies such as biomaterial scaffolds and neuro-modulation therapies. In addition, the review discusses the importance of acute clinical management, including the role of hemodynamic management as well as timing and technical aspects of surgery as key factors mitigating the secondary injury following SCI. In conclusion, this review underscores the ongoing scientific efforts to enhance patient outcomes and quality of life, focusing on upcoming strategies for the management of traumatic SCI. Each section provides a working knowledge of the fundamental preclinical and patient trials relevant to clinicians while underscoring the pathophysiologic rationale for the therapies.
Collapse
Affiliation(s)
- Gregor Fischer
- Department of Neurosurgery, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
- Spine Center of Eastern Switzerland, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
| | - Linda Bättig
- Department of Neurosurgery, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
- Spine Center of Eastern Switzerland, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
| | - Martin N. Stienen
- Department of Neurosurgery, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
- Spine Center of Eastern Switzerland, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
| | - Armin Curt
- Spinal Cord Injury Center, University Hospital Balgrist, Zurich, Switzerland
| | - Michael G. Fehlings
- Division of Neurosurgery and Spine Program, Department of Surgery, University of Toronto, Toronto, ON, Canada
- Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Nader Hejrati
- Department of Neurosurgery, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
- Spine Center of Eastern Switzerland, Cantonal Hospital St.Gallen, Medical School of St.Gallen, St.Gallen, Switzerland
| |
Collapse
|
|
11
|
Daadi EW, Daadi ES, Oh T, Li M, Kim J, Daadi MM. Combining physical & cognitive training with iPSC-derived dopaminergic neuron transplantation promotes graft integration & better functional outcome in parkinsonian marmosets. Exp Neurol 2024; 374:114694. [PMID: 38272159 DOI: 10.1016/j.expneurol.2024.114694] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/09/2024] [Accepted: 01/15/2024] [Indexed: 01/27/2024]
Abstract
Parkinson's disease (PD) is a relentlessly progressive and currently incurable neurodegenerative disease with significant unmet medical needs. Since PD stems from the degeneration of midbrain dopaminergic (DA) neurons in a defined brain location, PD patients are considered optimal candidates for cell replacement therapy. Clinical trials for cell transplantation in PD are beginning to re-emerge worldwide with a new focus on induced pluripotent stem cells (iPSCs) as a source of DA neurons since they can be derived from adult somatic cells and produced in large quantities under current good manufacturing practices. However, for this therapeutic strategy to be realized as a viable clinical option, fundamental translational challenges need to be addressed including the manufacturing process, purity and efficacy of the cells, the method of delivery, the extent of host reinnervation and the impact of patient-centered adjunctive interventions. In this study we report on the impact of physical and cognitive training (PCT) on functional recovery in the nonhuman primate (NHP) model of PD after cell transplantation. We observed that at 6 months post-transplant, the PCT group returned to normal baseline in their daily activity measured by actigraphy, significantly improved in their sensorimotor and cognitive tasks, and showed enhanced synapse formation between grafted cells and host cells. We also describe a robust, simple, efficient, scalable, and cost-effective manufacturing process of engraftable DA neurons derived from iPSCs. This study suggests that integrating PCT with cell transplantation therapy could promote optimal graft functional integration and better outcome for patients with PD.
Collapse
Affiliation(s)
- Etienne W Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA
| | - Elyas S Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA
| | - Thomas Oh
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA
| | - Mingfeng Li
- Department of Neuroscience, Yale School of Medicine, New Haven, CT 06510, USA
| | - Jeffrey Kim
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA; Department of Cell Systems & Anatomy, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA
| | - Marcel M Daadi
- Southwest National Primate Research Center, Texas Biomedical Research Institute, 8715 W. Military Drive, San Antonio, TX 78227, USA; Department of Cell Systems & Anatomy, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA; Department of Radiology, Long School of Medicine, University of Texas Health at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229, USA.
| |
Collapse
|
|
12
|
Saijo Y, Nagoshi N, Kawai M, Kitagawa T, Suematsu Y, Ozaki M, Shinozaki M, Kohyama J, Shibata S, Takeuchi K, Nakamura M, Yuzaki M, Okano H. Human-induced pluripotent stem cell-derived neural stem/progenitor cell ex vivo gene therapy with synaptic organizer CPTX for spinal cord injury. Stem Cell Reports 2024; 19:383-398. [PMID: 38366597 PMCID: PMC10937157 DOI: 10.1016/j.stemcr.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 01/12/2024] [Accepted: 01/15/2024] [Indexed: 02/18/2024] Open
Abstract
The transplantation of neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise in spinal cord injury (SCI) model animals. Establishing a functional synaptic connection between the transplanted and host neurons is crucial for motor function recovery. To boost therapeutic outcomes, we developed an ex vivo gene therapy aimed at promoting synapse formation by expressing the synthetic excitatory synapse organizer CPTX in hiPSC-NS/PCs. Using an immunocompromised transgenic rat model of SCI, we evaluated the effects of transplanting CPTX-expressing hiPSC-NS/PCs using histological and functional analyses. Our findings revealed a significant increase in excitatory synapse formation at the transplantation site. Retrograde monosynaptic tracing indicated extensive integration of transplanted neurons into the surrounding neuronal tracts facilitated by CPTX. Consequently, locomotion and spinal cord conduction significantly improved. Thus, ex vivo gene therapy targeting synapse formation holds promise for future clinical applications and offers potential benefits to individuals with SCI.
Collapse
Affiliation(s)
- Yusuke Saijo
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
| | - Momotaro Kawai
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Takahiro Kitagawa
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yu Suematsu
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masahiro Ozaki
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Jun Kohyama
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Shinsuke Shibata
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Division of Microscopic Anatomy, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Kosei Takeuchi
- Department of Medical Cell Biology, Aichi Medical University School of Medicine, 1-1 Yazago-Karimata, Nagakute, Aichi 430-1195, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Michisuke Yuzaki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
| |
Collapse
|
|
13
|
Jagrit V, Koffler J, Dulin JN. Combinatorial strategies for cell transplantation in traumatic spinal cord injury. Front Neurosci 2024; 18:1349446. [PMID: 38510468 PMCID: PMC10951004 DOI: 10.3389/fnins.2024.1349446] [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: 12/04/2023] [Accepted: 02/20/2024] [Indexed: 03/22/2024] Open
Abstract
Spinal cord injury (SCI) substantially reduces the quality of life of affected individuals. Recovery of function is therefore a primary concern of the patient population and a primary goal for therapeutic interventions. Currently, even with growing numbers of clinical trials, there are still no effective treatments that can improve neurological outcomes after SCI. A large body of work has demonstrated that transplantation of neural stem/progenitor cells (NSPCs) can promote regeneration of the injured spinal cord by providing new neurons that can integrate into injured host neural circuitry. Despite these promising findings, the degree of functional recovery observed after NSPC transplantation remains modest. It is evident that treatment of such a complex injury cannot be addressed with a single therapeutic approach. In this mini-review, we discuss combinatorial strategies that can be used along with NSPC transplantation to promote spinal cord regeneration. We begin by introducing bioengineering and neuromodulatory approaches, and highlight promising work using these strategies in integration with NSPCs transplantation. The future of NSPC transplantation will likely include a multi-factorial approach, combining stem cells with biomaterials and/or neuromodulation as a promising treatment for SCI.
Collapse
Affiliation(s)
- Vipin Jagrit
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Jacob Koffler
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
- Veterans Affairs Medical Center, San Diego, CA, United States
| | - Jennifer N. Dulin
- Department of Biology, Texas A&M University, College Station, TX, United States
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, United States
| |
Collapse
|
|
14
|
Hosseini SM, Borys B, Karimi-Abdolrezaee S. Neural stem cell therapies for spinal cord injury repair: an update on recent preclinical and clinical advances. Brain 2024; 147:766-793. [PMID: 37975820 DOI: 10.1093/brain/awad392] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/22/2023] [Accepted: 11/02/2023] [Indexed: 11/19/2023] Open
Abstract
Traumatic spinal cord injury (SCI) is a leading cause of lifelong disabilities. Permanent sensory, motor and autonomic impairments after SCI are substantially attributed to degeneration of spinal cord neurons and axons, and disintegration of neural network. To date, minimal regenerative treatments are available for SCI with an unmet need for new therapies to reconstruct the damaged spinal cord neuron-glia network and restore connectivity with the supraspinal pathways. Multipotent neural precursor cells (NPCs) have a unique capacity to generate neurons, oligodendrocytes and astrocytes. Due to this capacity, NPCs have been an attractive cell source for cellular therapies for SCI. Transplantation of NPCs has been extensively tested in preclinical models of SCI in the past two decades. These studies have identified opportunities and challenges associated with NPC therapies. While NPCs have the potential to promote neuroregeneration through various mechanisms, their low long-term survival and integration within the host injured spinal cord limit the functional benefits of NPC-based therapies for SCI. To address this challenge, combinatorial strategies have been developed to optimize the outcomes of NPC therapies by enriching SCI microenvironment through biomaterials, genetic and pharmacological therapies. In this review, we will provide an in-depth discussion on recent advances in preclinical NPC-based therapies for SCI. We will discuss modes of actions and mechanism by which engrafted NPCs contribute to the repair process and functional recovery. We will also provide an update on current clinical trials and new technologies that have facilitated preparation of medical-grade human NPCs suitable for transplantation in clinical studies.
