|
1
|
Dhar A, Moinuddin FM, Zamanian CA, Sharar AD, Dominari A, Graepel S, Windebank AJ, Bydon M. SOX Genes in Spinal Cord Injury: Redefining Neural Stem Cell Regeneration Strategies. Mol Neurobiol 2025:10.1007/s12035-025-04882-w. [PMID: 40156684 DOI: 10.1007/s12035-025-04882-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
The study design is literature review. The sex-determining region Y gene (SRY)-related high mobility group box (HMG)-box (SOX) gene family has primarily been associated with neural development and sex determination and is a key component of human embryonic development. Recent studies on zebrafish models have demonstrated that the unique ability of the latter for central nervous tissue (CNS) repair following injury is largely mediated by SOX genes. Given that efforts aimed at the structural regeneration and functional restoration of neural tissue still represent a major therapeutic challenge in patients suffering CNS injury, these findings have initiated a discussion regarding the development of novel therapeutic strategies for SCI focusing on neural tissue regeneration. Spinal cord injury (SCI), in particular, represents a field that could greatly benefit from studies related to the function of the SOX genes. Neuro-informatics Laboratory, Mayo Clinic, Rochester, MN. A literature review was conducted, with a focus on SOX gene that has been described in the experimental studies of SCI. In this review, the existing evidence linking the SOX gene family to the pathophysiology of SCI is summarized, and future research steps regarding the potential implications of the SOX genes in neurological recovery following SCI are discussed, especially focusing on highlighting potential therapeutic targets. The potential implications of the latter could play a crucial role in future efforts to advance the treatment approaches to SCI.
Collapse
Affiliation(s)
- Ashis Dhar
- Mayo Clinic Neuro-Informatics Laboratory, Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA
| | - F M Moinuddin
- Mayo Clinic Neuro-Informatics Laboratory, Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA
| | - Cameron A Zamanian
- Mayo Clinic Neuro-Informatics Laboratory, Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA
| | - Ahnaf Dil Sharar
- Mayo Clinic Neuro-Informatics Laboratory, Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA
| | - Asimina Dominari
- Mayo Clinic Neuro-Informatics Laboratory, Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA
| | - Stephen Graepel
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA
| | | | - Mohamad Bydon
- Mayo Clinic Neuro-Informatics Laboratory, Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
- Department of Neurological Surgery, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
2
|
Smith AN, Nagrabski S, Baker L, Kramer AH, Sharp DJ, Byrnes KR. Fidgetin-like 2 knockdown increases acute neuroinflammation and improves recovery in a rat model of spinal cord injury. J Neuroinflammation 2025; 22:73. [PMID: 40065364 PMCID: PMC11895163 DOI: 10.1186/s12974-025-03344-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 01/10/2025] [Indexed: 03/14/2025] Open
Abstract
Spinal cord injury (SCI) can cause permanent dysfunction proceeding from multifaceted neuroinflammatory processes that contribute to damage and repair. Fidgetin-like 2 (FL2), a microtubule-severing enzyme that negatively regulates axon growth, microglial functions, and wound healing, has emerged as a potential therapeutic target for central nervous system injuries and neuroinflammation. To test the hypothesis that FL2 knockdown increases acute neuroinflammation and improves recovery after SCI, we examined the effects of nanoparticle-encapsulated FL2 siRNA treatment after a moderate contusion SCI in rats. SCI significantly increased FL2 expression in the lesion site and rostral to the lesion 1 day post-injury (dpi). A single treatment of FL2 siRNA after injury led to modestly improved locomotor recovery consistent with the preservation of corticospinal tract function, accompanied by reduced inflammation and increased presence of oligodendrocytes. In determining the acute effects of treatment, RNA sequencing and gene set enrichment analyses revealed that FL2 siRNA modulates early cellular responses, including chemokine signaling, both pro- and anti-inflammatory immune reactions, and neurotransmitter signaling pathways at 1, 4, and 7 dpi. Follow-up analyses at 4 dpi using dual in situ hybridization and immunohistochemistry demonstrated that SCI increased FL2 mRNA and that FL2 was colocalized with microglia/macrophages. FL2 downregulation resulted in a marked accumulation of microglia at the lesion site, accompanied by increased inflammatory markers (IL-1β, TGF-β1, and CD68). The results suggest SCI induces an increase in FL2 expression that undermines acute inflammatory responses as well as spinal cord integrity and growth. Overall, our study suggests that targeting FL2 holds promise as a therapeutic strategy for treating SCI.
Collapse
Affiliation(s)
- Austin N Smith
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Samantha Nagrabski
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | | | | | - David J Sharp
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kimberly R Byrnes
- Neuroscience Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
- Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
| |
Collapse
|
|
3
|
Mestriner RG, Kalsi-Ryan S, Gholamrezaei G, Balbinot G. Editorial: Rehabilitation to guide functional plasticity and regeneration with novel cellular, pharmacological and neuromodulation therapies. FRONTIERS IN REHABILITATION SCIENCES 2025; 6:1563975. [PMID: 40018653 PMCID: PMC11865205 DOI: 10.3389/fresc.2025.1563975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 01/31/2025] [Indexed: 03/01/2025]
Affiliation(s)
- Régis Gemerasca Mestriner
- Biomedical Gerontology Program of the School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
- Neurosciences, Motor Behavior and Rehabilitation Research Group (NECORE), PUCRS, Porto Alegre, Brazil
- School of Health and Life Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil
- Geriatric and Gerontology Institute, PUCRS, Porto Alegre, Brazil
| | - Sukhvinder Kalsi-Ryan
- KITE Research Institute|Toronto Rehab, University Health Network, Toronto, ON, Canada
| | - Gita Gholamrezaei
- KITE Research Institute|Toronto Rehab, University Health Network, Toronto, ON, Canada
| | - Gustavo Balbinot
- Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
- Movement Neurorehabilitation and Neurorepair Laboratory, Simon Fraser University, Burnaby, BC, Canada
- Institute for Neuroscience and Neurotechnology, Simon Fraser University, Burnaby, BC, Canada
| |
Collapse
|
|
4
|
Hao P, Yang Z, So KF, Li X. A core scientific problem in the treatment of central nervous system diseases: newborn neurons. Neural Regen Res 2024; 19:2588-2601. [PMID: 38595278 PMCID: PMC11168522 DOI: 10.4103/nrr.nrr-d-23-01775] [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: 11/24/2023] [Revised: 01/06/2024] [Accepted: 02/22/2024] [Indexed: 04/11/2024] Open
Abstract
It has long been asserted that failure to recover from central nervous system diseases is due to the system's intricate structure and the regenerative incapacity of adult neurons. Yet over recent decades, numerous studies have established that endogenous neurogenesis occurs in the adult central nervous system, including humans'. This has challenged the long-held scientific consensus that the number of adult neurons remains constant, and that new central nervous system neurons cannot be created or renewed. Herein, we present a comprehensive overview of the alterations and regulatory mechanisms of endogenous neurogenesis following central nervous system injury, and describe novel treatment strategies that target endogenous neurogenesis and newborn neurons in the treatment of central nervous system injury. Central nervous system injury frequently results in alterations of endogenous neurogenesis, encompassing the activation, proliferation, ectopic migration, differentiation, and functional integration of endogenous neural stem cells. Because of the unfavorable local microenvironment, most activated neural stem cells differentiate into glial cells rather than neurons. Consequently, the injury-induced endogenous neurogenesis response is inadequate for repairing impaired neural function. Scientists have attempted to enhance endogenous neurogenesis using various strategies, including using neurotrophic factors, bioactive materials, and cell reprogramming techniques. Used alone or in combination, these therapeutic strategies can promote targeted migration of neural stem cells to an injured area, ensure their survival and differentiation into mature functional neurons, and facilitate their integration into the neural circuit. Thus can integration replenish lost neurons after central nervous system injury, by improving the local microenvironment. By regulating each phase of endogenous neurogenesis, endogenous neural stem cells can be harnessed to promote effective regeneration of newborn neurons. This offers a novel approach for treating central nervous system injury.
Collapse
Affiliation(s)
- Peng Hao
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Zhaoyang Yang
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Kwok-Fai So
- Guangdong-HongKong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, Guangdong Province, China
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong Province, China
- Department of Ophthalmology and State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong Special Administration Region, China
- Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, Guangdong Province, China
- Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Xiaoguang Li
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
- Department of Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| |
Collapse
|
|
5
|
Liu H, Yi J, Zhang C, Li Y, Wang Q, Wang S, Dai S, Zheng Z, Jiang T, Gao P, Xue A, Huang Z, Kong F, Wang Y, He B, Guo X, Li Q, Chen J, Yin G, Zhao S. Macrophage GIT1 promotes oligodendrocyte precursor cell differentiation and remyelination after spinal cord injury. Glia 2024; 72:1674-1692. [PMID: 38899731 DOI: 10.1002/glia.24577] [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: 08/29/2023] [Revised: 05/02/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024]
Abstract
Spinal cord injury (SCI) can result in severe motor and sensory deficits, for which currently no effective cure exists. The pathological process underlying this injury is extremely complex and involves many cell types in the central nervous system. In this study, we have uncovered a novel function for macrophage G protein-coupled receptor kinase-interactor 1 (GIT1) in promoting remyelination and functional repair after SCI. Using GIT1flox/flox Lyz2-Cre (GIT1 CKO) mice, we identified that GIT1 deficiency in macrophages led to an increased generation of tumor necrosis factor-alpha (TNFα), reduced proportion of mature oligodendrocytes (mOLs), impaired remyelination, and compromised functional recovery in vivo. These effects in GIT1 CKO mice were reversed with the administration of soluble TNF inhibitor. Moreover, bone marrow transplantation from GIT1 CWT mice reversed adverse outcomes in GIT1 CKO mice, further indicating the role of macrophage GIT1 in modulating spinal cord injury repair. Our in vitro experiments showed that macrophage GIT1 plays a critical role in secreting TNFα and influences the differentiation of oligodendrocyte precursor cells (OPCs) after stimulation with myelin debris. Collectively, our data uncovered a new role of macrophage GIT1 in regulating the transformation of OPCs into mOLs, essential for functional remyelination after SCI, suggesting that macrophage GIT1 could be a promising treatment target of SCI.
Collapse
Affiliation(s)
- Hao Liu
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiang Yi
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Orthopedics, Yancheng Third People's Hospital, Yancheng, Jiangsu, China
| | - Chenxi Zhang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yin Li
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qian Wang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shenyu Wang
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Siming Dai
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ziyang Zheng
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tao Jiang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Peng Gao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ao Xue
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhenfei Huang
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fanqi Kong
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yongxiang Wang
- Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou, China
- Northern Jiangsu People's Hospital, Yangzhou, China
| | - Baorong He
- Department of Spine Surgery, Honghui-hospital, Xi'an Jiaotong Uinversity, School of Medicine, Xi'an, China
| | - Xiaodong Guo
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qingqing Li
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jian Chen
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoyong Yin
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shujie Zhao
- Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
- Jiangsu Institute of Functional Reconstruction and Rehabilitation, Nanjing, Jiangsu, China
- Spinal Cord Disease Research Center, Nanjing Medical University, Nanjing, Jiangsu, China
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
6
|
dos Santos ACR, Laurindo RP, Pestana FM, Heringer LDS, Canedo NHS, Martinez AMB, Marques SA. Exercise Volume Can Modulate the Regenerative Response to Spinal Cord Injury in Mice. Neurotrauma Rep 2024; 5:721-737. [PMID: 39144452 PMCID: PMC11319863 DOI: 10.1089/neur.2024.0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2024] Open
Abstract
Traumatic spinal cord injury (SCI) causes debilitating motor and sensory deficits that impair functional performance, and physical rehabilitation is currently the only established therapeutic reality in the clinical setting. In this study, we aimed to assess the effect of exercise of different volume and timing of intervention on functional recovery and neuromuscular regeneration in a mouse model of compressive SCI. Mice were assigned to one of four groups: laminectomy only (SHAM); injured, without treadmill training (SCI); injured, treadmill trained for 10 min until day 56 postinjury (TMT1); and injured, treadmill trained for two 10-min cycles with a 10-min pause between them until day 28 postinjury followed by the TMT1 protocol until day 56 postinjury (TMT3). On day 7 postinjury, animals started an eight-week treadmill-training exercise protocol and were trained three times a week. TMT3 mice had the best results in terms of neuroregeneration, functional recovery, and muscle plasticity as measured by functional and morphometric parameters. In conclusion, the volume of exercise can modulate the quality of the regenerative response to injury, when started in the acute phase and adjusted according to the inflammatory window.