Collapse
Affiliation(s)
- Seyed Mojtaba Hosseini
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
- Manitoba Multiple Sclerosis Research Center, Winnipeg, Manitoba R3E 0J9, Canada
| | - Ben Borys
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
| | - Soheila Karimi-Abdolrezaee
- Department of Physiology and Pathophysiology, Spinal Cord Research Centre, Rady Faculty of Health Sciences, University of Manitoba Winnipeg, Manitoba R3E 0J9, Canada
- Manitoba Multiple Sclerosis Research Center, Winnipeg, Manitoba R3E 0J9, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada
| |
Collapse
|
|
15
|
Tashiro S, Shibata S, Nagoshi N, Zhang L, Yamada S, Tsuji T, Nakamura M, Okano H. Do Pharmacological Treatments Act in Collaboration with Rehabilitation in Spinal Cord Injury Treatment? A Review of Preclinical Studies. Cells 2024; 13:412. [PMID: 38474376 PMCID: PMC10931131 DOI: 10.3390/cells13050412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/18/2024] [Accepted: 02/24/2024] [Indexed: 03/14/2024] Open
Abstract
There is no choice other than rehabilitation as a practical medical treatment to restore impairments or improve activities after acute treatment in people with spinal cord injury (SCI); however, the effect is unremarkable. Therefore, researchers have been seeking effective pharmacological treatments. These will, hopefully, exert a greater effect when combined with rehabilitation. However, no review has specifically summarized the combinatorial effects of rehabilitation with various medical agents. In the current review, which included 43 articles, we summarized the combinatorial effects according to the properties of the medical agents, namely neuromodulation, neurotrophic factors, counteraction to inhibitory factors, and others. The recovery processes promoted by rehabilitation include the regeneration of tracts, neuroprotection, scar tissue reorganization, plasticity of spinal circuits, microenvironmental change in the spinal cord, and enforcement of the musculoskeletal system, which are additive, complementary, or even synergistic with medication in many cases. However, there are some cases that lack interaction or even demonstrate competition between medication and rehabilitation. A large fraction of the combinatorial mechanisms remains to be elucidated, and very few studies have investigated complex combinations of these agents or targeted chronically injured spinal cords.
Collapse
Affiliation(s)
- Syoichi Tashiro
- Department of Rehabilitation Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
- Department of Rehabilitation Medicine, Faculty of Medicine, Kyorin University, Tokyo 181-8611, Japan
| | - Shinsuke Shibata
- Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Liang Zhang
- Department of Rehabilitation Medicine, Faculty of Medicine, Kyorin University, Tokyo 181-8611, Japan
| | - Shin Yamada
- Department of Rehabilitation Medicine, Faculty of Medicine, Kyorin University, Tokyo 181-8611, Japan
| | - Tetsuya Tsuji
- Department of Rehabilitation Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, School of Medicine, Keio University, Tokyo 160-8582, Japan
| |
Collapse
|
|
16
|
Calderone A, Cardile D, De Luca R, Quartarone A, Corallo F, Calabrò RS. Brain Plasticity in Patients with Spinal Cord Injuries: A Systematic Review. Int J Mol Sci 2024; 25:2224. [PMID: 38396902 PMCID: PMC10888628 DOI: 10.3390/ijms25042224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 02/09/2024] [Accepted: 02/11/2024] [Indexed: 02/25/2024] Open
Abstract
A spinal cord injury (SCI) causes changes in brain structure and brain function due to the direct effects of nerve damage, secondary mechanisms, and long-term effects of the injury, such as paralysis and neuropathic pain (NP). Recovery takes place over weeks to months, which is a time frame well beyond the duration of spinal shock and is the phase in which the spinal cord remains unstimulated below the level of injury and is associated with adaptations occurring throughout the nervous system, often referred to as neuronal plasticity. Such changes occur at different anatomical sites and also at different physiological and molecular biological levels. This review aims to investigate brain plasticity in patients with SCIs and its influence on the rehabilitation process. Studies were identified from an online search of the PubMed, Web of Science, and Scopus databases. Studies published between 2013 and 2023 were selected. This review has been registered on OSF under (n) 9QP45. We found that neuroplasticity can affect the sensory-motor network, and different protocols or rehabilitation interventions can activate this process in different ways. Exercise rehabilitation training in humans with SCIs can elicit white matter plasticity in the form of increased myelin water content. This review has demonstrated that SCI patients may experience plastic changes either spontaneously or as a result of specific neurorehabilitation training, which may lead to positive outcomes in functional recovery. Clinical and experimental evidence convincingly displays that plasticity occurs in the adult CNS through a variety of events following traumatic or non-traumatic SCI. Furthermore, efficacy-based, pharmacological, and genetic approaches, alone or in combination, are increasingly effective in promoting plasticity.
Collapse
Affiliation(s)
- Andrea Calderone
- Graduate School of Health Psychology, Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy;
| | - Davide Cardile
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C.da Casazza, 98124 Messina, Italy
| | - Rosaria De Luca
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C.da Casazza, 98124 Messina, Italy
| | - Angelo Quartarone
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C.da Casazza, 98124 Messina, Italy
| | - Francesco Corallo
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C.da Casazza, 98124 Messina, Italy
| | - Rocco Salvatore Calabrò
- IRCCS Centro Neurolesi Bonino-Pulejo, S.S. 113 Via Palermo, C.da Casazza, 98124 Messina, Italy
| |
Collapse
|
|
17
|
Yoshida T, Tashiro S, Nagoshi N, Shinozaki M, Shibata T, Inoue M, Ogawa S, Shibata S, Tsuji T, Okano H, Nakamura M. Chronic Spinal Cord Injury Regeneration with Combined Therapy Comprising Neural Stem/Progenitor Cell Transplantation, Rehabilitation, and Semaphorin 3A Inhibitor. eNeuro 2024; 11:ENEURO.0378-23.2024. [PMID: 38262737 PMCID: PMC10866332 DOI: 10.1523/eneuro.0378-23.2024] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 12/20/2023] [Accepted: 01/12/2024] [Indexed: 01/25/2024] Open
Abstract
Spinal cord injury (SCI) often results in various long-term sequelae, and chronically injured spinal cords exhibit a refractory feature, showing a limited response to cell transplantation therapies. To our knowledge, no preclinical studies have reported a treatment approach with results surpassing those of treatment comprising rehabilitation alone. In this study of rats with SCI, we propose a novel combined therapy involving a semaphorin 3A inhibitor (Sema3Ai), which enhances axonal regeneration, as the third treatment element in combination with neural stem/progenitor cell transplantation and rehabilitation. This comprehensive therapeutic strategy achieved significant improvements in host-derived neuronal and oligodendrocyte differentiation at the SCI epicenter and promoted axonal regeneration even in the chronically injured spinal cord. The elongated axons established functional electrical connections, contributing to significant enhancements in locomotor mobility when compared with animals treated with transplantation and rehabilitation. As a result, our combined transplantation, Sema3Ai, and rehabilitation treatment have the potential to serve as a critical step forward for chronic SCI patients, improving their ability to regain motor function.
Collapse
Affiliation(s)
- Takashi Yoshida
- Departments of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Syoichi Tashiro
- Departments of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Narihito Nagoshi
- Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Munehisa Shinozaki
- Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Takahiro Shibata
- Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Mitsuhiro Inoue
- Regenerative and Cellular Medicine Kobe Center, Sumitomo Pharma, Kobe, Hyogo 650-0047, Japan
| | - Shoji Ogawa
- Formulation Research & Development Laboratories, Sumitomo Pharma, Suita, Osaka 564-0053, Japan
| | - Shinsuke Shibata
- Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
- Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata-shi, Niigata 951-8510, Japan
| | - Tetsuya Tsuji
- Departments of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masaya Nakamura
- Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| |
Collapse
|
|
18
|
Kim SJ, Ko WK, Han GH, Lee D, Cho MJ, Sheen SH, Sohn S. Axon guidance gene-targeted siRNA delivery system improves neural stem cell transplantation therapy after spinal cord injury. Biomater Res 2023; 27:101. [PMID: 37840145 PMCID: PMC10577901 DOI: 10.1186/s40824-023-00434-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/18/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND Neural stem cells (NSCs) derived from the embryonic spinal cord are excellent candidates for the cellular regeneration of lost neural cells after spinal cord injury (SCI). Semaphorin 3 A (Sema3A) is well known as being implicated in the major axon guidance of the growth cone as a repulsive function during the development of the central nervous system, yet its function in NSC transplantation therapy for SCI has not been investigated. Here, we report for the first time that embryonic spinal cord-derived NSCs significantly express Sema3A in the SCI environment, potentially facilitating inhibition of cell proliferation after transplantation. METHODS siRNA-Sema3A was conjugated with poly-l-lysin-coated gold nanoparticles (AuNPs) through a charge interaction process. NSCs were isolated from embryonic spinal cords of rats. Then, the cells were embedded into a dual-degradable hydrogel with the siRNA- Sema3A loaded-AuNPs and transplanted after complete SCI in rats. RESULTS The knockdown of Sema3A by delivering siRNA nanoparticles via dual-degradable hydrogels led to a significant increase in cell survival and neuronal differentiation of the transplanted NSCs after SCI. Of note, the knockdown of Sema3A increased the synaptic connectivity of transplanted NSC in the injured spinal cord. Moreover, extracellular matrix molecule and functional recovery were significantly improved in Sema3A-inhibited rats compared to those in rats with only NSCs transplanted. CONCLUSIONS These findings demonstrate the important role of Sema3A in NSC transplantation therapy, which may be considered as a future cell transplantation therapy for SCI cases.
Collapse
Affiliation(s)
- Seong Jun Kim
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang- gu, Seongnam-si, 13496, Gyeonggi-do, Republic of Korea
- Department of Biomedical Science, CHA University, 335, Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea
| | - Wan-Kyu Ko
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang- gu, Seongnam-si, 13496, Gyeonggi-do, Republic of Korea
- Department of Biomedical Science, CHA University, 335, Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea
| | - Gong Ho Han
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang- gu, Seongnam-si, 13496, Gyeonggi-do, Republic of Korea
- Department of Biomedical Science, CHA University, 335, Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea
| | - Daye Lee
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang- gu, Seongnam-si, 13496, Gyeonggi-do, Republic of Korea
- Department of Biomedical Science, CHA University, 335, Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea
| | - Min Jai Cho
- Department of Neurosurgery, Chungbuk National University, 776, 1Sunhawn-ro, Seowon-gu, Cheongju-si, 28644, Republic of Korea
| | - Seung Hun Sheen
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang- gu, Seongnam-si, 13496, Gyeonggi-do, Republic of Korea
| | - Seil Sohn
- Department of Neurosurgery, CHA Bundang Medical Center, CHA University, 59, Yatap-ro, Bundang- gu, Seongnam-si, 13496, Gyeonggi-do, Republic of Korea.
- Department of Biomedical Science, CHA University, 335, Pangyo-ro, Bundang-gu, Seongnam-si, 13488, Gyeonggi-do, Republic of Korea.
| |
Collapse
|
|
19
|
Shibata T, Tashiro S, Nakamura M, Okano H, Nagoshi N. A Review of Treatment Methods Focusing on Human Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cell Transplantation for Chronic Spinal Cord Injury. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1235. [PMID: 37512047 PMCID: PMC10384869 DOI: 10.3390/medicina59071235] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 06/19/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023]
Abstract
Cell transplantation therapy using human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) has attracted attention as a regenerative therapy for spinal cord injury (SCI), and its efficacy in treating the subacute phase of SCI has been reported in numerous studies. However, few studies have focused on treatment in the chronic phase, which accounts for many patients, suggesting that there are factors that are difficult to overcome in the treatment of chronic SCI. The search for therapeutic strategies that focus on chronic SCI is fraught with challenges, and the combination of different therapies is thought to be the key to a solution. In addition, many issues remain to be addressed, including the investigation of therapeutic approaches for more severe injury models of chronic SCI and the acquisition of practical motor function. This review summarizes the current progress in regenerative therapy for SCI and discusses the prospects for regenerative medicine, particularly in animal models of chronic SCI.
Collapse
Affiliation(s)
- Takahiro Shibata
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Syoichi Tashiro
- Department of Rehabilitation Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| |
Collapse
|
|
20
|
Keikhaei R, Abdi E, Darvishi M, Ghotbeddin Z, Hamidabadi HG. Combined treatment of high-intensity interval training with neural stem cell generation on contusive model of spinal cord injury in rats. Brain Behav 2023; 13:e3043. [PMID: 37165750 PMCID: PMC10338768 DOI: 10.1002/brb3.3043] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 04/17/2023] [Accepted: 04/20/2023] [Indexed: 05/12/2023] Open
Abstract
INTRODUCTION Spinal cord injury (SCI) leads to inflammation, axonal degeneration, and gliosis. A combined treatment of exercise and neural stem cells (NSC) has been proposed to improve neural repair. This study evaluated a combined treatment of high-intensity interval training (HIIT) with NSC generation from adipose-derived stem cells (ADSCs) on a contusive model of SCI in rats. MATERIALS AND METHODS In vitro, rat ADSCs were isolated from the perinephric regions of Sprague-Dawley rats using enzymatic digestion. The ADSCs were transdifferentiated into neurospheres using B27, EGF, and bFGF. After production of NSC, they were labeled using green fluorescent protein (GFP). For the in vivo study, rats were divided into eight groups: control group, sham operation group, sham operation + HIIT group, sham operation + NSC group, SCI group, SCI + HIIT group, SCI + NSC group, and SCI/HIIT/NSC group. Laminectomy was carried out at the T12 level using the impactor system. HIIT was performed three times per week. To assess behavioral function, the Basso-Beattie-Bresnahan (BBB) locomotor test and H-reflex was carried out once a week for 12 weeks. We examined glial fibrillary acidic protein (GFAP), S100β, and NF200 expression. RESULTS NSC transplantation, HIIT and combined therapy with NSC transplantation, and the HIIT protocol improved locomotor function with decreased maximum H to maximum M reflexes (H/M ratio) and increased the Basso-Beattie-Bresnahan score. CONCLUSION Combined therapy in contused rats using the HIIT protocol and neurosphere-derived NSC transplantation improves functional and histological outcomes.
Collapse
Affiliation(s)
- Reza Keikhaei
- School of MedicineTehran University of Medical SciencesTehranIran
| | - Elahe Abdi
- Isfahan Neurosciences Research CenterIsfahan University of Medical SciencesIsfahanIran
| | - Marzieh Darvishi
- Shefa Neuroscience Research CenterKhatam Alanbia HospitalTehranIran
- Department of Anatomy, Faculty of MedicineIlam University of Medical SciencesIlamIran
| | - Zohreh Ghotbeddin
- Department of Physiology, Faculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
- Stem Cell and Transgenic Technology Research CenterShahid Chamran University of AhvazAhvazIran
| | - Hatef Ghasemi Hamidabadi
- Department of Anatomy & Cell Biology, Faculty of MedicineMazandaran University of Medical SciencesSariIran
- Immunogenetic Research CenterDepartment of Anatomy & Cell Biology, Faculty of MedicineMazandaran University of Medical SciencesSariIran
| |
Collapse
|
|
21
|
Aceves M, Tucker A, Chen J, Vo K, Moses J, Amar Kumar P, Thomas H, Miranda D, Dampf G, Dietz V, Chang M, Lukose A, Jang J, Nadella S, Gillespie T, Trevino C, Buxton A, Pritchard AL, Green P, McCreedy DA, Dulin JN. Developmental stage of transplanted neural progenitor cells influences anatomical and functional outcomes after spinal cord injury in mice. Commun Biol 2023; 6:544. [PMID: 37208439 PMCID: PMC10199026 DOI: 10.1038/s42003-023-04893-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/02/2023] [Indexed: 05/21/2023] Open
Abstract
Neural progenitor cell (NPC) transplantation is a promising therapeutic strategy for replacing lost neurons following spinal cord injury (SCI). However, how graft cellular composition influences regeneration and synaptogenesis of host axon populations, or recovery of motor and sensory functions after SCI, is poorly understood. We transplanted developmentally-restricted spinal cord NPCs, isolated from E11.5-E13.5 mouse embryos, into sites of adult mouse SCI and analyzed graft axon outgrowth, cellular composition, host axon regeneration, and behavior. Earlier-stage grafts exhibited greater axon outgrowth, enrichment for ventral spinal cord interneurons and Group-Z spinal interneurons, and enhanced host 5-HT+ axon regeneration. Later-stage grafts were enriched for late-born dorsal horn interneuronal subtypes and Group-N spinal interneurons, supported more extensive host CGRP+ axon ingrowth, and exacerbated thermal hypersensitivity. Locomotor function was not affected by any type of NPC graft. These findings showcase the role of spinal cord graft cellular composition in determining anatomical and functional outcomes following SCI.
Collapse
Affiliation(s)
- Miriam Aceves
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA
| | - Ashley Tucker
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA
| | - Joseph Chen
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Katie Vo
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Joshua Moses
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | | | - Hannah Thomas
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Diego Miranda
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Gabrielle Dampf
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Valerie Dietz
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Matthew Chang
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Aleena Lukose
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Julius Jang
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Sneha Nadella
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Tucker Gillespie
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Christian Trevino
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
| | - Andrew Buxton
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Anna L Pritchard
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | | | - Dylan A McCreedy
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA
- Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA
| | - Jennifer N Dulin
- Department of Biology, Texas A&M University, College Station, TX, 77843, USA.
- Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, 77843, USA.
| |
Collapse
|
|
22
|
Hashimoto S, Nagoshi N, Shinozaki M, Nakanishi K, Suematsu Y, Shibata T, Kawai M, Kitagawa T, Ago K, Kamata Y, Yasutake K, Koya I, Ando Y, Minoda A, Shindo T, Shibata S, Matsumoto M, Nakamura M, Okano H. Microenvironmental modulation in tandem with human stem cell transplantation enhances functional recovery after chronic complete spinal cord injury. Biomaterials 2023; 295:122002. [PMID: 36736008 DOI: 10.1016/j.biomaterials.2023.122002] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/16/2022] [Accepted: 01/12/2023] [Indexed: 01/27/2023]
Abstract
While rapid advancements in regenerative medicine strategies for spinal cord injury (SCI) have been made, most research in this field has focused on the early stages of incomplete injury. However, the majority of patients experience chronic severe injury; therefore, treatments for these situations are fundamentally important. Here, we hypothesized that environmental modulation via a clinically relevant hepatocyte growth factor (HGF)-releasing scaffold and human iPS cell-derived neural stem/progenitor cells (hNS/PCs) transplantation contributes to functional recovery after chronic complete transection SCI. Effective release of HGF from a collagen scaffold induced progressive axonal elongation and increased grafted cell viability by activating microglia/macrophages and meningeal cells, inhibiting inflammation, reducing scar formation, and enhancing vascularization. Furthermore, hNS/PCs transplantation enhanced endogenous neuronal regrowth, the extension of graft axons, and the formation of circuits around the lesion and lumbar enlargement between host and graft neurons, resulting in the restoration of locomotor and urinary function. This study presents an effective therapeutic strategy for severe chronic SCI and provides evidence for the feasibility of regenerative medicine strategies using clinically relevant materials.
Collapse
Affiliation(s)
- Shogo Hashimoto
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Katsuyuki Nakanishi
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yu Suematsu
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Takahiro Shibata
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Momotaro Kawai
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Takahiro Kitagawa
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kentaro Ago
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yasuhiro Kamata
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Kaori Yasutake
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Ikuko Koya
- Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan
| | - Yoshinari Ando
- Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan
| | - Aki Minoda
- Center for Integrative Medical Sciences, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, 230-0045, Japan
| | - Tomoko Shindo
- Electron Microscope Laboratory, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shinsuke Shibata
- Electron Microscope Laboratory, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Morio Matsumoto
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| |
Collapse
|
|
23
|
Shibata T, Tashiro S, Shibata S, Shinozaki M, Shindo T, Hashimoto S, Kawai M, Kitagawa T, Ago K, Matsumoto M, Nakamura M, Okano H, Nagoshi N. Rehabilitative Training Enhances Therapeutic Effect of Human-iPSC-Derived Neural Stem/Progenitor Cells Transplantation in Chronic Spinal Cord Injury. Stem Cells Transl Med 2023; 12:83-96. [PMID: 36647673 PMCID: PMC9985116 DOI: 10.1093/stcltm/szac089] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 12/19/2022] [Indexed: 01/18/2023] Open
Abstract
Cell transplantation therapy using human-induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) is a new therapeutic strategy for spinal cord injury (SCI). Preclinical studies have demonstrated the efficacy of hiPSC-NS/PCs transplantation in the subacute phase of SCI. However, locomotor recovery secondary to hiPSC-NS/PCs transplantation is limited in the chronic phase, suggesting that additional treatment, including rehabilitative training, is required to ensure recovery. The therapeutic potential of hiPSC-NS/PCs that qualify for clinical application is yet to be fully delineated. Therefore, in this study, we investigated the therapeutic effect of the combined therapy of clinical-grade hiPSC-NS/PCs transplantation and rehabilitative training that could produce synergistic effects in a rodent model of chronic SCI. Our findings indicated that rehabilitative training promoted the survival rate and neuronal differentiation of transplanted hiPSC-NS/PCs. The combination therapy was able to enhance the expressions of the BDNF and NT-3 proteins in the spinal cord tissue. Moreover, rehabilitation promoted neuronal activity and increased 5-HT-positive fibers at the lumbar enlargement. Consequently, the combination therapy significantly improved motor functions. The findings of this study suggest that the combined therapy of hiPSC-NS/PCs transplantation and rehabilitative training has the potential to promote functional recovery even when initiated during chronic SCI.