Collapse
Affiliation(s)
| | - Renata Pereira Laurindo
- Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Marques Pestana
- Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiza dos Santos Heringer
- Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Ana Maria Blanco Martinez
- Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Suelen Adriani Marques
- Graduate Program in Pathological Anatomy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Neurobiology Department, Institute of Biology, Federal Fluminense University, Rio de Janeiro, Brazil
| |
Collapse
|
|
7
|
Liu D, Shen H, Zhang K, Shen Y, Wen R, He X, Long G, Li X. Functional Hydrogel Co-Remolding Migration and Differentiation Microenvironment for Severe Spinal Cord Injury Repair. Adv Healthc Mater 2024; 13:e2301662. [PMID: 37937326 DOI: 10.1002/adhm.202301662] [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: 05/31/2023] [Revised: 10/25/2023] [Indexed: 11/09/2023]
Abstract
Spinal cord injury (SCI) activates nestin+ neural stem cells (NSCs), which can be regarded as potential seed cells for neuronal regeneration. However, the lesion microenvironment seriously hinders the migration of the nestin+ cells to the lesion epicenter and their differentiation into neurons to rebuild neural circuits. In this study, a photosensitive hydrogel scaffold is prepared as drug delivery carrier. Genetically engineered SDF1α and NT3 are designed and the scaffold is binary modified to reshape the lesion microenvironment. The binary modified scaffold can effectively induce the migration and neuronal differentiation of nestin+ NSCs in vitro. When implanted into a rat complete SCI model, many of the SCI-activated nestin+ cells migrate into the lesion site and give rise to neurons in short-term. Meanwhile, long-term repair results also show that implantation of the binary modified scaffold can effectively promote the maturation, functionalization and synaptic network reconstruction of neurons in the lesion site. In addition, animals treated with binary scaffold also showed better improvement in motor functions. The therapeutic strategy based on remolding the migration and neuronal differentiation lesion microenvironment provides a new insight into SCI repair by targeting activated nestin+ cells, which exhibits excellent clinical transformation prospects.
Collapse
Affiliation(s)
- Dingyang Liu
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan Province, 410078, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China
| | - He Shen
- Key Laboratory for Nano-Bio Interface Research, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China
| | - Kai Zhang
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan Province, 410078, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China
| | - Yeyu Shen
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan Province, 410078, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China
| | - Runlin Wen
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan Province, 410078, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China
| | - Xinghui He
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan Province, 410078, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China
| | - Ge Long
- Department of Anesthesia, the Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410078, China
| | - Xing Li
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Central South University, Changsha, Hunan Province, 410078, China
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China
| |
Collapse
|
|
8
|
Perez JC, Poulen G, Cardoso M, Boukhaddaoui H, Gazard CM, Courtand G, Bertrand SS, Gerber YN, Perrin FE. CSF1R inhibition at chronic stage after spinal cord injury modulates microglia proliferation. Glia 2023; 71:2782-2798. [PMID: 37539655 DOI: 10.1002/glia.24451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 07/03/2023] [Accepted: 07/21/2023] [Indexed: 08/05/2023]
Abstract
Traumatic spinal cord injury (SCI) induces irreversible autonomic and sensory-motor impairments. A large number of patients exhibit chronic SCI and no curative treatment is currently available. Microglia are predominant immune players after SCI, they undergo highly dynamic processes, including proliferation and morphological modification. In a translational aim, we investigated whether microglia proliferation persists at chronic stage after spinal cord hemisection and whether a brief pharmacological treatment could modulate microglial responses. We first carried out a time course analysis of SCI-induced microglia proliferation associated with morphological analysis up to 84 days post-injury (dpi). Second, we analyzed outcomes on microglia of an oral administration of GW2580, a colony stimulating factor-1 receptor tyrosine kinase inhibitor reducing selectively microglia proliferation. After SCI, microglia proliferation remains elevated at 84 dpi. The percentage of proliferative microglia relative to proliferative cells increases over time reaching almost 50% at 84 dpi. Morphological modifications of microglia processes are observed up to 84 dpi and microglia cell body area is transiently increased up to 42 dpi. A transient post-injury GW2580-delivery at two chronic stages after SCI (42 and 84 dpi) reduces microglia proliferation and modifies microglial morphology evoking an overall limitation of secondary inflammation. Finally, transient GW2580-delivery at chronic stage after SCI modulates myelination processes. Together our study shows that there is a persistent microglia proliferation induced by SCI and that a pharmacological treatment at chronic stage after SCI modulates microglial responses. Thus, a transient oral GW2580-delivery at chronic stage after injury may provide a promising therapeutic strategy for chronic SCI patients.
Collapse
Affiliation(s)
| | - Gaetan Poulen
- MMDN, Univ. Montpellier, EPHE, INSERM, Montpellier, France
| | - Maida Cardoso
- UMR 5221, Univ. Montpellier, CNRS, Montpellier, France
| | | | | | | | | | | | - Florence Evelyne Perrin
- MMDN, Univ. Montpellier, EPHE, INSERM, Montpellier, France
- Institut Universitaire de France (IUF), Paris, France
| |
Collapse
|
|
9
|
Metcalfe M, David BT, Langley BC, Hill CE. Elevation of NAD + by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery. Exp Neurol 2023; 368:114479. [PMID: 37454712 DOI: 10.1016/j.expneurol.2023.114479] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 06/28/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023]
Abstract
Spinal cord injury (SCI)-induced tissue damage spreads to neighboring spared cells in the hours, days, and weeks following injury, leading to exacerbation of tissue damage and functional deficits. Among the biochemical changes is the rapid reduction of cellular nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for energy metabolism and an essential cofactor for non-redox NAD+-dependent enzymes with critical functions in sensing and repairing damaged tissue. NAD+ depletion propagates tissue damage. Augmenting NAD+ by exogenous application of NAD+, its synthesizing enzymes, or its cellular precursors mitigates tissue damage. Nicotinamide riboside (NR) is considered to be one of the most promising NAD+ precursors for clinical application due to its ability to safely and effectively boost cellular NAD+ synthesis in rats and humans. Moreover, various preclinical studies have demonstrated that NR can provide tissue protection. Despite these promising findings, little is known about the potential benefits of NR in the context of SCI. In the current study, we tested whether NR administration could effectively increase NAD+ levels in the injured spinal cord and whether this augmentation of NAD+ would promote spinal cord tissue protection and ultimately lead to improvements in locomotor function. Our findings indicate that administering NR (500 mg/kg) intraperitoneally from four days before to two weeks after a mid-thoracic contusion-SCI injury, effectively doubles NAD+ levels in the spinal cord of Long-Evans rats. Moreover, NR administration plays a protective role in preserving spinal cord tissue post-injury, particularly in neurons and axons, as evident from the observed gray and white matter sparing. Additionally, it enhances motor function, as evaluated through the BBB subscore and missteps on the horizontal ladderwalk. Collectively, these findings demonstrate that administering NR, a precursor of NAD+, increases NAD+ within the injured spinal cord and effectively mitigates the tissue damage and functional decline that occurs following SCI.
Collapse
Affiliation(s)
- Mariajose Metcalfe
- Burke Neurological Institute, White Plains, NY, United States; Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States.
| | - Brian T David
- Burke Neurological Institute, White Plains, NY, United States; Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States.
| | - Brett C Langley
- Burke Neurological Institute, White Plains, NY, United States; Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States.
| | - Caitlin E Hill
- Burke Neurological Institute, White Plains, NY, United States; Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States.
| |
Collapse
|
|
10
|
Mungenast L, Nieminen R, Gaiser C, Faia-Torres AB, Rühe J, Suter-Dick L. Electrospun decellularized extracellular matrix scaffolds promote the regeneration of injured neurons. BIOMATERIALS AND BIOSYSTEMS 2023; 11:100081. [PMID: 37427248 PMCID: PMC10329103 DOI: 10.1016/j.bbiosy.2023.100081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/23/2023] [Accepted: 06/17/2023] [Indexed: 07/11/2023] Open
Abstract
Traumatic injury to the spinal cord (SCI) causes the transection of neurons, formation of a lesion cavity, and remodeling of the microenvironment by excessive extracellular matrix (ECM) deposition and scar formation leading to a regeneration-prohibiting environment. Electrospun fiber scaffolds have been shown to simulate the ECM and increase neural alignment and neurite outgrowth contributing to a growth-permissive matrix. In this work, electrospun ECM-like fibers providing biochemical and topological cues are implemented into a scaffold to represent an oriented biomaterial suitable for the alignment and migration of neural cells in order to improve spinal cord regeneration. The successfully decellularized spinal cord ECM (dECM), with no visible cell nuclei and dsDNA content < 50 ng/mg tissue, showed preserved ECM components, such as glycosaminoglycans and collagens. Serving as the biomaterial for 3D printer-assisted electrospinning, highly aligned and randomly distributed dECM fiber scaffolds (< 1 µm fiber diameter) were fabricated. The scaffolds were cytocompatible and supported the viability of a human neural cell line (SH-SY5Y) for 14 days. Cells were selectively differentiated into neurons, as confirmed by immunolabeling of specific cell markers (ChAT, Tubulin ß), and followed the orientation given by the dECM scaffolds. After generating a lesion site on the cell-scaffold model, cell migration was observed and compared to reference poly-ε-caprolactone fiber scaffolds. The aligned dECM fiber scaffold promoted the fastest and most efficient lesion closure, indicating superior cell guiding capabilities of dECM-based scaffolds. The strategy of combining decellularized tissues with controlled deposition of fibers to optimize biochemical and topographical cues opens the way for clinically relevant central nervous system scaffolding solutions.
Collapse
Affiliation(s)
- Lena Mungenast
- Institute for Chemistry and Bioanalytics, University of Applied Sciences FHNW, Hofackerstrasse 30, Muttenz 4132, Switzerland
| | - Ronya Nieminen
- Institute for Chemistry and Bioanalytics, University of Applied Sciences FHNW, Hofackerstrasse 30, Muttenz 4132, Switzerland
| | - Carine Gaiser
- Institute for Chemistry and Bioanalytics, University of Applied Sciences FHNW, Hofackerstrasse 30, Muttenz 4132, Switzerland
| | - Ana Bela Faia-Torres
- Institute for Chemistry and Bioanalytics, University of Applied Sciences FHNW, Hofackerstrasse 30, Muttenz 4132, Switzerland
| | - Jürgen Rühe
- Department of Microsystems Engineering, IMTEK, University of Freiburg, Freiburg 79110, Germany
| | - Laura Suter-Dick
- Institute for Chemistry and Bioanalytics, University of Applied Sciences FHNW, Hofackerstrasse 30, Muttenz 4132, Switzerland
- SCAHT: Swiss Centre for Applied Human Toxicology, Missionsstrasse 64, Basel 4055, Switzerland
| |
Collapse
|
|
11
|
Perez-Gianmarco L, Kukley M. Understanding the Role of the Glial Scar through the Depletion of Glial Cells after Spinal Cord Injury. Cells 2023; 12:1842. [PMID: 37508505 PMCID: PMC10377788 DOI: 10.3390/cells12141842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/30/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Spinal cord injury (SCI) is a condition that affects between 8.8 and 246 people in a million and, unlike many other neurological disorders, it affects mostly young people, causing deficits in sensory, motor, and autonomic functions. Promoting the regrowth of axons is one of the most important goals for the neurological recovery of patients after SCI, but it is also one of the most challenging goals. A key event after SCI is the formation of a glial scar around the lesion core, mainly comprised of astrocytes, NG2+-glia, and microglia. Traditionally, the glial scar has been regarded as detrimental to recovery because it may act as a physical barrier to axon regrowth and release various inhibitory factors. However, more and more evidence now suggests that the glial scar is beneficial for the surrounding spared tissue after SCI. Here, we review experimental studies that used genetic and pharmacological approaches to ablate specific populations of glial cells in rodent models of SCI in order to understand their functional role. The studies showed that ablation of either astrocytes, NG2+-glia, or microglia might result in disorganization of the glial scar, increased inflammation, extended tissue degeneration, and impaired recovery after SCI. Hence, glial cells and glial scars appear as important beneficial players after SCI.
Collapse
Affiliation(s)
- Lucila Perez-Gianmarco
- Achucarro Basque Center for Neuroscience, 48940 Leioa, PC, Spain
- Department of Neurosciences, University of the Basque Country, 48940 Leioa, PC, Spain
| | - Maria Kukley
- Achucarro Basque Center for Neuroscience, 48940 Leioa, PC, Spain
- IKERBASQUE Basque Foundation for Science, 48009 Bilbao, PC, Spain
| |
Collapse
|
|
12
|
Shafqat A, Albalkhi I, Magableh HM, Saleh T, Alkattan K, Yaqinuddin A. Tackling the glial scar in spinal cord regeneration: new discoveries and future directions. Front Cell Neurosci 2023; 17:1180825. [PMID: 37293626 PMCID: PMC10244598 DOI: 10.3389/fncel.2023.1180825] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/08/2023] [Indexed: 06/10/2023] Open
Abstract
Axonal regeneration and functional recovery are poor after spinal cord injury (SCI), typified by the formation of an injury scar. While this scar was traditionally believed to be primarily responsible for axonal regeneration failure, current knowledge takes a more holistic approach that considers the intrinsic growth capacity of axons. Targeting the SCI scar has also not reproducibly yielded nearly the same efficacy in animal models compared to these neuron-directed approaches. These results suggest that the major reason behind central nervous system (CNS) regeneration failure is not the injury scar but a failure to stimulate axon growth adequately. These findings raise questions about whether targeting neuroinflammation and glial scarring still constitute viable translational avenues. We provide a comprehensive review of the dual role of neuroinflammation and scarring after SCI and how future research can produce therapeutic strategies targeting the hurdles to axonal regeneration posed by these processes without compromising neuroprotection.
Collapse
|
|
13
|
Pai B, Tome-Garcia J, Cheng WS, Nudelman G, Beaumont KG, Ghatan S, Panov F, Caballero E, Sarpong K, Marcuse L, Yoo J, Jiang Y, Schaefer A, Akbarian S, Sebra R, Pinto D, Zaslavsky E, Tsankova NM. High-resolution transcriptomics informs glial pathology in human temporal lobe epilepsy. Acta Neuropathol Commun 2022; 10:149. [PMID: 36274170 PMCID: PMC9590125 DOI: 10.1186/s40478-022-01453-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 09/30/2022] [Indexed: 11/16/2022] Open
Abstract
The pathophysiology of epilepsy underlies a complex network dysfunction between neurons and glia, the molecular cell type-specific contributions of which remain poorly defined in the human disease. In this study, we validated a method that simultaneously isolates neuronal (NEUN +), astrocyte (PAX6 + NEUN-), and oligodendroglial progenitor (OPC) (OLIG2 + NEUN-) enriched nuclei populations from non-diseased, fresh-frozen human neocortex and then applied it to characterize the distinct transcriptomes of such populations isolated from electrode-mapped temporal lobe epilepsy (TLE) surgical samples. Nuclear RNA-seq confirmed cell type specificity and informed both common and distinct pathways associated with TLE in astrocytes, OPCs, and neurons. Compared to postmortem control, the transcriptome of epilepsy astrocytes showed downregulation of mature astrocyte functions and upregulation of development-related genes. To gain further insight into glial heterogeneity in TLE, we performed single cell transcriptomics (scRNA-seq) on four additional human TLE samples. Analysis of the integrated TLE dataset uncovered a prominent subpopulation of glia that express a hybrid signature of both reactive astrocyte and OPC markers, including many cells with a mixed GFAP + OLIG2 + phenotype. A further integrated analysis of this TLE scRNA-seq dataset and a previously published normal human temporal lobe scRNA-seq dataset confirmed the unique presence of hybrid glia only in TLE. Pseudotime analysis revealed cell transition trajectories stemming from this hybrid population towards both OPCs and reactive astrocytes. Immunofluorescence studies in human TLE samples confirmed the rare presence of GFAP + OLIG2 + glia, including some cells with proliferative activity, and functional analysis of cells isolated directly from these samples disclosed abnormal neurosphere formation in vitro. Overall, cell type-specific isolation of glia from surgical epilepsy samples combined with transcriptomic analyses uncovered abnormal glial subpopulations with de-differentiated phenotype, motivating further studies into the dysfunctional role of reactive glia in temporal lobe epilepsy.
Collapse
Affiliation(s)
- Balagopal Pai
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jessica Tome-Garcia
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Wan Sze Cheng
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - German Nudelman
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kristin G Beaumont
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
| | - Saadi Ghatan
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Fedor Panov
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Elodia Caballero
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kwadwo Sarpong
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lara Marcuse
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jiyeoun Yoo
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yan Jiang
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Anne Schaefer
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Schahram Akbarian
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Robert Sebra
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
| | - Dalila Pinto
- Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Icahn Institute for Data Science and Genomic Technology, New York, NY, 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Elena Zaslavsky
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| | - Nadejda M Tsankova
- Department of Pathology and Laboratory Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
| |
Collapse
|
|
14
|
Ribeiro M, Ayupe AC, Beckedorff FC, Levay K, Rodriguez S, Tsoulfas P, Lee JK, Nascimento-Dos-Santos G, Park KK. Retinal ganglion cell expression of cytokine enhances occupancy of NG2 cell-derived astrocytes at the nerve injury site: Implication for axon regeneration. Exp Neurol 2022; 355:114147. [PMID: 35738417 PMCID: PMC10648309 DOI: 10.1016/j.expneurol.2022.114147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/27/2022] [Accepted: 06/14/2022] [Indexed: 11/18/2022]
Abstract
Following injury in the central nervous system, a population of astrocytes occupy the lesion site, form glial bridges and facilitate axon regeneration. These astrocytes originate primarily from resident astrocytes or NG2+ oligodendrocyte progenitor cells. However, the extent to which these cell types give rise to the lesion-filling astrocytes, and whether the astrocytes derived from different cell types contribute similarly to optic nerve regeneration remain unclear. Here we examine the distribution of astrocytes and NG2+ cells in an optic nerve crush model. We show that optic nerve astrocytes partially fill the injury site over time after a crush injury. Viral mediated expression of a growth-promoting factor, ciliary neurotrophic factor (CNTF), in retinal ganglion cells (RGCs) promotes axon regeneration without altering the lesion size or the degree of lesion-filling GFAP+ cells. Strikingly, using inducible NG2CreER driver mice, we found that CNTF overexpression in RGCs increases the occupancy of NG2+ cell-derived astrocytes in the optic nerve lesion. An EdU pulse-chase experiment shows that the increase in NG2 cell-derived astrocytes is not due to an increase in cell proliferation. Lastly, we performed RNA-sequencing on the injured optic nerve and reveal that CNTF overexpression in RGCs results in significant changes in the expression of distinct genes, including those that encode chemokines, growth factor receptors, and immune cell modulators. Even though CNTF-induced axon regeneration has long been recognized, this is the first evidence of this procedure affecting glial cell fate at the optic nerve crush site. We discuss possible implication of these results for axon regeneration.
Collapse
Affiliation(s)
- Marcio Ribeiro
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA; Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, AA7103 MCN/VUIIS, 1161 21st Ave. S., Nashville, TN 37232, USA
| | - Ana C Ayupe
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Felipe C Beckedorff
- Sylvester Comprehensive Cancer Center, Department of Human Genetics, Biomedical Research Building, University of Miami Miller School of Medicine, Room 715, 1501 NW 10th Avenue, Miami, FL 33136, USA
| | - Konstantin Levay
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Sara Rodriguez
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Pantelis Tsoulfas
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Jae K Lee
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Gabriel Nascimento-Dos-Santos
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA
| | - Kevin K Park
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
| |
Collapse
|
|
15
|
Miranpuri GS, Bali P, Nguyen J, Kim JJ, Modgil S, Mehra P, Buttar S, Brown G, Yutuc N, Singh H, Wood A, Singh J, Anand A. Role of Microglia and Astrocytes in Spinal Cord Injury Induced Neuropathic Pain. Ann Neurosci 2022; 28:219-228. [PMID: 35341227 PMCID: PMC8948321 DOI: 10.1177/09727531211046367] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/03/2021] [Indexed: 12/30/2022] Open
Abstract
Background: Spinal cord injuries incite varying degrees of symptoms in patients, ranging
from weakness and incoordination to paralysis. Common amongst spinal cord
injury (SCI) patients, neuropathic pain (NP) is a debilitating medical
condition. Unfortunately, there remain many clinical impediments in treating
NP because there is a lack of understanding regarding the mechanisms behind
SCI-induced NP (SCINP). Given that more than 450,000 people in the United
States alone suffer from SCI, it is unsatisfactory that current treatments
yield poor results in alleviating and treating NP. Summary: In this review, we briefly discussed the models of SCINP along with the
mechanisms of NP progression. Further, current treatment modalities are
herein explored for SCINP involving pharmacological interventions targeting
glia cells and astrocytes. Key message: The studies presented in this review provide insight for new directions
regarding SCINP alleviation. Given the severity and incapacitating effects
of SCINP, it is imperative to study the pathways involved and find new
therapeutic targets in coordination with stem cell research, and to develop
a new gold-standard in SCINP treatment.
Collapse
Affiliation(s)
- Gurwattan S Miranpuri
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Parul Bali
- Department of Biological Sciences, Indian Institute of Science Education & Research Mohali, India
| | - Justyn Nguyen
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Jason J Kim
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Shweta Modgil
- Neuroscience research lab, Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Priya Mehra
- Neuroscience research lab, Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.,Department of Biotechnology, Panjab University, Chandigarh, India
| | - Seah Buttar
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Greta Brown
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Noemi Yutuc
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Harpreet Singh
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Aleksandar Wood
- Department of Neurological Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States
| | - Jagtar Singh
- Department of Biotechnology, Panjab University, Chandigarh, India
| | - Akshay Anand
- Neuroscience research lab, Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.,CCRYN- Collaborative Centre for Mind Body Intervention through Yoga.,Centre of Phenomenology and Cognitive Sciences, Panjab University, Chandigarh, India
| |
Collapse
|
|
16
|
Perez JC, Gerber YN, Perrin FE. Dynamic Diversity of Glial Response Among Species in Spinal Cord Injury. Front Aging Neurosci 2021; 13:769548. [PMID: 34899275 PMCID: PMC8662749 DOI: 10.3389/fnagi.2021.769548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/29/2021] [Indexed: 12/11/2022] Open
Abstract
The glial scar that forms after traumatic spinal cord injury (SCI) is mostly composed of microglia, NG2 glia, and astrocytes and plays dual roles in pathophysiological processes induced by the injury. On one hand, the glial scar acts as a chemical and physical obstacle to spontaneous axonal regeneration, thus preventing functional recovery, and, on the other hand, it partly limits lesion extension. The complex activation pattern of glial cells is associated with cellular and molecular crosstalk and interactions with immune cells. Interestingly, response to SCI is diverse among species: from amphibians and fishes that display rather limited (if any) glial scarring to mammals that exhibit a well-identifiable scar. Additionally, kinetics of glial activation varies among species. In rodents, microglia become activated before astrocytes, and both glial cell populations undergo activation processes reflected amongst others by proliferation and migration toward the injury site. In primates, glial cell activation is delayed as compared to rodents. Here, we compare the spatial and temporal diversity of the glial response, following SCI amongst species. A better understanding of mechanisms underlying glial activation and scar formation is a prerequisite to develop timely glial cell-specific therapeutic strategies that aim to increase functional recovery.
Collapse
Affiliation(s)
| | - Yannick N Gerber
- MMDN, Université de Montpellier, EPHE, INSERM, Montpellier, France
| | - Florence E Perrin
- MMDN, Université de Montpellier, EPHE, INSERM, Montpellier, France.,Institut Universitaire de France (IUF), Paris, France
| |
Collapse
|
|
17
|
Jung HH, Koh CS, Park M, Kim JH, Woo HN, Lee H, Chang JW. Microglial deactivation by adeno-associated virus expressing small-hairpin GCH1 has protective effects against neuropathic pain development in a spinothalamic tract-lesion model. CNS Neurosci Ther 2021; 28:36-45. [PMID: 34845843 PMCID: PMC8673712 DOI: 10.1111/cns.13751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022] Open
Abstract
AIMS Neuropathic pain after spinal cord injury is one of the most difficult clinical problems after the loss of mobility, and pharmacological or neuromodulation therapy showed limited efficacy. In this study, we examine the possibility of pain modulation by a recombinant adeno-associated virus (rAAV) encoding small-hairpin RNA against GCH1 (rAAV-shGCH1) in a spinal cord injury model in which neuropathic pain was induced by a spinothalamic tract (STT) lesion. METHODS Micro-electric lesioning was used to damage the left STT in rats (n = 32), and either rAAV-shGCH1 (n = 19) or rAAV control (n = 6) was injected into the dorsal horn of the rats at the same time. On postoperative days 3, 7, and 14, we evaluated neuropathic pain using a behavioral test and microglial activation by immunohistochemical staining. RESULTS A pain modulation effect of shGCH1 was observed from postoperative days 3 to 14. The mechanical withdrawal threshold was 13.0 ± 0.95 in the shGCH1 group, 4.3 ± 1.37 in the control group, and 3.49 ± 0.85 in sham on postoperative day 3 (p < 0.0001) and continued to postoperative day 14 (shGCH1 vs. control: 11.4 ± 1.1 vs. 2.05 ± 0.60, p < 0.001 and shGCH1 vs. sham: 11.4 ± 1.1 vs. 1.43 ± 0.54, p < 0.001). Immunohistochemical staining of the spinal cord dorsal horn showed deactivation of microglia in the shGCH1 group without any change of delayed pattern of astrocyte activation as in STT model. CONCLUSIONS Neuropathic pain after spinal cord injury can be modulated bilaterally by deactivating microglial activation after a unilateral injection of rAAV-shGCH1 into the dorsal horn of a STT lesion spinal cord pain model. This new attempt would be another therapeutic approach for NP after SCI, which once happens; there is no clear curative options still now.