Collapse
Affiliation(s)
- Takahiro Shibata
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.,Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Syoichi Tashiro
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Shinsuke Shibata
- Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata City, Niigata, Japan.,Electron Microscope Laboratory, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Tomoko Shindo
- Electron Microscope Laboratory, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Shogo Hashimoto
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.,Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Momotaro Kawai
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Takahiro Kitagawa
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Kentaro Ago
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Morio Matsumoto
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| |
Collapse
|
|
24
|
Su QS, Zhuang DL, Nasser MI, Sai X, Deng G, Li G, Zhu P. Stem Cell Therapies for Restorative Treatments of Central Nervous System Ischemia-Reperfusion Injury. Cell Mol Neurobiol 2023; 43:491-510. [PMID: 35129759 PMCID: PMC11415191 DOI: 10.1007/s10571-022-01204-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 02/01/2022] [Indexed: 11/27/2022]
Abstract
Ischemic damage to the central nervous system (CNS) is a catastrophic postoperative complication of aortic occlusion subsequent to cardiovascular surgery that can cause brain impairment and sometimes even paraplegia. Over recent years, numerous studies have investigated techniques for protecting and revascularizing the nervous system during intraoperative ischemia; however, owing to a lack of knowledge of the physiological distinctions between the brain and spinal cord, as well as the limited availability of testing techniques and treatments for ischemia-reperfusion injury, the cause of brain and spinal cord ischemia-reperfusion injury remains poorly understood, and no adequate response steps are currently available in the clinic. Given the limited ability of the CNS to repair itself, it is of great clinical value to make full use of the proliferative and differentiation potential of stem cells to repair nerves in degenerated and necrotic regions by stem cell transplantation or mobilization, thereby introducing a novel concept for the treatment of severe CNS ischemia-reperfusion injury. This review summarizes the most recent advances in stem cell therapy for ischemia-reperfusion injury in the brain and spinal cord, aiming to advance basic research and the clinical use of stem cell therapy as a promising treatment for this condition.
Collapse
Affiliation(s)
- Qi-Song Su
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China
| | - Dong-Lin Zhuang
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- College of Medicine, Shantou University, Shantou, 515063, Guangdong, China
| | - Moussa Ide Nasser
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
| | - Xiyalatu Sai
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao City, 028000, Inner Mongolia, China
| | - Gang Deng
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China
- School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China
| | - Ge Li
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China.
| | - Ping Zhu
- Medical Research Center, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, Guangdong, China.
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, 510080, Guangdong, China.
- College of Medicine, Shantou University, Shantou, 515063, Guangdong, China.
- Guangdong Provincial Key Laboratory of Structural Heart Disease, Guangzhou, 510100, Guangdong, China.
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, China.
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao City, 028000, Inner Mongolia, China.
| |
Collapse
|
|
25
|
Kawai M, Nagoshi N, Okano H, Nakamura M. A review of regenerative therapy for spinal cord injury using human iPS cells. NORTH AMERICAN SPINE SOCIETY JOURNAL 2023; 13:100184. [PMID: 36479183 PMCID: PMC9720571 DOI: 10.1016/j.xnsj.2022.100184] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/14/2022] [Accepted: 11/14/2022] [Indexed: 06/17/2023]
Abstract
Spinal cord injury (SCI) has been considered to cause sudden, irreversible loss of function in patients. However, developments in stem cell biology and regenerative medicine are changing this conventional notion. Here we reviewed the overview of regenerative medicine of SCI. As a consequence of the establishment of human induced pluripotent stem cells (hiPSCs), hiPSC-based therapies for SCI, such as neural stem/progenitor cell (NS/PC) transplantation, have emerged as promising therapeutic modalities. Using several animal models, hiPSC-NS/PC transplantation into subacute injured spinal cords has been repeatedly demonstrated to improve locomotor function. Some biological mechanisms underlying this improvement have been proposed. In particular, combined with advanced neuroscience techniques such as designer receptors exclusively activated by designer drugs (DREADDs), neuronal relay theory, in which the transplanted cell-derived neurons reconstruct disrupted neuronal circuits, was proven to be involved histologically, pharmaceutically, electrophysiologically, and via in vivo bioimaging. Based on these findings, hiPSC-NS/PC transplantation for subacute SCI was moved ahead to a clinical study on human patients. At the same time, the search for effective treatments for chronic SCI is proceeding gradually, combining hiPSC-NS/PC transplantation with other treatment modalities such as rehabilitation, pharmaceutical interventions, or optimal scaffolds. In addition to NS/PCs, oligodendrocyte precursor cells (OPCs) are also a promising cell source for transplantation, as demyelinated axons affected by SCI can be repaired by OPCs. Therapies with OPCs derived from hiPSCs are still in preclinical studies but have shown favorable outcomes in animal models. In the future, several therapeutic options may be available according to the pathological conditions and the time period of SCI. Moreover, the application of regenerative therapy for the spinal cord could be broadened to degenerative disorders, such as spinal canal stenosis. Summary sentence: A historical review of human induced pluripotent stem cell (hiPSC) based cell transplantation therapy for spinal cord injury (SCI), in particular about footsteps of hiPSC-derived neural stem/progenitor cell transplantation, recent clinical study, and its future perspective.
Collapse
Affiliation(s)
- Momotaro Kawai
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| |
Collapse
|
|
26
|
Castany S, Bagó-Mas A, Vela JM, Verdú E, Bretová K, Svobodová V, Dubový P, Boadas-Vaello P. Transient Reflexive Pain Responses and Chronic Affective Nonreflexive Pain Responses Associated with Neuroinflammation Processes in Both Spinal and Supraspinal Structures in Spinal Cord-Injured Female Mice. Int J Mol Sci 2023; 24:ijms24021761. [PMID: 36675275 PMCID: PMC9863935 DOI: 10.3390/ijms24021761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/10/2023] [Accepted: 01/14/2023] [Indexed: 01/18/2023] Open
Abstract
Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase.
Collapse
Affiliation(s)
- Sílvia Castany
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Catalonia, Spain
| | - Anna Bagó-Mas
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Catalonia, Spain
- Department of Anatomy, Division of Neuroanatomy, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - José Miguel Vela
- WeLab Barcelona, Parc Científic de Barcelona, 08028 Barcelona, Catalonia, Spain
| | - Enrique Verdú
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Catalonia, Spain
| | - Karolina Bretová
- Department of Anatomy, Division of Neuroanatomy, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - Viktorie Svobodová
- Department of Anatomy, Division of Neuroanatomy, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - Petr Dubový
- Department of Anatomy, Division of Neuroanatomy, Faculty of Medicine, Masaryk University, 625 00 Brno, Czech Republic
| | - Pere Boadas-Vaello
- Research Group of Clinical Anatomy, Embryology and Neuroscience (NEOMA), Department of Medical Sciences, University of Girona, 17003 Girona, Catalonia, Spain
- Correspondence:
| |
Collapse
|
|
27
|
Wu Y, Peng X, Ang S, Gao Y, Chi Y, Wang J, Tang C, Zhou X, Feng Y, Zhang K, Zou Q, Chen M. Bcl- xL Promotes the Survival of Motor Neurons Derived from Neural Stem Cells. BIOLOGY 2023; 12:biology12010132. [PMID: 36671824 PMCID: PMC9856060 DOI: 10.3390/biology12010132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/18/2023]
Abstract
Neural stem cell (NSC) transplantation creates new hope for the treatment of neurodegenerative disorders by direct differentiation into neurons. However, this technique is limited by poor survival and functional neuron deficiency. In this research study, we generated pro-survival murine NSCs (mNSCs) via the ectopic expression of Bcl-xL. A doxycycline (Dox)-inducible Ngn2-Isl1-Lhx3 system was also integrated into the mNSC genome. The four gene-modified mNSCs can rapidly and effectively differentiate into motor neurons after Dox treatments. Ectopic Bcl-xL could resist replating-induced stress, glutamate toxicity, neuronal apoptosis and remarkably promote the survival of motor neurons. Taken together, we established genetically modified mNSCs with improved survival, which may be useful for motor neuron degenerative diseases.
Collapse
Affiliation(s)
- Yunqin Wu
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Xiaohua Peng
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Song Ang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
- International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
| | - Yue Gao
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Yue Chi
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Jinling Wang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Chengcheng Tang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Xiaoqing Zhou
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Yanxian Feng
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
| | - Kun Zhang
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
- International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
| | - Qingjian Zou
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
- Correspondence: (Q.Z.); (M.C.)
| | - Min Chen
- Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, South China Institute of Large Animal Models for Biomedicine, Wuyi University, Jiangmen 529020, China
- International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China
- Correspondence: (Q.Z.); (M.C.)
| |
Collapse
|
|
28
|
Kitagawa T, Nagoshi N, Okano H, Nakamura M. A Narrative Review of Advances in Neural Precursor Cell Transplantation Therapies for Spinal Cord Injury. Neurospine 2022; 19:935-945. [PMID: 36597632 PMCID: PMC9816589 DOI: 10.14245/ns.2244628.314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/11/2022] [Indexed: 12/27/2022] Open
Abstract
A spinal cord injury (SCI) is a destructive event that causes a permanent deficit in neurological function because of poor regenerative potential. Transplantation therapies have attracted attention for restoration of the injured spinal cord, and transplantation of neural precursor cells (NPCs) has been studied worldwide. Several groups have demonstrated functional recovery via this therapeutic intervention due to the multiple beneficial effects of NPC transplantation, such as reconstruction of neuronal circuits, remyelination of axons, and neuroprotection by trophic factors. Our group developed a method to induce NPCs from human induced pluripotent stem cells (hiPSCs) and established a transplantation strategy for SCI. Functional improvement in SCI animals treated with hiPSC-NPCs was observed, and the safety of transplanting these cells was evaluated from multiple perspectives. With selection of a safe cell line and pretreatment of the cells to encourage maturation and differentiation, hiPSC-NPC transplantation therapy is now in the clinical phase of testing for subacute SCI. In addition, a research challenge will be to expand the efficacy of transplantation therapy for chronic SCI. More comprehensive strategies involving combination treatments are required to treat this problematic situation.
Collapse
Affiliation(s)
- Takahiro Kitagawa
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan,Corresponding Author Narihito Nagoshi Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
29
|
Lee S, Nam H, Joo KM, Lee SH. Advances in Neural Stem Cell Therapy for Spinal Cord Injury: Safety, Efficacy, and Future Perspectives. Neurospine 2022; 19:946-960. [PMID: 36351442 PMCID: PMC9816608 DOI: 10.14245/ns.2244658.329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating central nervous system injury that leads to severe disabilities in motor and sensory functions, causing significant deterioration in patients' quality of life. Owing to the complexity of SCI pathophysiology, there has been no effective treatment for reversing neural tissue damage and recovering neurological functions. Several novel therapies targeting different stages of pathophysiological mechanisms of SCI have been developed. Among these, treatments using stem cells have great potential for the regeneration of damaged neural tissues. In this review, we have summarized recent preclinical and clinical studies focusing on neural stem cells (NSCs). NSCs are multipotent cells with specific differentiation capabilities for neural lineage. Several preclinical studies have demonstrated the regenerative effects of transplanted NSCs in SCI animal models through both paracrine effects and direct neuronal differentiation, restoring synaptic connectivity and neural networks. Based on the positive results of several preclinical studies, phase I and II clinical trials using NSCs have been performed. Despite several hurdles and issues that need to be addressed in the clinical use of NSCs in patients with SCI, gradual progress in the technical development and therapeutic efficacy of NSCs treatments has enhanced the prospects for cell-based treatments in SCI.
Collapse
Affiliation(s)
- Sungjoon Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyun Nam
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Stem Cell and Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea,Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea
| | - Kyeung-Min Joo
- Stem Cell and Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea,Single Cell Network Research Center, Sungkyunkwan University School of Medicine, Suwon, Korea,Department of Anatomy & Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea,Corresponding Author Kyeung-Min Joo Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon 16419, Korea
| | - Sun-Ho Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea,Stem Cell and Regenerative Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea,Co-corresponding Author Sun-Ho Lee Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
| |
Collapse
|
|
30
|
Restoring After Central Nervous System Injuries: Neural Mechanisms and Translational Applications of Motor Recovery. Neurosci Bull 2022; 38:1569-1587. [DOI: 10.1007/s12264-022-00959-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/29/2022] [Indexed: 11/06/2022] Open
Abstract
AbstractCentral nervous system (CNS) injuries, including stroke, traumatic brain injury, and spinal cord injury, are leading causes of long-term disability. It is estimated that more than half of the survivors of severe unilateral injury are unable to use the denervated limb. Previous studies have focused on neuroprotective interventions in the affected hemisphere to limit brain lesions and neurorepair measures to promote recovery. However, the ability to increase plasticity in the injured brain is restricted and difficult to improve. Therefore, over several decades, researchers have been prompted to enhance the compensation by the unaffected hemisphere. Animal experiments have revealed that regrowth of ipsilateral descending fibers from the unaffected hemisphere to denervated motor neurons plays a significant role in the restoration of motor function. In addition, several clinical treatments have been designed to restore ipsilateral motor control, including brain stimulation, nerve transfer surgery, and brain–computer interface systems. Here, we comprehensively review the neural mechanisms as well as translational applications of ipsilateral motor control upon rehabilitation after CNS injuries.
Collapse
|
|
31
|
Sun X, Huang LY, Pan HX, Li LJ, Wang L, Pei GQ, Wang Y, Zhang Q, Cheng HX, He CQ, Wei Q. Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway. Neural Regen Res 2022; 18:1067-1075. [PMID: 36254995 PMCID: PMC9827790 DOI: 10.4103/1673-5374.355762] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway.
Collapse
Affiliation(s)
- Xin Sun
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Li-Yi Huang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Hong-Xia Pan
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Li-Juan Li
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Lu Wang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Gai-Qin Pei
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Yang Wang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Qing Zhang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Hong-Xin Cheng
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Cheng-Qi He
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Quan Wei
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China,Correspondence to: Quan Wei, .
| |
Collapse
|
|
32
|
Tashiro S, Nakamura M, Okano H. Regenerative Rehabilitation and Stem Cell Therapy Targeting Chronic Spinal Cord Injury: A Review of Preclinical Studies. Cells 2022; 11:cells11040685. [PMID: 35203335 PMCID: PMC8870591 DOI: 10.3390/cells11040685] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 02/04/2023] Open
Abstract
Stem cell medicine has led to functional recovery in the acute-to-subacute phase of spinal cord injury (SCI), but not yet in the chronic phase, during which various molecular mechanisms drastically remodel the tissue and render it treatment-resistant. Researchers are attempting to identify effective combinatorial treatments that can overcome the refractory state of the chronically injured spinal cord. Regenerative rehabilitation, combinatorial treatment with regenerative medicine that aims to elicit synergistic effects, is being developed. Rehabilitation upon SCI in preclinical studies has recently attracted more attention because it is safe, induces neuronal plasticity involving transplanted stem cells and sensorimotor circuits, and is routinely implemented in human clinics. However, regenerative rehabilitation has not been extensively reviewed, and only a few reviews have focused on the use of physical medicine modalities for rehabilitative purposes, which might be more important in the chronic phase. Here, we summarize regenerative rehabilitation studies according to the effector, site, and mechanism. Specifically, we describe effects on transplanted cells, microstructures at and distant from the lesion, and molecular changes. To establish a treatment regimen that induces robust functional recovery upon chronic SCI, further investigations are required of combinatorial treatments incorporating stem cell therapy, regenerative rehabilitation, and medication.
Collapse
Affiliation(s)
- Syoichi Tashiro
- Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku City, Tokyo 160-8582, Japan
- Department of Rehabilitation Medicine, Kyorin University School of Medicine, Mitaka City, Tokyo 181-8611, Japan
- Correspondence: (S.T.); (M.N.); (H.O.); Tel.: +81-3-5363-3833 (S.T.)
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku City, Tokyo 160-8582, Japan
- Correspondence: (S.T.); (M.N.); (H.O.); Tel.: +81-3-5363-3833 (S.T.)
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Shinjuku City, Tokyo 160-8582, Japan
- Correspondence: (S.T.); (M.N.); (H.O.); Tel.: +81-3-5363-3833 (S.T.)
| |
Collapse
|
|
33
|
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
|
|
34
|
Obara K, Shirai K, Hamada Y, Arakawa N, Yamane M, Takaoka N, Aki R, Hoffman RM, Amoh Y. Chronic spinal cord injury functionally repaired by direct implantation of encapsulated hair-follicle-associated pluripotent (HAP) stem cells in a mouse model: Potential for clinical regenerative medicine. PLoS One 2022; 17:e0262755. [PMID: 35085322 PMCID: PMC8794105 DOI: 10.1371/journal.pone.0262755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 01/04/2022] [Indexed: 11/30/2022] Open
Abstract
Chronic spinal cord injury (SCI) is a highly debilitating and recalcitrant disease with limited treatment options. Although various stem cell types have shown some clinical efficacy for injury repair they have not for SCI. Hair-follicle-associated pluripotent (HAP) stem cells have been shown to differentiate into neurons, Schwan cells, beating cardiomyocytes and many other type of cells, and have effectively regenerated acute spinal cord injury in mouse models. In the present report, HAP stem cells from C57BL/6J mice, encapsulated in polyvinylidene fluoride membranes (PFM), were implanted into the severed thoracic spinal cord of C57BL/6J or athymic nude mice in the early chronic phase. After implantation, HAP stem cells differentiated to neurons, astrocytes and oligodendrocytes in the regenerated thoracic spinal cord of C57BL/6J and nude mice. Quantitative motor function analysis, with the Basso Mouse Scale for Locomotion (BMS) score, demonstrated a significant functional improvement in the HAP-stem-cell-implanted mice, compared to non-implanted mice. HAP stem cells have critical advantages over other stem cells: they do not develop teratomas; do not loose differentiation ability when cryopreserved and thus are bankable; are autologous, readily obtained from anyone; and do not require genetic manipulation. HAP stem cells therefore have greater clinical potential for SCI repair than induced pluripotent stem cells (iPSCs), neuronal stem cells (NSCs)/neural progenitor cells (NPCs) or embryonic stem cells (ESCs). The present report demonstrates future clinical potential of HAP-stem-cell repair of chronic spinal cord injury, currently a recalcitrant disease.
Collapse
Affiliation(s)
- Koya Obara
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Kyoumi Shirai
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yuko Hamada
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Nobuko Arakawa
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Michiko Yamane
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Nanako Takaoka
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ryoichi Aki
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Robert M. Hoffman
- AntiCancer, Inc., San Diego, California, United States of America
- Department of Surgery, University of California San Diego, San Diego, California, United States of America
- * E-mail: (YA); (RMH)
| | - Yasuyuki Amoh
- Department of Dermatology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
- * E-mail: (YA); (RMH)
| |
Collapse
|
|
35
|
Nakano A, Yang X, Kuboyama T, Inada Y, Tohda C. Intrathecal Infusion of Diosgenin during the Chronic Phase of Spinal Cord Injury Ameliorates Motor Function and Axonal Density. NEUROCHEM J+ 2021. [DOI: 10.1134/s1819712421040085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
|
|
36
|
Sato Y, Kondo T, Shibata R, Nakamura M, Okano H, Ushiba J. Functional reorganization of locomotor kinematic synergies reflects the neuropathology in a mouse model of spinal cord injury. Neurosci Res 2021; 177:78-84. [PMID: 34921835 DOI: 10.1016/j.neures.2021.12.002] [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: 10/07/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 11/27/2022]
Abstract
Spinal cord injury (SCI) disrupts motor commands to modular structures of the spinal cord, limiting the ability to walk. Evidence suggests that these modules are conserved across species from rodent to human and subserve adaptive walking by controlling coordinated joint movements (kinematic synergies). Since SCI causes uncoordinated joint movements of the lower limbs during walking, there may be a disorder of the modular structures that control them. To gain insights into this complex process, we recorded the kinematics of intact and SCI mice when walking on a treadmill and applied principal component analysis to extract kinematic synergies. Most SCI mice walked stably on the treadmill, but their kinematic synergies were generally different from those of intact mice. We classified the kinematic synergies of SCI mice into three groups based on the similarity of the extracted first three synergy components. We found that these three groups had different degrees of spinal cord damage. This suggests that differences in kinematic synergies reflect underlying SCI neuropathology. These results may help guide the development of different rehabilitation approaches and future physiological experiments to understand the mechanisms of motor control and recovery.