Collapse
Affiliation(s)
- Hyun Ho Jung
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Chin Su Koh
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Minkyung Park
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hyun Kim
- Department of Microbiology, University of Ulsan College of Medicine, Seoul, Korea.,Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea
| | - Ha-Na Woo
- Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea.,Department of Biochemistry & Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Heuiran Lee
- Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Korea.,Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Woo Chang
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.,Brain Korea 21 PLUS Project for Medical Science and Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
18
|
Establishing the ground squirrel as a superb model for retinal ganglion cell disorders and optic neuropathies. J Transl Med 2021; 101:1289-1303. [PMID: 34253851 PMCID: PMC8753557 DOI: 10.1038/s41374-021-00637-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 01/08/2023] Open
Abstract
Retinal ganglion cell (RGC) death occurs after optic nerve injury due to acute trauma or chronic degenerative conditions such as optic neuropathies (e.g., glaucoma). Currently, there are no effective therapies to prevent permanent vision loss resulting from RGC death, underlining the need for research on the pathogenesis of RGC disorders. Modeling human RGC/optic nerve diseases in non-human primates is ideal because of their similarity to humans, but has practical limitations including high cost and ethical considerations. In addition, many retinal degenerative disorders are age-related making the study in primate models prohibitively slow. For these reasons, mice and rats are commonly used to model RGC injuries. However, as nocturnal mammals, these rodents have retinal structures that differ from primates - possessing less than one-tenth of the RGCs found in the primate retina. Here we report the diurnal thirteen-lined ground squirrel (TLGS) as an alternative model. Compared to other rodent models, the number and distribution of RGCs in the TLGS retina are closer to primates. The TLGS retina possesses ~600,000 RGCs with the highest density along the equatorial retina matching the location of the highest cone density (visual streak). TLGS and primate retinas also share a similar interlocking pattern between RGC axons and astrocyte processes in the retina nerve fiber layer (RNFL). In addition, using TLGS we establish a new partial optic nerve injury model that precisely controls the extent of injury while sparing a portion of the retina as an ideal internal control for investigating the pathophysiology of axon degeneration and RGC death. Moreover, in vivo optical coherence tomography (OCT) imaging and ex vivo microscopic examinations of the retina in optic nerve injured TLGS confirm RGC loss precedes proximal axon degeneration, recapitulating human pathology. Thus, the TLGS retina is an excellent model, for translational research in neurodegeneration and therapeutic neuroprotection.
Collapse
|
|
19
|
IgM Immunoglobulin Influences Recovery after Cervical Spinal Cord Injury by Modulating the IgG Autoantibody Response. eNeuro 2021; 8:ENEURO.0491-19.2021. [PMID: 34413082 PMCID: PMC8431822 DOI: 10.1523/eneuro.0491-19.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 06/06/2021] [Accepted: 06/10/2021] [Indexed: 12/24/2022] Open
Abstract
Spinal cord injury (SCI) results in the development of detrimental autoantibodies against the lesioned spinal cord. IgM immunoglobulin maintains homeostasis against IgG-autoantibody responses, but its effect on SCI recovery remains unknown. In the present study we investigated the role of IgM immunoglobulin in influencing recovery after SCI. To this end, we induced cervical SCI at the C6/C7 level in mice that lacked secreted IgM immunoglobulin [IgM-knock-out (KO)] and their wild-type (WT) littermate controls. Overall, the absence of secretory IgM resulted in worse outcomes as compared with WT mice with SCI. At two weeks after injury, IgM-KO mice had significantly more IgG antibodies, which fixed the complement system, in the injured spinal cord parenchyma. In addition to these findings, IgM-KO mice had more parenchymal T-lymphocytes as well as CD11b+ microglia/macrophages, which co-localized with myelin. At 10 weeks after injury, IgM-KO mice showed significant impairment in neurobehavioral recovery, such as deteriorated coordination, reduced hindlimb swing speed and print area. These neurobehavioral detriments were coupled with increased lesional tissue and myelin loss. Taken together, this study provides the first evidence for the importance of IgM immunoglobulin in modulating recovery after SCI and suggests that modulating IgM could be a novel therapeutic approach to enhance recovery after SCI.
Collapse
|
|
20
|
Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease. Cells 2021; 10:cells10082045. [PMID: 34440814 PMCID: PMC8392301 DOI: 10.3390/cells10082045] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 02/07/2023] Open
Abstract
Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cerebrospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, proliferation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine.
Collapse
|
|
21
|
Corticospinal Motor Circuit Plasticity After Spinal Cord Injury: Harnessing Neuroplasticity to Improve Functional Outcomes. Mol Neurobiol 2021; 58:5494-5516. [PMID: 34341881 DOI: 10.1007/s12035-021-02484-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 07/07/2021] [Indexed: 10/20/2022]
Abstract
Spinal cord injury (SCI) is a devastating condition that affects approximately 294,000 people in the USA and several millions worldwide. The corticospinal motor circuitry plays a major role in controlling skilled movements and in planning and coordinating movements in mammals and can be damaged by SCI. While axonal regeneration of injured fibers over long distances is scarce in the adult CNS, substantial spontaneous neural reorganization and plasticity in the spared corticospinal motor circuitry has been shown in experimental SCI models, associated with functional recovery. Beneficially harnessing this neuroplasticity of the corticospinal motor circuitry represents a highly promising therapeutic approach for improving locomotor outcomes after SCI. Several different strategies have been used to date for this purpose including neuromodulation (spinal cord/brain stimulation strategies and brain-machine interfaces), rehabilitative training (targeting activity-dependent plasticity), stem cells and biological scaffolds, neuroregenerative/neuroprotective pharmacotherapies, and light-based therapies like photodynamic therapy (PDT) and photobiomodulation (PMBT). This review provides an overview of the spontaneous reorganization and neuroplasticity in the corticospinal motor circuitry after SCI and summarizes the various therapeutic approaches used to beneficially harness this neuroplasticity for functional recovery after SCI in preclinical animal model and clinical human patients' studies.
Collapse
|
|
22
|
Kwiecien JM, Dąbrowski W, Yaron JR, Zhang L, Delaney KH, Lucas AR. The Role of Astrogliosis in Formation of the Syrinx in Spinal Cord Injury. Curr Neuropharmacol 2021; 19:294-303. [PMID: 32691715 PMCID: PMC8033977 DOI: 10.2174/1570159x18666200720225222] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/09/2020] [Accepted: 07/16/2020] [Indexed: 12/28/2022] Open
Abstract
A massive localized trauma to the spinal cord results in complex pathologic events driven by necrosis and vascular damage which in turn leads to hemorrhage and edema. Severe, destructive and very protracted inflammatory response is characterized by infiltration by phagocytic macrophages of a site of injury which is converted into a cavity of injury (COI) surrounded by astroglial reaction mounted by the spinal cord. The tissue response to the spinal cord injury (SCI) has been poorly understood but the final outcome appears to be a mature syrinx filled with the cerebrospinal fluid with related neural tissue loss and permanent neurologic deficits. This paper reviews known pathologic mechanisms involved in the formation of the COI after SCI and discusses the integrative role of reactive astrogliosis in mechanisms involved in the removal of edema after the injury. A large proportion of edema fluid originating from the trauma and then from vasogenic edema related to persistent severe inflammation, may be moved into the COI in an active process involving astrogliosis and specifically over-expressed aquaporins.
Collapse
Affiliation(s)
- Jacek M. Kwiecien
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Wojciech Dąbrowski
- Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, ul. Jaczewskiego 8, Lublin 20-090 Poland
| | - Jordan R Yaron
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ, U.S.A
| | - Liqiang Zhang
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ, U.S.A
| | - Kathleen H. Delaney
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Alexandra R. Lucas
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ, U.S.A
| |
Collapse
|
|
23
|
Rezvan M, Meknatkhah S, Hassannejad Z, Sharif-Alhoseini M, Zadegan SA, Shokraneh F, Vaccaro AR, Lu Y, Rahimi-Movaghar V. Time-dependent microglia and macrophages response after traumatic spinal cord injury in rat: a systematic review. Injury 2020; 51:2390-2401. [PMID: 32665068 DOI: 10.1016/j.injury.2020.07.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 06/28/2020] [Accepted: 07/02/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To acquire evidence-based knowledge in temporal and spatial patterns of microglia/macrophages changes to facilitate finding proper intervention time for functional restoration after traumatic spinal cord injury (TSCI). SETTING Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran. METHODS We searched PubMed and EMBASE via Ovid SP with no temporal and linguistic restrictions. Besides, hand-search was performed in the bibliographies of relevant studies. The experimental non-interventional and non-transgenic animal studies confined to the rat species which assess the pathological change of microglia /macrophages at the specified time were included. RESULTS We found 15,315 non-duplicate studies. Screening through title and abstract narrowed down to 607 relevant articles, 31 of them were selected based on the inclusion criteria. The reactivity of the microglia/macrophages initiates in early hours PI in contusion, compression and transection models. Cells activity reached a maximum within 48 h to 28 days in compression, 7 days in contusion and between 4 and 60 days in transection models. Inflammatory response occurred at the epicenter, in or near the lesion site in both gray and white matter in all three injury models with a maximum extension of one centimeter caudal and rostral to the epicenter in the gray matter in contusion and transection models. CONCLUSION This study was designed to study spatial-temporal changes in the activation of microglia/macrophages overtime after TSCI. We were able to demonstrate time-dependent cell morphological changes after TSCI. The peak times of cell reactivity and the areas where the cells responded to the injury were determined.
Collapse
Affiliation(s)
- Motahareh Rezvan
- Department of Medical Laser, Medical Laser Research Center, Yara Institute, ACECR, Tehran, Iran; Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sogol Meknatkhah
- Laboratory of Neuro-Organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran
| | - Zahra Hassannejad
- Pediatric Urology and Regenerative Medicine Research Center, Children's Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Sharif-Alhoseini
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shayan A Zadegan
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farhad Shokraneh
- King's Technology Evaluation Centre (KiTEC), London Institute of Healthcare Engineering, School of Biomedical Engineering and Imaging Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Alexander R Vaccaro
- Department of Orthopedics and Neurosurgery, The Rothman Institute, Thomas Jefferson University, Philadelphia, PA, United States
| | - Yi Lu
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Vafa Rahimi-Movaghar
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
24
|
Moradi K, Golbakhsh M, Haghighi F, Afshari K, Nikbakhsh R, Khavandi MM, Faghani S, Badripour A, Etemadi A, Ashraf-Ganjouei A, Bagheri S, Dehpour AR. Inhibition of phosphodiesterase IV enzyme improves locomotor and sensory complications of spinal cord injury via altering microglial activity: Introduction of Roflumilast as an alternative therapy. Int Immunopharmacol 2020; 86:106743. [PMID: 32619958 DOI: 10.1016/j.intimp.2020.106743] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 06/06/2020] [Accepted: 06/23/2020] [Indexed: 02/02/2023]
Abstract
Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [F (24, 270) = 280.7, p < 0.001], thermal sensitivity [F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications.
Collapse
Affiliation(s)
- Kamyar Moradi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Golbakhsh
- Department of Orthopedic Surgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Farinaz Haghighi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Khashayar Afshari
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Rajan Nikbakhsh
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahdi Khavandi
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahriar Faghani
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Badripour
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Etemadi
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ashraf-Ganjouei
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sayna Bagheri
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ahmad Reza Dehpour
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
25
|
Pukos N, McTigue DM. Delayed short-term tamoxifen treatment does not promote remyelination or neuron sparing after spinal cord injury. PLoS One 2020; 15:e0235232. [PMID: 32735618 PMCID: PMC7394399 DOI: 10.1371/journal.pone.0235232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 06/10/2020] [Indexed: 12/18/2022] Open
Abstract
The tamoxifen-dependent Cre/lox system in transgenic mice has become an important research tool across all scientific disciplines for manipulating gene expression in specific cell types. In these mouse models, Cre-recombination is not induced until tamoxifen is administered, which allows researchers to have temporal control of genetic modifications. Interestingly, tamoxifen has been identified as a potential therapy for spinal cord injury (SCI) and traumatic brain injury patients due to its neuroprotective properties. It is also reparative in that it stimulates oligodendrocyte differentiation and remyelination after toxin-induced demyelination. However, it is unknown whether tamoxifen is neuroprotective and neuroreparative when administration is delayed after SCI. To properly interpret data from transgenic mice in which tamoxifen treatment is delayed after SCI, it is necessary to identify the effects of tamoxifen alone on anatomical and functional recovery. In this study, female and male mice received a moderate mid-thoracic spinal cord contusion. Mice were then gavaged with corn oil or a high dose of tamoxifen from 19-22 days post-injury, and sacrificed 42 days post-injury. All mice underwent behavioral testing for the duration of the study, which revealed that tamoxifen treatment did not impact hindlimb motor recovery. Similarly, histological analyses revealed that tamoxifen had no effect on white matter sparing, total axon number, axon sprouting, glial reactivity, cell proliferation, oligodendrocyte number, or myelination, but tamoxifen did decrease the number of neurons in the dorsal and ventral horn. Semi-thin sections confirmed that axon demyelination and remyelination were unaffected by tamoxifen. Sex-specific responses to tamoxifen were also assessed, and there were no significant differences between female and male mice. These data suggest that delayed tamoxifen administration after SCI does not change functional recovery or improve tissue sparing in female or male mice.
Collapse
Affiliation(s)
- Nicole Pukos
- Neuroscience Graduate Program, The Ohio State University, Columbus, OH, United States of America
- Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, United States of America
| | - Dana M. McTigue
- Belford Center for Spinal Cord Injury, The Ohio State University, Columbus, OH, United States of America
- Department of Neuroscience, Wexner Medical Center, Ohio State University, Columbus, OH, United States of America
| |
Collapse
|
|
26
|
Noori L, Arabzadeh S, Mohamadi Y, Mojaverrostami S, Mokhtari T, Akbari M, Hassanzadeh G. Intrathecal administration of the extracellular vesicles derived from human Wharton's jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats. Neurosci Res 2020; 170:87-98. [PMID: 32717259 DOI: 10.1016/j.neures.2020.07.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 07/10/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023]
Abstract
Activation of inflammasome complexes during spinal cord injury (SCI) lead to conversion of pro-inflammatory cytokines, interleukin-1beta (IL-1β) and interleukin-18 (IL-18) to their active form to initiates the neuroinflammation. Mesenchymal stem cells (MSCs) showed anti-inflammatory properties through their extracellular vehicles (EVs). We investigated immunomodulatory potential of human Wharton's jelly mesenchymal stem cells derived extracellular vesicles (hWJ-MSC-EVs) on inflammasome activity one week after SCI in rats. The gene expression and protein level of IL-1β, IL-18, tumor necrosis factor alpha (TNF-α) and caspase1, were assessed by QPCR and western blotting. Immunohistochemistry (IHC) was done to measure the glial fibrillary acidic protein (GFAP) and Nestin expression. Cell death, histological evaluation and hind limb locomotion was studied by TUNEL assay, Nissl staining and Basso, Beattie, Bresnaham (BBB), respectively. Our finding represented that intrathecally administrated of hWJ-MSC-EVs significantly attenuated expression of the examined factors in both mRNA (P < 0.05 and P ≤ 0.01) and protein levels (P < 0.05 and P ≤ 0.01), decreased GFAP and increased Nestin expression (P < 0.05), reduced cell death and revealed the higher number of typical neurons in ventral horn of spinal cord. Consequently, progress in locomotion. We came to the conclusion that hWJ-MSC-EVs has the potential to control the inflammasome activity after SCI in rats. Moreover, EVs stimulated the neural progenitor cells and modulate the astrocyte activity.
Collapse
Affiliation(s)
- Leila Noori
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Arabzadeh
- Department of Biology, School of Basic Sciences, Ale Taha Institute of Higher Education, Tehran, Iran
| | - Yousef Mohamadi
- Department of Anatomy, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Sina Mojaverrostami
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Tahmineh Mokhtari
- CAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
| | - Mohammad Akbari
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Hassanzadeh
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Neuroscience and addiction studies, School of advanced technologies in medicine, Tehran University of Medical Sciences, Tehran, Iran; Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran.
| |
Collapse
|
|
27
|
Chambel SS, Tavares I, Cruz CD. Chronic Pain After Spinal Cord Injury: Is There a Role for Neuron-Immune Dysregulation? Front Physiol 2020; 11:748. [PMID: 32733271 PMCID: PMC7359877 DOI: 10.3389/fphys.2020.00748] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/08/2020] [Indexed: 12/14/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating event with a tremendous impact in the life of the affected individual and family. Traumatic injuries related to motor vehicle accidents, falls, sports, and violence are the most common causes. The majority of spinal lesions is incomplete and occurs at cervical levels of the cord, causing a disruption of several ascending and descending neuronal pathways. Additionally, many patients develop chronic pain and describe it as burning, stabbing, shooting, or shocking and often arising with no stimulus. Less frequently, people with SCI also experience pain out of context with the stimulus (e.g., light touch). While abolishment of the endogenous descending inhibitory circuits is a recognized cause for chronic pain, an increasing number of studies suggest that uncontrolled release of pro- and anti-inflammatory mediators by neurons, glial, and immune cells is also important in the emergence and maintenance of SCI-induced chronic pain. This constitutes the topic of the present mini-review, which will focus on the importance of neuro-immune dysregulation for pain after SCI.
Collapse
Affiliation(s)
- Sílvia S Chambel
- Department of Biomedicine, Experimental Biology Unit, Faculty of Medicine, University of Porto, Porto, Portugal.,Translational NeuroUrology Group, Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Porto, Portugal
| | - Isaura Tavares
- Department of Biomedicine, Experimental Biology Unit, Faculty of Medicine, University of Porto, Porto, Portugal.,Pain Research Group, Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Porto, Portugal
| | - Célia D Cruz
- Department of Biomedicine, Experimental Biology Unit, Faculty of Medicine, University of Porto, Porto, Portugal.,Translational NeuroUrology Group, Instituto de Investigação e Inovação em Saúde - i3S, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
28
|
Yue Y, Zhao J, Li X, Zhang L, Su Y, Fan H. Involvement of Shh/Gli1 signaling in the permeability of blood-spinal cord barrier and locomotion recovery after spinal cord contusion. Neurosci Lett 2020; 728:134947. [PMID: 32276104 DOI: 10.1016/j.neulet.2020.134947] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 02/10/2020] [Accepted: 03/29/2020] [Indexed: 11/18/2022]
Abstract
Shh/Gli1 signaling plays important roles in development of spinal cord. How it is involved in spinal cord injury (SCI) remains unclear. In this study, we explored the roles of Shh/Gli1 signaling in SCI by using Shh signaling reporter Gli1lz mice and Gli1 mutant Gli1lz/lz mice. For detecting the Shh/Gli1 signaling after SCI, X-gal staining and double-immunostaining of Shh/PDGFR-β, Shh/GFAP and LacZ/GFAP was conducted at 3 days post injury (dpi) on Gli1lz mice. To investigate the effects of Gli1 mutation on pathological changes after SCI, astrocytic proliferation and the content of intra-parenchymal Evans Blue were evaluated at 7dpi in wild-type and Gli1lz/lz mice. Furthermore, locomotor recovery was assessed by BMS scoring at 1, 3, 5 and 7dpi. The results of X-gal staining and immunohistochemistry showed that Shh/Gli1 signaling was mainly activated in reactive astrocytes after SCI. The 5-bromo-2-deoxyuridine (BrdU) incorporation assay showed that mutation of Gli1 did not affect the proliferation of astrocytes. However, the leakage of Evans Blue was significantly increased in the injured cord of Gli1lz/lz mice compared to wild-type mice. In addition, locomotor recovery was significantly impaired in the Gli1lz/lz mice. The findings demonstrated that Shh/Gli1 signaling could be induced in reactive astrocytes by SCI, and plays important role in permeability of blood-spinal cord barrier (BSCB) and locomotor recovery after SCI.
Collapse
Affiliation(s)
- Yili Yue
- Department of Pathophysiology, School of Medicine, Yan'an University, Yan'an, Shaanxi, 716000, China.
| | - Jiqian Zhao
- Department of Anatomy, Hebei Medical University, Shijiazhuang, Hebei, 051330, China.
| | - Xiaoji Li
- Department of Pathophysiology, School of Medicine, Yan'an University, Yan'an, Shaanxi, 716000, China.
| | - Li Zhang
- Institute of Basic Medical Sciences, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, No. 1 Xin Wang Road, Xi'an, Shaanxi, 710021, China.
| | - Yuhong Su
- Department of Anatomy, Hebei Medical University, Shijiazhuang, Hebei, 051330, China.
| | - Hong Fan
- Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China; Department of Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
| |
Collapse
|
|
29
|
Yang T, Dai Y, Chen G, Cui S. Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury. Front Cell Neurosci 2020; 14:78. [PMID: 32317938 PMCID: PMC7147295 DOI: 10.3389/fncel.2020.00078] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 03/18/2020] [Indexed: 12/19/2022] Open
Abstract
Recovery from spinal cord injury (SCI) remains an unsolved problem. As a major component of the SCI lesion, the glial scar is primarily composed of scar-forming astrocytes and plays a crucial role in spinal cord regeneration. In recent years, it has become increasingly accepted that the glial scar plays a dual role in SCI recovery. However, the underlying mechanisms of this dual role are complex and need further clarification. This dual role also makes it difficult to manipulate the glial scar for therapeutic purposes. Here, we briefly discuss glial scar formation and some representative components associated with scar-forming astrocytes. Then, we analyze the dual role of the glial scar in a dynamic perspective with special attention to scar-forming astrocytes to explore the underlying mechanisms of this dual role. Finally, taking the dual role of the glial scar into account, we provide several pieces of advice on novel therapeutic strategies targeting the glial scar and scar-forming astrocytes.
Collapse
Affiliation(s)
- Tuo Yang
- Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.,Medical School of Nantong University, Nantong, China
| | - YuJuan Dai
- Medical School of Nantong University, Nantong, China
| | - Gang Chen
- Department of Tissue and Embryology, Medical School of Nantong University, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, China
| | - ShuSen Cui
- Department of Hand Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
30
|
Gattlen C, Deftu AF, Tonello R, Ling Y, Berta T, Ristoiu V, Suter MR. The inhibition of Kir2.1 potassium channels depolarizes spinal microglial cells, reduces their proliferation, and attenuates neuropathic pain. Glia 2020; 68:2119-2135. [PMID: 32220118 DOI: 10.1002/glia.23831] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 11/11/2022]
Abstract
Spinal microglia change their phenotype and proliferate after nerve injury, contributing to neuropathic pain. For the first time, we have characterized the electrophysiological properties of microglia and the potential role of microglial potassium channels in the spared nerve injury (SNI) model of neuropathic pain. We observed a strong increase of inward currents restricted at 2 days after injury associated with hyperpolarization of the resting membrane potential (RMP) in microglial cells compared to later time-points and naive animals. We identified pharmacologically and genetically the current as being mediated by Kir2.1 ion channels whose expression at the cell membrane is increased 2 days after SNI. The inhibition of Kir2.1 with ML133 and siRNA reversed the RMP hyperpolarization and strongly reduced the currents of microglial cells 2 days after SNI. These electrophysiological changes occurred coincidentally to the peak of microglial proliferation following nerve injury. In vitro, ML133 drastically reduced the proliferation of BV2 microglial cell line after both 2 and 4 days in culture. In vivo, the intrathecal injection of ML133 significantly attenuated the proliferation of microglia and neuropathic pain behaviors after nerve injury. In summary, our data implicate Kir2.1-mediated microglial proliferation as an important therapeutic target in neuropathic pain.