Collapse
Affiliation(s)
- Yuta Sato
- Graduate School of Science and Technology, Keio University, Kanagawa, Japan; Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Saitama, Japan
| | - Takahiro Kondo
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Reo Shibata
- Department of Orhopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orhopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Junichi Ushiba
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Kanagawa, Japan.
| |
Collapse
|
|
37
|
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
|
|
38
|
Kawai M, Imaizumi K, Ishikawa M, Shibata S, Shinozaki M, Shibata T, Hashimoto S, Kitagawa T, Ago K, Kajikawa K, Shibata R, Kamata Y, Ushiba J, Koga K, Furue H, Matsumoto M, Nakamura M, Nagoshi N, Okano H. Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function. Cell Rep 2021; 37:110019. [PMID: 34818559 DOI: 10.1016/j.celrep.2021.110019] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 10/06/2021] [Accepted: 10/28/2021] [Indexed: 02/07/2023] Open
Abstract
In cell transplantation therapy for spinal cord injury (SCI), grafted human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) mainly differentiate into neurons, forming synapses in a process similar to neurodevelopment. In the developing nervous system, the activity of immature neurons has an important role in constructing and maintaining new synapses. Thus, we investigate how enhancing the activity of transplanted hiPSC-NS/PCs affects both the transplanted cells themselves and the host tissue. We find that chemogenetic stimulation of hiPSC-derived neural cells enhances cell activity and neuron-to-neuron interactions in vitro. In a rodent model of SCI, consecutive and selective chemogenetic stimulation of transplanted hiPSC-NS/PCs also enhances the expression of synapse-related genes and proteins in surrounding host tissues and prevents atrophy of the injured spinal cord, thereby improving locomotor function. These findings provide a strategy for enhancing activity within the graft to improve the efficacy of cell transplantation therapy for SCI.
Collapse
Affiliation(s)
- Momotaro Kawai
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Kent Imaizumi
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Mitsuru Ishikawa
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Shinsuke Shibata
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Takahiro Shibata
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Shogo Hashimoto
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Takahiro Kitagawa
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Kentaro Ago
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Keita Kajikawa
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Reo Shibata
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Yasuhiro Kamata
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Junichi Ushiba
- Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku, Yokohama 223-8522, Japan
| | - Keisuke Koga
- Department of Neurophysiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Hidemasa Furue
- Department of Neurophysiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
| | - Morio Matsumoto
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
| | - Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
| |
Collapse
|
|
39
|
Shinozaki M, Nagoshi N, Nakamura M, Okano H. Mechanisms of Stem Cell Therapy in Spinal Cord Injuries. Cells 2021; 10:cells10102676. [PMID: 34685655 PMCID: PMC8534136 DOI: 10.3390/cells10102676] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 12/13/2022] Open
Abstract
Every year, 0.93 million people worldwide suffer from spinal cord injury (SCI) with irretrievable sequelae. Rehabilitation, currently the only available treatment, does not restore damaged tissues; therefore, the functional recovery of patients remains limited. The pathophysiology of spinal cord injuries is heterogeneous, implying that potential therapeutic targets differ depending on the time of injury onset, the degree of injury, or the spinal level of injury. In recent years, despite a significant number of clinical trials based on various types of stem cells, these aspects of injury have not been effectively considered, resulting in difficult outcomes of trials. In a specialty such as cancerology, precision medicine based on a patient’s characteristics has brought indisputable therapeutic advances. The objective of the present review is to promote the development of precision medicine in the field of SCI. Here, we first describe the multifaceted pathophysiology of SCI, with the temporal changes after injury, the characteristics of the chronic phase, and the subtypes of complete injury. We then detail the appropriate targets and related mechanisms of the different types of stem cell therapy for each pathological condition. Finally, we highlight the great potential of stem cell therapy in cervical SCI.
Collapse
Affiliation(s)
- Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;
| | - Narihito Nagoshi
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (M.N.)
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; (N.N.); (M.N.)
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;
- Correspondence:
| |
Collapse
|
|
40
|
Itoi T, Kawata S, Fukuda Y, Maejima S. Effect of a Corset on the Gait of Healthy Beagle Dogs. Animals (Basel) 2021; 11:ani11092650. [PMID: 34573619 PMCID: PMC8471024 DOI: 10.3390/ani11092650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/27/2021] [Accepted: 09/08/2021] [Indexed: 11/04/2022] Open
Abstract
Simple Summary In recent years, corsets have been used in the prevention of nerve diseases in dogs and in their rehabilitation following surgery. The Anifull Dog’s Corset Pro, made by Daiya Industry Co., Ltd., is manufactured and sold for this purpose, but no studies have yet been conducted to verify its effectiveness. To evaluate the effects of the corset, we analyzed the gait of healthy beagle dogs that were or were not wearing the Anifull Dog’s Corset Pro. We found no difference in the walking speed of the dogs, but wearing the corset reduced the horizontal sway of the back. In conclusion, this corset does not affect the gait of dogs and may help body stability. Therefore, the Anifull Dog’s Corset Pro may be useful for the treatment of dog nerve conditions. Abstract The prognosis for intervertebral disc disease (IVDD), a common neurologic disease in dogs, varies, with some cases requiring long-term rehabilitation. Corsets are used as part of the physical rehabilitation of dogs, and one of these, the Anifull Dog’s Corset Pro, is manufactured and sold by Daiya Industry Co., Ltd. This corset is used to relieve pain caused by spinal cord and vertebral diseases, and to prevent neurological conditions from worsening, by limiting spinal movement. However, the effect of the Anifull Dog’s Corset Pro on gait has not yet been clarified. Therefore, we aimed to evaluate the effects of this corset on the gait of dogs using kinematic and kinetic analyses. Five healthy beagle dogs wearing corsets were trotted, kinematic and kinetic parameters were measured using motion capture and force plates, and the results were compared to those obtained when the dogs were not wearing a corset. The range of motion of the angle formed by the 13th thoracic vertebra and the 7th lumbar vertebra at the apex of the 7th cervical vertebra was significantly reduced in the corset-wearing dogs. Thus, the Anifull Dog’s Corset Pro may improve trunk stability without affecting gait.
Collapse
Affiliation(s)
- Takamasa Itoi
- Faculty of Veterinary Medicine, Okayama University of Science, Imabari 794-8555, Ehime, Japan
- Department of Comparative Animal Science, Kurashiki University of Science and the Arts, Kurashiki 712-8505, Okayama, Japan
- Correspondence:
| | - Shuji Kawata
- Anifull, Division of Vet Supplies, Daiya Industry Co., Ltd., Okayama 701-0203, Okayama, Japan;
| | - Yoshiyuki Fukuda
- Department of R&D, Daiya Industry Co., Ltd., Okayama 701-0203, Okayama, Japan;
| | - Saori Maejima
- Animal Rehabilitation Community, Okayama 701-1332, Okayama, Japan;
| |
Collapse
|
|
41
|
Treadmill training based on the overload principle promotes locomotor recovery in a mouse model of chronic spinal cord injury. Exp Neurol 2021; 345:113834. [PMID: 34370998 DOI: 10.1016/j.expneurol.2021.113834] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/16/2021] [Accepted: 08/02/2021] [Indexed: 11/21/2022]
Abstract
Rehabilitative treatment, including treadmill training, is considered an important strategy for restoring motor function after spinal cord injury (SCI). However, many unexplained problems persist regarding the appropriate rehabilitative method and the mechanism underlying the beneficial effects of rehabilitation. Moreover, only a few preclinical studies have been performed on rehabilitative interventions for chronic SCI, although most patients have chronic injuries. In fact, several preclinical studies reported that rehabilitative training was less effective when applied during the chronic phase than when applied sooner. While numerous studies have examined the effects of treadmill training during the subacute phase, the training conditions vary considerably among preclinical reports. Therefore, establishing a standard training protocol is essential for achieving beneficial rehabilitation effects at the chronic stage. Since the difficulty of applying an appropriate training load hinders training at constant speeds, it is important to adjust the training intensity in accordance with the exercise tolerance of an individual animal to provide further functional recovery benefits. Here, we created a novel quadrupedal treadmill training protocol based on the overload principle for mice with incomplete thoracic SCI. We subjected SCI model mice to rehabilitative training according to the protocol for two consecutive weeks starting at 42 days after injury. We examined the treadmill speeds at which the mice were able to run based on the severity of paresis and investigated the impact of the protocol on functional recovery. Assessment of running speed changes during the treadmill training period revealed faster treadmill speeds for mice with mild paresis than for those with severe paresis. The training parameters, including the speed and distance traveled, were positively correlated with the changes in motor function. These results suggest that the most suitable running speed during treadmill training differs according to the level of motor dysfunction and that running longer distances has a positive impact on motor functional recovery. Based on this established protocol, we compared functional and histological results between the chronic SCI groups with and without rehabilitation. The gait analyses showed significantly better functional improvement in the rehabilitation group than in the nonrehabilitation group. Histological analyses revealed that the BDNF- and VGLUT1-positive areas of lumbar enlargement were significantly increased in the rehabilitation group. These findings implied that rehabilitation promoted not only motor performance but also motor control, including forelimb-hindlimb coordination, even in chronic SCI, resulting in functional improvement by treadmill training alone. Therefore, rehabilitative training based on the overload principle appears to be one of the appropriate treatment options for incomplete thoracic SCI, and evidence of its efficacy exists in actual clinical settings.