Collapse
Affiliation(s)
- Christophe Gattlen
- Pain Center, Department of Anesthesiology, Lausanne University Hospital and University of Lausanne (CHUV), Lausanne, Switzerland.,Faculty of Biology and Medicine (FBM), University of Lausanne (UNIL), Lausanne, Switzerland
| | - Alexandru-Florian Deftu
- Pain Center, Department of Anesthesiology, Lausanne University Hospital and University of Lausanne (CHUV), Lausanne, Switzerland.,Faculty of Biology and Medicine (FBM), University of Lausanne (UNIL), Lausanne, Switzerland.,Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Raquel Tonello
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
| | - Yuejuan Ling
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.,Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neurodegeneration, University of Nantong, Nantong, Jiangsu, China
| | - Temugin Berta
- Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA
| | - Violeta Ristoiu
- Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Marc René Suter
- Pain Center, Department of Anesthesiology, Lausanne University Hospital and University of Lausanne (CHUV), Lausanne, Switzerland.,Faculty of Biology and Medicine (FBM), University of Lausanne (UNIL), Lausanne, Switzerland.,Department of Fundamental Neurosciences, Faculty of Biology and Medicine (FBM), University of Lausanne (UNIL), Lausanne, Switzerland
| |
Collapse
|
|
31
|
González SL, Coronel MF, Raggio MC, Labombarda F. Progesterone receptor-mediated actions and the treatment of central nervous system disorders: An up-date of the known and the challenge of the unknown. Steroids 2020; 153:108525. [PMID: 31634489 DOI: 10.1016/j.steroids.2019.108525] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 09/30/2019] [Accepted: 10/09/2019] [Indexed: 01/04/2023]
Abstract
Progesterone has been shown to exert a wide range of remarkable protective actions in experimental models of central nervous system injury or disease. However, the intimate mechanisms involved in each of these beneficial effects are not fully depicted. In this review, we intend to give the readers a thorough revision on what is known about the participation of diverse receptors and signaling pathways in progesterone-mediated neuroprotective, pro-myelinating and anti-inflammatory outcomes, as well as point out to novel regulatory mechanisms that could open new perspectives in steroid-based therapies.
Collapse
Affiliation(s)
- Susana L González
- Laboratorio de Nocicepción y Dolor Neuropático, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina; Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, C1121ABG Buenos Aires, Argentina.
| | - María F Coronel
- Laboratorio de Nocicepción y Dolor Neuropático, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina; Facultad de Ciencias Biomédicas, Universidad Austral, Presidente Perón 1500, B1629AHJ Pilar, Buenos Aires, Argentina
| | - María C Raggio
- Laboratorio de Nocicepción y Dolor Neuropático, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina
| | - Florencia Labombarda
- Laboratorio de Bioquímica Neuroendócrina, Instituto de Biología y Medicina Experimental, CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina; Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, C1121ABG Buenos Aires, Argentina
| |
Collapse
|
|
32
|
Baek A, Shin JC, Lee MY, Kim SH, Kim J, Cho SR. Parasympathetic Effect Induces Cell Cycle Activation in Upper Limbs of Paraplegic Patients with Spinal Cord Injury. Int J Mol Sci 2019; 20:ijms20235982. [PMID: 31783707 PMCID: PMC6929129 DOI: 10.3390/ijms20235982] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 11/21/2019] [Accepted: 11/23/2019] [Indexed: 01/04/2023] Open
Abstract
The present study aimed to investigate gene expression changes related to cell cycle activation in patients with spinal cord injury (SCI) and to further evaluate the difference between the upper and lower limbs of SCI patients. Fibroblasts were obtained from the upper and lower limbs of SCI patients and healthy subjects. To investigate gene expression profiling in the fibroblasts from SCI patients compared to the healthy subjects, RNA-Seq transcriptome analysis was performed. To validate the parasympathetic effects on cell cycle activation, fibroblasts from upper or lower limbs of SCI patients were treated with the anticholinergic agents tiotropium or acetylcholine, and quantitative RT-PCR and Western blot were conducted. Cell proliferation was significantly increased in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. The pathway and genes involved in cell cycle were identified by RNA-Seq transcriptome analysis. Expression of cell-cycle-related genes CCNB1, CCNB2, PLK1, BUB1, and CDC20 were significantly higher in the upper limbs of SCI patients compared with the lower limbs of SCI patients and healthy subjects. When the fibroblasts were treated with tiotropium the upper limbs and acetylcholine in the lower limbs, the expression of cell-cycle-related genes and cell proliferation were significantly modulated. This study provided the insight that cell proliferation and cell cycle activation were observed to be significantly increased in the upper limbs of SCI patients via the parasympathetic effect.
Collapse
Affiliation(s)
- Ahreum Baek
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (A.B.); (J.C.S.); (M.-Y.L.)
- Department of Rehabilitation Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Ji Cheol Shin
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (A.B.); (J.C.S.); (M.-Y.L.)
| | - Min-Young Lee
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (A.B.); (J.C.S.); (M.-Y.L.)
| | - Sung Hoon Kim
- Department of Rehabilitation Medicine, Yonsei University Wonju College of Medicine, Wonju 26426, Korea;
| | - Jiyong Kim
- Department of Physical Medicine and Rehabilitation, Inje University Ilsanpaik Hospital, 170 Juhwa-ro, Ilsanseo-gu, Goyang 10380, Korea
- Correspondence: (J.K.); (S.-R.C.); Tel.: +82-31-910-7885 (J.K.); +82-2-2228-3715 (S.-R.C.); Fax: +82-31-910-7786 (J.K.); +82-2-363-2795 (S.-R.C.)
| | - Sung-Rae Cho
- Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Korea; (A.B.); (J.C.S.); (M.-Y.L.)
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
- Yonsei Stem Cell Center, Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul 03722, Korea
- Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul 03722, Korea
- Correspondence: (J.K.); (S.-R.C.); Tel.: +82-31-910-7885 (J.K.); +82-2-2228-3715 (S.-R.C.); Fax: +82-31-910-7786 (J.K.); +82-2-363-2795 (S.-R.C.)
| |
Collapse
|
|
33
|
Yu B, Yao C, Wang Y, Mao S, Wang Y, Wu R, Feng W, Chen Y, Yang J, Xue C, Liu D, Ding F, Gu X. The Landscape of Gene Expression and Molecular Regulation Following Spinal Cord Hemisection in Rats. Front Mol Neurosci 2019; 12:287. [PMID: 31824262 PMCID: PMC6883948 DOI: 10.3389/fnmol.2019.00287] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/12/2019] [Indexed: 01/25/2023] Open
Abstract
Spinal cord injury (SCI) is a challenging clinical problem worldwide. The cellular state and molecular expression in spinal cord tissue after injury are extremely complex and closely related to functional recovery. However, the spatial and temporal changes of gene expression and regulation in various cell types after SCI are still unclear. Here, we collected the rostral and caudal regions to the lesion at 11 time points over a period of 28 days after rat hemisection SCI. Combining whole-transcriptome sequencing and bioinformatic analysis, we identified differentially expressed genes (DEGs) between spinal cord tissue from injured and sham-operated animals. Significantly altered biological processes were enriched from DEGs in astrocytes, microglia, oligodendrocytes, immune cells, and vascular systems after SCI. We then identified dynamic trends in these processes using the average expression profiles of DEGs. Gene expression and regulatory networks for selected biological processes were also constructed to illustrate the complicate difference between rostral and caudal tissues. Finally, we validated the expressions of some key genes from these networks, including α-synuclein, heme oxygenase 1, bone morphogenetic protein 2, activating transcription factor 3, and leukemia inhibitory factor. Collectively, we provided a comprehensive network of gene expression and regulation to shed light on the molecular characteristics of critical biological processes that occur after SCI, which will broaden the understanding of SCI and facilitate clinical therapeutics for SCI.
Collapse
Affiliation(s)
- Bin Yu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Affiliated Hospital of Nantong University, Nantong University, Nantong, China
| | - Chun Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yongjun Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Susu Mao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yaxian Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Ronghua Wu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Wei Feng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yanping Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Jian Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Chengbin Xue
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Dong Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Fei Ding
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xiaosong Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.,Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Affiliated Hospital of Nantong University, Nantong University, Nantong, China
| |
Collapse
|
|
34
|
Seira O, Liu J, Assinck P, Ramer M, Tetzlaff W. KIF2A characterization after spinal cord injury. Cell Mol Life Sci 2019; 76:4355-4368. [PMID: 31041455 PMCID: PMC11105463 DOI: 10.1007/s00018-019-03116-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 04/05/2019] [Accepted: 04/24/2019] [Indexed: 01/23/2023]
Abstract
Axons in the central nervous system (CNS) typically fail to regenerate after injury. This failure is multi-factorial and caused in part by disruption of the axonal cytoskeleton. The cytoskeleton, in particular microtubules (MT), plays a critical role in axonal transport and axon growth during development. In this regard, members of the kinesin superfamily of proteins (KIFs) regulate the extension of primary axons toward their targets and control the growth of collateral branches. KIF2A negatively regulates axon growth through MT depolymerization. Using three different injury models to induce SCI in adult rats, we examined the temporal and cellular expression of KIF2A in the injured spinal cord. We observed a progressive increase of KIF2A expression with maximal levels at 10 days to 8 weeks post-injury as determined by Western blot analysis. KIF2A immunoreactivity was present in axons, spinal neurons and mature oligodendrocytes adjacent to the injury site. Results from the present study suggest that KIF2A at the injured axonal tips may contribute to neurite outgrowth inhibition after injury, and that its increased expression in inhibitory spinal neurons adjacent to the injury site might contribute to an intrinsic wiring-control mechanism associated with neuropathic pain. Further studies will determine whether KIF2A may be a potential target for the development of regeneration-promoting or pain-preventing therapies.
Collapse
Affiliation(s)
- Oscar Seira
- International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Centre, University of British Columbia (UBC), 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada.
- Department of Zoology, University of British Columbia (UBC), Vancouver, Canada.
| | - Jie Liu
- International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Centre, University of British Columbia (UBC), 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Peggy Assinck
- International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Centre, University of British Columbia (UBC), 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
- Graduate Program in Neuroscience, University of British Columbia (UBC), Vancouver, Canada
- MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, UK
| | - Matt Ramer
- International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Centre, University of British Columbia (UBC), 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
- Department of Zoology, University of British Columbia (UBC), Vancouver, Canada
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries (ICORD), Blusson Spinal Cord Centre, University of British Columbia (UBC), 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
- Department of Zoology, University of British Columbia (UBC), Vancouver, Canada
- Department of Surgery, University of British Columbia (UBC), Vancouver, Canada
| |
Collapse
|
|
35
|
Pukos N, Goodus MT, Sahinkaya FR, McTigue DM. Myelin status and oligodendrocyte lineage cells over time after spinal cord injury: What do we know and what still needs to be unwrapped? Glia 2019; 67:2178-2202. [PMID: 31444938 DOI: 10.1002/glia.23702] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 07/29/2019] [Accepted: 07/30/2019] [Indexed: 01/04/2023]
Abstract
Spinal cord injury (SCI) affects over 17,000 individuals in the United States per year, resulting in sudden motor, sensory and autonomic impairments below the level of injury. These deficits may be due at least in part to the loss of oligodendrocytes and demyelination of spared axons as it leads to slowed or blocked conduction through the lesion site. It has long been accepted that progenitor cells form new oligodendrocytes after SCI, resulting in the acute formation of new myelin on demyelinated axons. However, the chronicity of demyelination and the functional significance of remyelination remain contentious. Here we review work examining demyelination and remyelination after SCI as well as the current understanding of oligodendrocyte lineage cell responses to spinal trauma, including the surprisingly long-lasting response of NG2+ oligodendrocyte progenitor cells (OPCs) to proliferate and differentiate into new myelinating oligodendrocytes for months after SCI. OPCs are highly sensitive to microenvironmental changes, and therefore respond to the ever-changing post-SCI milieu, including influx of blood, monocytes and neutrophils; activation of microglia and macrophages; changes in cytokines, chemokines and growth factors such as ciliary neurotrophic factor and fibroblast growth factor-2; glutamate excitotoxicity; and axon degeneration and sprouting. We discuss how these changes relate to spontaneous oligodendrogenesis and remyelination, the evidence for and against demyelination being an important clinical problem and if remyelination contributes to motor recovery.
Collapse
Affiliation(s)
- Nicole Pukos
- Neuroscience Graduate Program, Ohio State University, Columbus, Ohio.,Belford Center for Spinal Cord Injury, Ohio State University, Columbus, Ohio
| | - Matthew T Goodus
- Belford Center for Spinal Cord Injury, Ohio State University, Columbus, Ohio.,Department of Neuroscience, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Fatma R Sahinkaya
- Neuroscience Graduate Program, Ohio State University, Columbus, Ohio
| | - Dana M McTigue
- Belford Center for Spinal Cord Injury, Ohio State University, Columbus, Ohio.,Department of Neuroscience, Wexner Medical Center, Ohio State University, Columbus, Ohio
| |
Collapse
|
|
36
|
Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Plemel JR, Tetzlaff W. The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury. Glia 2019; 68:227-245. [PMID: 31433109 DOI: 10.1002/glia.23706] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/24/2019] [Accepted: 08/01/2019] [Indexed: 12/27/2022]
Abstract
Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed population of progenitor cells in the adult central nervous system, which allows these cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after traumatic spinal cord injury (SCI), compromising efficient conduction and, potentially, the long-term health of axons. In response, OPCs proliferate and then differentiate into new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in highly efficient remyelination following experimental SCI in which nearly all intact demyelinated axons are remyelinated in rodent models. However, myelin regeneration comprises only one role of OPCs following SCI. OPCs contribute to scar formation after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter their gene expression following demyelination, express cytokines and perpetuate the immune response. Here, we review the functional contribution of myelin regeneration and other recently uncovered roles of OPCs and their progeny to repair following SCI.
Collapse
Affiliation(s)
- Greg J Duncan
- Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, Oregon
| | - Sohrab B Manesh
- Graduate Program in Neuroscience, International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), Vancouver, British Columbia, Canada
| | - Brett J Hilton
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Peggy Assinck
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Jason R Plemel
- Department of Medicine, Division of Neurology, Neuroscience and Mental Health Institute, University of Alberta, Calgary, Alberta, Canada
| | - Wolfram Tetzlaff
- Graduate Program in Neuroscience, International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), Vancouver, British Columbia, Canada.,Departments of Zoology and Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| |
Collapse
|
|
37
|
Oligodendrogliogenesis and Axon Remyelination after Traumatic Spinal Cord Injuries in Animal Studies: A Systematic Review. Neuroscience 2019; 402:37-50. [PMID: 30685542 DOI: 10.1016/j.neuroscience.2019.01.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/12/2019] [Accepted: 01/14/2019] [Indexed: 12/20/2022]
Abstract
Extensive oligodendrocyte death after acute traumatic spinal cord injuries (TSCI) leads to axon demyelination and subsequently may leave axons vulnerable to degeneration. Despite the present evidence showing spontaneous remyelination after TSCI the cellular origin of new myelin and the time course of the axon ensheathment/remyelination remained controversial issue. In this systematic review the trend of oligodendrocyte death after injury as well as the extent and the cellular origin of oligodendrogliogenesis were comprehensively evaluated. The study design was based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-guided systematic review. PubMed and EMBASE were searched with no temporal or linguistic restrictions. Also, hand-search was performed in the bibliographies of relevant articles. Non-interventional animal studies discussing different types of myelinating cells including oligodendrocytes, Schwann cells and oligodendrocyte progenitor cells (OPCs) were evaluated. The extent of oligodendrocyte death, oligodendrocyte differentiation and remyelination were the pathophysiological outcome measures. We found 12,359 studies, 34 of which met the inclusion criteria. The cumulative evidence shows extensive oligodendrocytes cell death during the first week post-injury (pi). OPCs and peripheral invading Schwann cells are the dominant cells contributing in myelin formation. The maximum OPC proliferation was observed at around 2 weeks pi and oligodendrogliogenesis continues at later stages until the number of oligodendrocytes return to normal tissue by one month pi. Taken together, the evidence in animals reveals the potential role for endogenous myelinating cells in the axon ensheathment/remyelination after TSCI and this can be the target of pharmacotherapy to induce oligodendrocyte differentiation and myelin formation post-injury.
Collapse
|
|
38
|
Mei X, Wang H, Zhang H, Liu C, Guo Z, Wang Y, Yuan Y, Zhao Z, Li D, Tang P. Blockade of receptor for advanced glycation end products promotes oligodendrocyte autophagy in spinal cord injury. Neurosci Lett 2019; 698:198-203. [PMID: 30660637 DOI: 10.1016/j.neulet.2019.01.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 01/14/2019] [Accepted: 01/16/2019] [Indexed: 12/19/2022]
Abstract
Receptor for advanced glycation end product (RAGE) is involved in neuronal inflammation, cell cycle and differentiation. However, the role of RAGE in autophagy in the process of spinal cord injury (SCI) is yet unknown. The present study investigated the effect of RAGE blockade on autophagy in SCI. A rat Allen SCI model was established and the animals were micro-injected with rabbit RAGE neutralizing antibody or rabbit polyclonal Ig G immediately after the injury. The oligodendrocytes(OLs) marker, 2', 3'-cyclic nucleotide 3'-phosphodiesterase(CNPase) and autophagy-related marker microtubule associated protein light chain 3B(LC3B) were evaluated by Western blot. Furthermore, myelin basic protein (MBP) and LC3B double staining were observed in the SCI via immunofluorescence. The results showed that RAGE blockade reduced the expression of CNPase, promoted LC3B-II/I and p62 expression after SCI. In addition, the MBP/LC3B double positive oligodendrocytes-expressing LC3B was up-regulated by RAGE blockade. Moreover, RAGE blockade attenuated the neuronal survival at ventral horn after SCI. The present study revealed the role of RAGE in maintaining oligodendrocyte autophagy to promote neuronal regeneration post-SCI.
Collapse
Affiliation(s)
- Xifan Mei
- Department of Orthopedic, Chinese PLA General Hospital, Beijing, 100853, PR China
| | - Hongyu Wang
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Hua Zhang
- Jinzhou Medical University, Jinzhou City, 121000, PR China
| | - Chang Liu
- Department of Endocrinology, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Zhanpeng Guo
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Yansong Wang
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Yajiang Yuan
- Department of Orthopedic, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Ziming Zhao
- Department of Stomatology, Second Affiliated Hospital of Jinzhou Medical University, Jinzhou City, PR China
| | - Dingding Li
- Department of Orthopedic, the First People's Hospital of Longquanyi District, Chengdu City, PR China
| | - Peifu Tang
- Department of Orthopedic, Chinese PLA General Hospital, Beijing, 100853, PR China.
| |
Collapse
|
|
39
|
Li X, Liu D, Xiao Z, Zhao Y, Han S, Chen B, Dai J. Scaffold-facilitated locomotor improvement post complete spinal cord injury: Motor axon regeneration versus endogenous neuronal relay formation. Biomaterials 2019; 197:20-31. [PMID: 30639547 DOI: 10.1016/j.biomaterials.2019.01.012] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 12/10/2018] [Accepted: 01/05/2019] [Indexed: 01/18/2023]
Abstract
Complete transected spinal cord injury (SCI) severely influences the quality of life and mortality rates of animals and patients. In the past decade, many simple and combinatorial therapeutic treatments have been tested in improving locomotor function in animals with this extraordinarily challenging SCI. The potential mechanism for promotion of locomotor function relies either on direct motor axon regeneration through the lesion gap or indirect neuronal relay bridging to functionally reconnect transected spinal stumps. In this review, we first compare the advantages and problems of complete transection SCI animal models with other prevailing SCI models used in motor axon regeneration research. Next, we enumerate some of the popular bio-scaffolds utilized in complete SCI repair in the last decade. Then, the current state of motor axon regeneration as well as its role on locomotor improvement of animals after complete SCI is discussed. Last, the current approach of directing endogenous neuronal relays formation to achieve motor function recovery by well-designed functional bio-scaffolds implantation in complete transected SCI animals is reviewed. Although facilitating neuronal relays formation by bio-scaffolds implantation appears to be more practical and feasible than directing motor axon regeneration in promoting locomotor outcome in animals after complete SCI, there are still challenges in neuronal relays formation, maintaining and debugging for spinal cord regenerative repair.
Collapse
Affiliation(s)
- Xing Li
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Xiangya Hospital, Central South University (CSU), Changsha, Hunan, 410008, China
| | - Dingyang Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China
| | - Zhifeng Xiao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yannan Zhao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Sufang Han
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Bing Chen
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Jianwu Dai
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
| |
Collapse
|
|
40
|
Yang Q, Zhou J. Neuroinflammation in the central nervous system: Symphony of glial cells. Glia 2018; 67:1017-1035. [DOI: 10.1002/glia.23571] [Citation(s) in RCA: 160] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/26/2018] [Accepted: 11/02/2018] [Indexed: 12/19/2022]
Affiliation(s)
- Qiao‐qiao Yang
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai China
| | - Jia‐wei Zhou
- Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai China
- University of Chinese Academy of Sciences Shanghai 200031 China
| |
Collapse
|
|
41
|
Tran AP, Warren PM, Silver J. The Biology of Regeneration Failure and Success After Spinal Cord Injury. Physiol Rev 2018. [PMID: 29513146 DOI: 10.1152/physrev.00017.2017] [Citation(s) in RCA: 571] [Impact Index Per Article: 81.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.
Collapse
Affiliation(s)
- Amanda Phuong Tran
- Department of Neurosciences, Case Western Reserve University , Cleveland, Ohio ; and School of Biomedical Sciences, University of Leeds , Leeds , United Kingdom
| | - Philippa Mary Warren
- Department of Neurosciences, Case Western Reserve University , Cleveland, Ohio ; and School of Biomedical Sciences, University of Leeds , Leeds , United Kingdom
| | - Jerry Silver
- Department of Neurosciences, Case Western Reserve University , Cleveland, Ohio ; and School of Biomedical Sciences, University of Leeds , Leeds , United Kingdom
| |
Collapse
|
|
42
|
Zheng W, Li Q, Zhao C, Da Y, Zhang HL, Chen Z. Differentiation of Glial Cells From hiPSCs: Potential Applications in Neurological Diseases and Cell Replacement Therapy. Front Cell Neurosci 2018; 12:239. [PMID: 30140204 PMCID: PMC6094089 DOI: 10.3389/fncel.2018.00239] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 07/17/2018] [Indexed: 12/20/2022] Open
Abstract
Glial cells are the most abundant cell type in the central nervous system (CNS) and play essential roles in maintaining brain homeostasis, forming myelin, and providing support and protection for neurons, etc. Over the past decade, significant progress has been made in the reprogramming field. Given the limited accessibility of human glial cells, in vitro differentiation of human induced pluripotent stem cells (hiPSCs) into glia may provide not only a valuable research tool for a better understanding of the functions of glia in the CNS but also a potential cellular source for clinical therapeutic purposes. In this review, we will summarize up-to-date novel strategies for the committed differentiation into the three major glial cell types, i.e., astrocyte, oligodendrocyte, and microglia, from hiPSCs, focusing on the non-neuronal cell effects on the pathology of some representative neurological diseases. Furthermore, the application of hiPSC-derived glial cells in neurological disease modeling will be discussed, so as to gain further insights into the development of new therapeutic targets for treatment of neurological disorders.
Collapse
Affiliation(s)
- Wei Zheng
- Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing, China.,Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Qian Li
- Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing, China.,Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China
| | - Chao Zhao
- Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
| | - Yuwei Da
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Hong-Liang Zhang
- Department of Life Sciences, National Natural Science Foundation of China, Beijing, China
| | - Zhiguo Chen
- Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing, China.,Key Laboratory of Neurodegeneration, Ministry of Education, Beijing, China.,Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, China
| |
Collapse
|
|
43
|
Sliwinski C, Nees TA, Puttagunta R, Weidner N, Blesch A. Sensorimotor Activity Partially Ameliorates Pain and Reduces Nociceptive Fiber Density in the Chronically Injured Spinal Cord. J Neurotrauma 2018; 35:2222-2238. [PMID: 29706124 DOI: 10.1089/neu.2017.5431] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
A large proportion of patients suffering from spinal cord injury (SCI) develop chronic central neuropathic pain. Previously, we and others have shown that sensorimotor training early after SCI can prevent the development of mechanical allodynia. To determine whether training initiated in the subchronic/chronic phase remains effective, correlates of below-level neuropathic pain were analyzed in the hindpaws 5-10 weeks after a moderate T11 contusion SCI (50 kDyn) in adult female C57BL/6 mice. In a comparison of SCI and sham mice 5 weeks post-injury, about 80% of injured animals developed mechanical hypersensitivity to light mechanical stimuli, whereas testing of noxious stimuli revealed hypo-responsiveness. Thermal sensitivity testing showed a decreased response latency after injury. Without intervention, mechanical and thermal hyper-responsiveness were evident until the end of the experiment (10 weeks). In contrast, treadmill training (2 × 15 min/day; 5 × /week) initiated 6 weeks post-injury resulted in partial amelioration of pain behavior and this effect remained stable. Analysis of calcitonin gene-related peptide (CGRP)-labeled fibers in lamina III-IV of the lumbar dorsal horn revealed an increase in labeling density after SCI. This was not due to changes in the number or size distribution of CGRP-labeled lumbar dorsal root ganglion neurons. Treadmill training reduced the CGRP-labeling density in the spinal cord of injured mice, whereas the density of non-peptidergic isolectin-B4 (IB4)+ fibers showed no changes in lamina IIi and a slight reduction of sparse IB4 labeling in laminae III-IV. Thus, sensorimotor activity initiated in the subchronic/chronic phase of SCI remains effective in ameliorating pain behavior and influencing structural changes of the nociceptive system.