Collapse
|
|
42
|
Torikoshi S, Morizane A, Shimogawa T, Samata B, Miyamoto S, Takahashi J. Exercise Promotes Neurite Extensions from Grafted Dopaminergic Neurons in the Direction of the Dorsolateral Striatum in Parkinson's Disease Model Rats. JOURNAL OF PARKINSONS DISEASE 2021; 10:511-521. [PMID: 31929121 PMCID: PMC7242856 DOI: 10.3233/jpd-191755] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background: Cell transplantation is expected to be a promising treatment for Parkinson’s disease (PD), in which re-innervation of the host striatum by grafted dopamine (DA) neurons is essential. In particular, the dorsolateral part of the striatum is important because it is the target of midbrain A9 DA neurons, which are degenerated in PD pathology. The effect of exercise on the survival and maturation of grafted neurons has been reported in several neurological disease models, but never in PD models. Objective: We investigated how exercise influences cell transplantation for PD, especially from the viewpoint of cell survival and neurite extensions. Methods: Ventral mesencephalic neurons from embryonic (E12.5) rats were transplanted into the striatum of adult 6-OHDA-lesioned rats. The host rats then underwent treadmill training as exercise after the transplantation. Six weeks after the transplantation, they were sacrificed, and the grafts in the striatum were analyzed. Results: The addition of exercise post-transplantation significantly increased the number of surviving DA neurons. Moreover, it promoted neurite extensions from the graft toward the dorsolateral part of the striatum. Conclusions: This study indicates a beneficial effect of exercise after cell transplantation in PD.
Collapse
Affiliation(s)
- Sadaharu Torikoshi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.,Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Asuka Morizane
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Takafumi Shimogawa
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.,Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Bumpei Samata
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| | - Susumu Miyamoto
- Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Jun Takahashi
- Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan
| |
Collapse
|
|
43
|
Bilchak JN, Caron G, Côté MP. Exercise-Induced Plasticity in Signaling Pathways Involved in Motor Recovery after Spinal Cord Injury. Int J Mol Sci 2021; 22:ijms22094858. [PMID: 34064332 PMCID: PMC8124911 DOI: 10.3390/ijms22094858] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 04/28/2021] [Accepted: 04/29/2021] [Indexed: 02/06/2023] Open
Abstract
Spinal cord injury (SCI) leads to numerous chronic and debilitating functional deficits that greatly affect quality of life. While many pharmacological interventions have been explored, the current unsurpassed therapy for most SCI sequalae is exercise. Exercise has an expansive influence on peripheral health and function, and by activating the relevant neural pathways, exercise also ameliorates numerous disorders of the central nervous system (CNS). While the exact mechanisms by which this occurs are still being delineated, major strides have been made in the past decade to understand the molecular underpinnings of this essential treatment. Exercise rapidly and prominently affects dendritic sprouting, synaptic connections, neurotransmitter production and regulation, and ionic homeostasis, with recent literature implicating an exercise-induced increase in neurotrophins as the cornerstone that binds many of these effects together. The field encompasses vast complexity, and as the data accumulate, disentangling these molecular pathways and how they interact will facilitate the optimization of intervention strategies and improve quality of life for individuals affected by SCI. This review describes the known molecular effects of exercise and how they alter the CNS to pacify the injury environment, increase neuronal survival and regeneration, restore normal neural excitability, create new functional circuits, and ultimately improve motor function following SCI.
Collapse
|
|
44
|
Davaa G, Hong JY, Kim TU, Lee SJ, Kim SY, Hong K, Hyun JK. Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation. Cells 2021; 10:143. [PMID: 33445717 PMCID: PMC7828206 DOI: 10.3390/cells10010143] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/07/2021] [Accepted: 01/11/2021] [Indexed: 11/16/2022] Open
Abstract
Exercise training is a traditional method to maximize remaining function in patients with spinal cord injury (SCI), but the exact mechanism by which exercise promotes recovery after SCI has not been identified; whether exercise truly has a beneficial effect on SCI also remains unclear. Previously, we showed that epigenetic changes in the brain motor cortex occur after SCI and that a treatment leading to epigenetic modulation effectively promotes functional recovery after SCI. We aimed to determine how exercise induces functional improvement in rats subjected to SCI and whether epigenetic changes are engaged in the effects of exercise. A spinal cord contusion model was established in rats, which were then subjected to treadmill exercise for 12 weeks. We found that the size of the lesion cavity and the number of macrophages were decreased more in the exercise group than in the control group after 12 weeks of injury. Immunofluorescence and DNA dot blot analysis revealed that levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the brain motor cortex were increased after exercise. Accordingly, the expression of ten-eleven translocation (Tet) family members (Tet1, Tet2, and Tet3) in the brain motor cortex also elevated. However, no macrophage polarization was induced by exercise. Locomotor function, including Basso, Beattie, and Bresnahan (BBB) and ladder scores, also improved in the exercise group compared to the control group. We concluded that treadmill exercise facilitates functional recovery in rats with SCI, and mechanistically epigenetic changes in the brain motor cortex may contribute to exercise-induced improvements.
Collapse
Affiliation(s)
- Ganchimeg Davaa
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea; (G.D.); (J.Y.H.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea
| | - Jin Young Hong
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea; (G.D.); (J.Y.H.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea
| | - Tae Uk Kim
- Department of Rehabilitation Medicine, College of Medicine, Dankook University, Cheonan 31116, Korea; (T.U.K.); (S.J.L.); (S.Y.K.)
| | - Seong Jae Lee
- Department of Rehabilitation Medicine, College of Medicine, Dankook University, Cheonan 31116, Korea; (T.U.K.); (S.J.L.); (S.Y.K.)
| | - Seo Young Kim
- Department of Rehabilitation Medicine, College of Medicine, Dankook University, Cheonan 31116, Korea; (T.U.K.); (S.J.L.); (S.Y.K.)
| | - Kwonho Hong
- Department of Stem Cell and Regenerative Biotechnology and Institute of Advanced Regenerative Science, Konkuk University, Seoul 05029, Korea;
| | - Jung Keun Hyun
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Korea; (G.D.); (J.Y.H.)
- Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea
- Department of Rehabilitation Medicine, College of Medicine, Dankook University, Cheonan 31116, Korea; (T.U.K.); (S.J.L.); (S.Y.K.)
- Wiregene, Co., Ltd., Cheonan 31116, Korea
| |
Collapse
|
|
45
|
Wang S, Jia Y, Cao X, Feng S, Na L, Dong H, Gao J, Zhang L. HUCMSCs transplantation combined with ultrashort wave therapy attenuates neuroinflammation in spinal cord injury through NUR77/ NF-κB pathway. Life Sci 2020; 267:118958. [PMID: 33383054 DOI: 10.1016/j.lfs.2020.118958] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 12/06/2020] [Accepted: 12/17/2020] [Indexed: 02/09/2023]
Abstract
AIMS Spinal cord injury (SCI) is a major cause of long-term physical impairment. Currently, treatment for SCI is limited to supportive measures, which can lead to permanent disability, representing a serious social burden. The present study aimed to evaluate the inflammatory microenvironment effects of human umbilical cord mesenchymal stem cells (HUCMSCs)+ Ultrashort Wave (USW) therapy on SCI and reveal possible mechanisms. MAIN METHODS Low-dose USW was treated one day after SCI, and HUCMSCs suspension was transferred to the lesion using a micro-syringe 7 days after SCI. The functional effects of HUCMSCs and USW, separately and combinedly, were measured, together with the infiltration of CD3+ cells, formation of A1 astrocytes and activation of NUR77/ NF-κB pathway. KEY FINDINGS Our results showed that HUCMSCs+USW therapy improved motor function of SCI rat, together with decreased infiltration of CD3+ T cells, and decreased induction of microglia and A1 astrocytes. And also USW treatment played a very important role on decreasing the infiltration of CD3+ T cells and IBA-1+ cells. Reduced production of pro-inflammatory cytokines IL-1β and IL-6 was also observed in rats receiving HUCMSCs+USW therapy, medicated by NUR77/NF-κB pathway. SIGNIFICANCE These findings indicated that HUCMSCs+USW therapy could attenuate inflammatory microenvironment through NUR77/NF-κB signaling pathway, which might contribute to its better outcome.
Collapse
Affiliation(s)
- Shuai Wang
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China; Department of Rehabilitation, Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People's Republic of China
| | - Yiying Jia
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Xiangyan Cao
- Kidney internal medicine, Tangdu Hospital of Air Force Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
| | - Sining Feng
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China
| | - Li Na
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China; Department of Neurology, People's Hospital of Liaoning Province, Shenyang 116044, People's Republic of China
| | - Hongxuan Dong
- Technology Department, Liaoning Qifu Stem Cell Biotechnology Co., Ltd., Shenyang 110136, People's Republic of China
| | - Jian Gao
- Technology Department, Liaoning Qifu Stem Cell Biotechnology Co., Ltd., Shenyang 110136, People's Republic of China
| | - Lixin Zhang
- Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
| |
Collapse
|
|
46
|
Kamata Y, Isoda M, Sanosaka T, Shibata R, Ito S, Okubo T, Shinozaki M, Inoue M, Koya I, Shibata S, Shindo T, Matsumoto M, Nakamura M, Okano H, Nagoshi N, Kohyama J. A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury. Stem Cells Transl Med 2020; 10:398-413. [PMID: 33226180 PMCID: PMC7900588 DOI: 10.1002/sctm.20-0269] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/05/2020] [Accepted: 10/25/2020] [Indexed: 12/13/2022] Open
Abstract
Cell-based therapy targeting spinal cord injury (SCI) is an attractive approach to promote functional recovery by replacing damaged tissue. We and other groups have reported the effectiveness of transplanting neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) in SCI animal models for neuronal replacement. Glial replacement is an additional approach for tissue repair; however, the lack of robust procedures to drive iPSCs into NS/PCs which can produce glial cells has hindered the development of glial cell transplantation for the restoration of neuronal functions after SCI. Here, we established a method to generate NS/PCs with gliogenic competence (gNS/PCs) optimized for clinical relevance and utilized them as a source of therapeutic NS/PCs for SCI. We could successfully generate gNS/PCs from clinically relevant hiPSCs, which efficiently produced astrocytes and oligodendrocytes in vitro. We also performed comparison between gNS/PCs and neurogenic NS/PCs based on single cell RNA-seq analysis and found that gNS/PCs were distinguished by expression of several transcription factors including HEY2 and NFIB. After gNS/PC transplantation, the graft did not exhibit tumor-like tissue formation, indicating the safety of them as a source of cell therapy. Importantly, the gNS/PCs triggered functional recovery in an SCI animal model, with remyelination of demyelinated axons and improved motor function. Given the inherent safety of gNS/PCs and favorable outcomes observed after their transplantation, cell-based medicine using the gNS/PCs-induction procedure described here together with clinically relevant iPSCs is realistic and would be beneficial for SCI patients.