Collapse
Affiliation(s)
| | - Timo A Nees
- 1 Spinal Cord Injury Center, Heidelberg University Hospital , Heidelberg, Germany .,2 Center for Orthopedic and Trauma Surgery, Heidelberg University Hospital , Heidelberg, Germany
| | - Radhika Puttagunta
- 1 Spinal Cord Injury Center, Heidelberg University Hospital , Heidelberg, Germany
| | - Norbert Weidner
- 1 Spinal Cord Injury Center, Heidelberg University Hospital , Heidelberg, Germany
| | - Armin Blesch
- 1 Spinal Cord Injury Center, Heidelberg University Hospital , Heidelberg, Germany .,3 Department of Neurological Surgery and Goodman Campbell Brain and Spine, Stark Neurosciences Research Institute, Indiana University School of Medicine , Indianapolis, Indiana
| |
Collapse
|
|
44
|
Oligodendroglia Are Particularly Vulnerable to Oxidative Damage after Neurotrauma In Vivo. J Neurosci 2018; 38:6491-6504. [PMID: 29915135 DOI: 10.1523/jneurosci.1898-17.2018] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 05/13/2018] [Accepted: 05/16/2018] [Indexed: 01/13/2023] Open
Abstract
Loss of function following injury to the CNS is worsened by secondary degeneration of neurons and glia surrounding the injury and is initiated by oxidative damage. However, it is not yet known which cellular populations and structures are most vulnerable to oxidative damage in vivo Using Nanoscale secondary ion mass spectrometry (NanoSIMS), oxidative damage was semiquantified within cellular subpopulations and structures of optic nerve vulnerable to secondary degeneration, following a partial transection of the optic nerve in adult female PVG rats. Simultaneous assessment of cellular subpopulations and structures revealed oligodendroglia as the most vulnerable to DNA oxidation following injury. 5-Ethynyl-2'-deoxyuridine (EdU) was used to label cells that proliferated in the first 3 d after injury. Injury led to increases in DNA, protein, and lipid damage in oligodendrocyte progenitor cells and mature oligodendrocytes at 3 d, regardless of proliferative state, associated with a decline in the numbers of oligodendrocyte progenitor cells at 7 d. O4+ preoligodendrocytes also exhibited increased lipid peroxidation. Interestingly, EdU+ mature oligodendrocytes derived after injury demonstrated increased early susceptibility to DNA damage and lipid peroxidation. However, EdU- mature oligodendrocytes with high 8-hydroxyguanosine immunoreactivity were more likely to be caspase3+ By day 28, newly derived mature oligodendrocytes had significantly reduced myelin regulatory factor gene mRNA, indicating that the myelination potential of these cells may be reduced. The proportion of caspase3+ oligodendrocytes remained higher in EdU- cells. Innovative use of NanoSIMS together with traditional immunohistochemistry and in situ hybridization have enabled the first demonstration of subpopulation specific oligodendroglial vulnerability to oxidative damage, due to secondary degeneration in vivoSIGNIFICANCE STATEMENT Injury to the CNS is characterized by oxidative damage in areas adjacent to the injury. However, the cellular subpopulations and structures most vulnerable to this damage remain to be elucidated. Here we use powerful NanoSIMS techniques to show increased oxidative damage in oligodendroglia and axons and to demonstrate that cells early in the oligodendroglial lineage are the most vulnerable to DNA oxidation. Further immunohistochemical and in situ hybridization investigation reveals that mature oligodendrocytes derived after injury are more vulnerable to oxidative damage than their counterparts existing at the time of injury and have reduced myelin regulatory factor gene mRNA, yet preexisting oligodendrocytes are more likely to die.
Collapse
|
|
45
|
To Be or Not to Be: Environmental Factors that Drive Myelin Formation during Development and after CNS Trauma. ACTA ACUST UNITED AC 2018. [DOI: 10.3390/neuroglia1010007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Oligodendrocytes are specialized glial cells that myelinate central nervous system (CNS) axons. Historically, it was believed that the primary role of myelin was to compactly ensheath axons, providing the insulation necessary for rapid signal conduction. However, mounting evidence demonstrates the dynamic importance of myelin and oligodendrocytes, including providing metabolic support to neurons and regulating axon protein distribution. As such, the development and maintenance of oligodendrocytes and myelin are integral to preserving CNS homeostasis and supporting proper functioning of widespread neural networks. Environmental signals are critical for proper oligodendrocyte lineage cell progression and their capacity to form functional compact myelin; these signals are markedly disturbed by injury to the CNS, which may compromise endogenous myelin repair capabilities. This review outlines some key environmental factors that drive myelin formation during development and compares that to the primary factors that define a CNS injury milieu. We aim to identify developmental factors disrupted after CNS trauma as well as pathogenic factors that negatively impact oligodendrocyte lineage cells, as these are potential therapeutic targets to promote myelin repair after injury or disease.
Collapse
|
|
46
|
The Effect of Human Mesenchymal Stem Cells Derived from Wharton's Jelly in Spinal Cord Injury Treatment Is Dose-Dependent and Can Be Facilitated by Repeated Application. Int J Mol Sci 2018; 19:ijms19051503. [PMID: 29772841 PMCID: PMC5983761 DOI: 10.3390/ijms19051503] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/09/2018] [Accepted: 05/15/2018] [Indexed: 12/15/2022] Open
Abstract
Human mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) were used for the treatment of the ischemic-compression model of spinal cord injury in rats. To assess the effectivity of the treatment, different dosages (0.5 or 1.5 million cells) and repeated applications were compared. Cells or saline were applied intrathecally by lumbar puncture for one week only, or in three consecutive weeks after injury. Rats were assessed for locomotor skills (BBB, rotarod, flat beam) for 9 weeks. Spinal cord tissue was morphometrically analyzed for axonal sprouting, sparing of gray and white matter and astrogliosis. Endogenous gene expression (Gfap, Casp3, Irf5, Cd86, Mrc1, Cd163) was studied with quantitative Real-time polymerase chain reaction (qRT PCR). Significant recovery of functional outcome was observed in all of the treated groups except for the single application of the lowest number of cells. Histochemical analyses revealed a gradually increasing effect of grafted cells, resulting in a significant increase in the number of GAP43+ fibers, a higher amount of spared gray matter and reduced astrogliosis. mRNA expression of macrophage markers and apoptosis was downregulated after the repeated application of 1.5 million cells. We conclude that the effect of hWJ-MSCs on spinal cord regeneration is dose-dependent and potentiated by repeated application.
Collapse
|
|
47
|
Li H, Kong W, Chambers CR, Yu D, Ganea D, Tuma RF, Ward SJ. The non-psychoactive phytocannabinoid cannabidiol (CBD) attenuates pro-inflammatory mediators, T cell infiltration, and thermal sensitivity following spinal cord injury in mice. Cell Immunol 2018; 329:1-9. [PMID: 29784129 DOI: 10.1016/j.cellimm.2018.02.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 02/27/2018] [Accepted: 02/28/2018] [Indexed: 01/27/2023]
Abstract
We evaluated the effects of the non-psychoactive cannabinoid cannabidiol (CBD) on the inflammatory response and recovery of function following spinal cord injury (SCI). Female C57Bl/6 mice were exposed to spinal cord contusion injury (T9-10) and received vehicle or CBD (1.5 mg/kg IP) injections for 10 weeks following injury. The effect of SCI and CBD treatment on inflammation was assessed via microarray, qRT-PCR and flow cytometry. Locomotor and bladder function and changes in thermal and mechanical hind paw sensitivity were also evaluated. There was a significant decrease in pro-inflammatory cytokines and chemokines associated with T-cell differentiation and invasion in the SCI-CBD group as well as a decrease in T cell invasion into the injured cord. A higher percentage of SCI mice in the vehicle-treated group (SCI-VEH) went on to develop moderate to severe (0-65.9% baseline thermal threshold) thermal sensitivity as compared with CBD-treated (SCI-CBD) mice. CBD did not affect recovery of locomotor or bladder function following SCI. Taken together, CBD treatment attenuated the development of thermal sensitivity following spinal cord injury and this effect may be related to protection against pathological T-cell invasion.
Collapse
Affiliation(s)
- Hongbo Li
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States.
| | - Weimin Kong
- Microbiology and Immunology Department, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States.
| | - Christina R Chambers
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States
| | - Daohai Yu
- Department of Clinical Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States.
| | - Doina Ganea
- Microbiology and Immunology Department, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States.
| | - Ronald F Tuma
- Center for Substance Abuse Research, Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia PA 19140, United States.
| | - Sara Jane Ward
- Center for Substance Abuse Research, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, United States.
| |
Collapse
|
|
48
|
Li X, Dai J. Bridging the gap with functional collagen scaffolds: tuning endogenous neural stem cells for severe spinal cord injury repair. Biomater Sci 2018; 6:265-271. [DOI: 10.1039/c7bm00974g] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Severe spinal cord injury (SCI) induces massive proliferation of spinal cord neural stem cells (NSCs), which are considered a promising cell source for therapeutic neural repair.
Collapse
Affiliation(s)
- Xing Li
- State Key Laboratory of Molecular Developmental Biology
- Institute of Genetics and Developmental Biology
- Chinese Academy of Sciences
- Beijing 100101
- China
| | - Jianwu Dai
- State Key Laboratory of Molecular Developmental Biology
- Institute of Genetics and Developmental Biology
- Chinese Academy of Sciences
- Beijing 100101
- China
| |
Collapse
|
|
49
|
Engineering new neurons: in vivo reprogramming in mammalian brain and spinal cord. Cell Tissue Res 2017; 371:201-212. [PMID: 29170823 DOI: 10.1007/s00441-017-2729-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 11/02/2017] [Indexed: 12/13/2022]
Abstract
Neurons are postmitotic. Once lost because of injury or degeneration, they do not regenerate in most regions of the mammalian central nervous system. Recent advancements nevertheless clearly reveal that new neurons can be reprogrammed from non-neuronal cells, especially glial cells, in the adult mammalian brain and spinal cord. Here, we give a brief overview concerning cell fate reprogramming in vivo and then focus on the underlying molecular and cellular mechanisms. Specifically, we critically review the cellular sources and the reprogramming factors for in vivo neuronal conversion. Influences of environmental cues and the challenges ahead are also discussed. The ability of inducing new neurons from an abundant and broadly distributed non-neuronal cell source brings new perspectives regarding regeneration-based therapies for traumatic brain and spinal cord injuries and degenerative diseases.
Collapse
|
|
50
|
Orlandin JR, Ambrósio CE, Lara VM. Glial scar-modulation as therapeutic tool in spinal cord injury in animal models. Acta Cir Bras 2017; 32:168-174. [PMID: 28300871 DOI: 10.1590/s0102-865020170209] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 01/20/2017] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Spinal Cord injury represents, in veterinary medicine, most of the neurological attendances and may result in permanent disability, death or euthanasia. Due to inflammation resulting from trauma, it originates the glial scar, which is a cell interaction complex system. Its function is to preserve the healthy circuits, however, it creates a physical and molecular barrier that prevents cell migration and restricts the neuroregeneration ability. METHODS This review aims to present innovations in the scene of treatment of spinal cord injury, approaching cell therapy, administration of enzyme, anti-inflammatory, and other active principles capable of modulating the inflammatory response, resulting in glial scar reduction and subsequent functional improvement of animals. RESULTS Some innovative therapies as cell therapy, administration of enzymes, immunosuppressant or other drugs cause the modulation of inflammatory response proved to be a promising tool for the reduction of gliosis. CONCLUSION Those tools promise to reduce gliosis and promote locomotor recovery in animals with spinal cord injury.
Collapse
Affiliation(s)
- Jéssica Rodrigues Orlandin
- Veterinary Medicine Department, Faculty of Animal Science and Food Engineering, Universidade de São Paulo, Pirassununga, SP, Brazil
| | | | | |
Collapse
|