Collapse
Affiliation(s)
- Yasuhiro Kamata
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Miho Isoda
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd, Kobe, Japan
| | - Tsukasa Sanosaka
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Reo Shibata
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Shuhei Ito
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Toshiki Okubo
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Munehisa Shinozaki
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Mitsuhiro Inoue
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan.,Regenerative & Cellular Medicine Kobe Center, Sumitomo Dainippon Pharma Co., Ltd, Kobe, Japan
| | - Ikuko Koya
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Shinsuke Shibata
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Tomoko Shindo
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Morio Matsumoto
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Masaya Nakamura
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| | - Narihito Nagoshi
- Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Jun Kohyama
- Department of Physiology, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
47
|
Nagoshi N, Okano H, Nakamura M. Regenerative therapy for spinal cord injury using iPSC technology. Inflamm Regen 2020; 40:40. [PMID: 33088363 PMCID: PMC7565344 DOI: 10.1186/s41232-020-00149-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 10/07/2020] [Indexed: 01/04/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating event that causes permanent neurologic impairments. Cell transplantation therapy using neural precursor cells (NPCs) is a promising intervention aiming to replace damaged neural tissue and restore certain functions. Because the protocol to produce human induced pluripotent stem cells (iPSCs) was first established, we have attempted to apply this technology for regenerative therapy in SCI. Our group reported beneficial effects of iPSC-derived NPC transplantation and addressed safety issues on tumorigenicity after grafting. These findings will soon be tested at the clinical trial stage, the protocol of which has already been approved by the Ministry of Health, Labour and Welfare in Japan. Current transplantation therapies treat patients at the subacute phase after injury, highlighting the need for effective treatments for chronic SCI. We recently demonstrated the modest efficacy of gamma secretase inhibitor treatment of iPSC-NPCs before transplantation at the chronic phase. However, more comprehensive strategies involving combinatory therapies are essential to enhance current spinal cord regeneration treatments.
Collapse
Affiliation(s)
- Narihito Nagoshi
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan
| | - Masaya Nakamura
- Department of Orthopaedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582 Japan
| |
Collapse
|
|
48
|
Yang Y, Cao TT, Tian ZM, Gao H, Wen HQ, Pang M, He WJ, Wang NX, Chen YY, Wang Y, Li H, Lin JW, Kang Z, Li MM, Liu B, Rong LM. Subarachnoid transplantation of human umbilical cord mesenchymal stem cell in rodent model with subacute incomplete spinal cord injury: Preclinical safety and efficacy study. Exp Cell Res 2020; 395:112184. [PMID: 32707134 DOI: 10.1016/j.yexcr.2020.112184] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 07/13/2020] [Accepted: 07/17/2020] [Indexed: 12/22/2022]
Abstract
Functional multipotency renders human umbilical cord mesenchymal stem cell (hUC-MSC) a promising candidate for the treatment of spinal cord injury (SCI). However, its safety and efficacy have not been fully understood for clinical translation. In this study, we performed cellular, kinematic, physiological, and anatomical analyses, either in vitro or in vivo, to comprehensively evaluate the safety and efficacy associated with subarachnoid transplantation of hUC-MSCs in rats with subacute incomplete SCI. Concerning safety, hUC-MSCs were shown to have normal morphology, excellent viability, steady proliferation, typical biomarkers, stable karyotype in vitro, and no tumorigenicity both in vitro and in vivo. Following subarachnoid transplantation of hUC-MSCs in the subject rodents, the biodistribution of hUC-MSCs was restricted to the spinal cord, and no toxicity to immune system or organ function was observed. Body weight, organ weight, and the ratio of the latter upon the former between stem cell-transplanted rats and placebo-injected rats revealed no statistical differences. Regarding efficacy, hUC-MSCs could differentiate into osteoblasts, chondrocytes, adipocytes and neural progenitor cells in vitro. While in vivo studies revealed that subarachnoid transplantation of stem cells resulted in significant improvement in locomotion, earlier automatic micturition recovery and reduced lesion size, which correlated with increased regeneration of tracking fiber and reduced parenchymal inflammation. In vivo luminescence imaging showed that a few of the transplanted luciferase-labeled hUC-MSCs tended to migrate towards the lesion epicenter. Shortened latency and enhanced amplitude were also observed in both motor and sensory evoked potentials, indicating improved signal conduction in the damaged site. Immunofluorescent staining confirmed that a few of the administrated hUC-MSCs integrated into the spinal cord parenchyma and differentiated into astrocytes and oligodendrocytes, but not neurons. Moreover, decreased astrogliosis, increased remyelination, and neuron regeneration could be observed. To the best of our knowledge, this preclinical study provides detailed safety and efficacy evidence regarding intrathecal transplantation of hUC-MSCs in treating SCI for the first time and thus, supports its initiation in the following clinical trial.
Collapse
Affiliation(s)
- Yang Yang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Ting-Ting Cao
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, 1023 Shatai South Road, Baiyun District, Guangzhou, Guangdong Province, People's Republic of China
| | - Zhen-Ming Tian
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Han Gao
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Hui-Quan Wen
- Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Mao Pang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Wei-Jie He
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Nan-Xiang Wang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Yu-Yong Chen
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Yang Wang
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - He Li
- Department of Physiology, School of Basic Medical Sciences, Southern Medical University, 1023 Shatai South Road, Baiyun District, Guangzhou, Guangdong Province, People's Republic of China
| | - Jun-Wei Lin
- Department of Obstetrics, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Zhuang Kang
- Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China
| | - Mang-Mang Li
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, 1023 Shatai South Road, Baiyun District, Guangzhou, Guangdong Province, People's Republic of China.
| | - Bin Liu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China.
| | - Li-Min Rong
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou, Guangdong Province, People's Republic of China.
| |
Collapse
|
|
49
|
Assinck P, Sparling JS, Dworski S, Duncan GJ, Wu DL, Liu J, Kwon BK, Biernaskie J, Miller FD, Tetzlaff W. Transplantation of Skin Precursor-Derived Schwann Cells Yields Better Locomotor Outcomes and Reduces Bladder Pathology in Rats with Chronic Spinal Cord Injury. Stem Cell Reports 2020; 15:140-155. [PMID: 32559459 PMCID: PMC7363874 DOI: 10.1016/j.stemcr.2020.05.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 12/20/2022] Open
Abstract
Cell transplantation for spinal cord injury (SCI) has largely been studied in sub-acute settings within 1–2 weeks of injury. In contrast, here we transplanted skin-derived precursors differentiated into Schwann cells (SKP-SCs) into the contused rat spinal cord 8 weeks post-injury (wpi). Twenty-one weeks later (29 wpi), SKP-SCs were found to have survived transplantation, integrated with host tissue, and mitigated the formation of a dense glial scar. Furthermore, transplanted SKP-SCs filled much of the lesion sites and greatly enhanced the presence of endogenous SCs, which myelinated thousands of sprouting/spared host axons in and around the injury site. In addition, SKP-SC transplantation improved locomotor outcomes and decreased pathological thickening of bladder wall. To date, functional improvements have very rarely been observed with cell transplantation beyond the sub-acute stage of injury. Hence, these findings indicate that skin-derived SCs are a promising candidate cell type for the treatment of chronic SCI.
SKP-SCs injected 8 weeks after SCI survive long-term and integrate with host tissue SKP-SC transplants boosted the presence of endogenous SCs in the chronic SCI site Treated spinal cords showed enhanced growth and SC myelination of axons Treated rats displayed better locomotor outcomes with reduced bladder pathologies
Collapse
Affiliation(s)
- Peggy Assinck
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada
| | - Joseph S Sparling
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Shaalee Dworski
- Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Greg J Duncan
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Zoology, University of British Columbia, Vancouver, BC, Canada
| | - Di L Wu
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada
| | - Jie Liu
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada
| | - Brian K Kwon
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Orthopaedics, University of British Columbia, Vancouver, BC, Canada
| | - Jeff Biernaskie
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Freda D Miller
- Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Zoology, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
| |
Collapse
|
|
50
|
Three Growth Factors Induce Proliferation and Differentiation of Neural Precursor Cells In Vitro and Support Cell-Transplantation after Spinal Cord Injury In Vivo. Stem Cells Int 2020; 2020:5674921. [PMID: 32774390 PMCID: PMC7399764 DOI: 10.1155/2020/5674921] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 03/10/2020] [Accepted: 03/16/2020] [Indexed: 11/25/2022] Open
Abstract
Stem cell therapy with neural precursor cells (NPCs) has the potential to improve neuroregeneration after spinal cord injury (SCI). Unfortunately, survival and differentiation of transplanted NPCs in the injured spinal cord remains low. Growth factors have been successfully used to improve NPC transplantation in animal models, but their extensive application is associated with a relevant financial burden and might hinder translation of findings into the clinical practice. In our current study, we assessed the potential of a reduced number of growth factors in different combinations and concentrations to increase proliferation and differentiation of NPCs in vitro. After identifying a “cocktail” (EGF, bFGF, and PDGF-AA) that directed cell fate towards the oligodendroglial and neuronal lineage while reducing astrocytic differentiation, we translated our findings into an in vivo model of cervical clip contusion/compression SCI at the C6 level in immunosuppressed Wistar rats, combining NPC transplantation and intrathecal administration of the growth factors 10 days after injury. Eight weeks after SCI, we could observe surviving NPCs in the injured animals that had mostly differentiated into oligodendrocytes and oligodendrocytic precursors. Moreover, “Stride length” and “Average Speed” in the CatWalk gait analysis were significantly improved 8 weeks after SCI, representing beneficial effects on the functional recovery with NPC transplantation and the administration of the three growth factors. Nevertheless, no effects on the BBB scores could be observed over the course of the experiment and regeneration of descending tracts as well as posttraumatic myelination remained unchanged. However, reactive astrogliosis, as well as posttraumatic inflammation and apoptosis was significantly reduced after NPC transplantation and GF administration. Our data suggest that NPC transplantation is feasible with the use of only EGF, bFGF, and PDGF-AA as supporting growth factors.
Collapse
|