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Saraswat Ohri S, Myers SA, Rood B, Brown BL, Chilton PM, Slomnicki L, Liu Y, Wei GZ, Andres KR, Mohan D, Howard RM, Whittemore SR, Hetman M. Reduced White Matter Damage and Lower Neuroinflammatory Potential of Microglia and Macrophages in Hri/Eif2ak1 -/- Mice After Contusive Spinal Cord Injury. Glia 2025; 73:1004-1021. [PMID: 39760211 DOI: 10.1002/glia.24669] [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: 05/22/2024] [Revised: 11/29/2024] [Accepted: 12/18/2024] [Indexed: 01/07/2025]
Abstract
Cellular stressors inhibit general protein synthesis while upregulating stress response transcripts and/or proteins. Phosphorylation of the translation factor eIF2α by one of the several stress-activated kinases is a trigger for such signaling, known as the integrated stress response (ISR). The ISR regulates cell survival and function under stress. Here, germline knockout mice were used to determine contributions by three major ISR kinases, HRI/EIF2AK1, GCN2/EIF2AK4, and PKR//EIF2AK2, to pathogenesis of moderate contusive spinal cord injury (SCI) at the thoracic T9 level. One-day post-injury (dpi), reduced levels of peIF2α were found in Hri -/- and Gcn2 -/-, but not in Pkr -/- mice. In addition, Hri -/- mice showed attenuated expression of the downstream ISR transcripts, Atf4 or Chop. Such differential effects of SCI-activated ISR correlated with a strong or moderate enhancement of locomotor recovery in Hri -/- or Gcn2 -/- mice, respectively. Hri -/- mice also showed reduced white matter loss, increased content of oligodendrocytes (OL) and attenuated neuroinflammation, including decreased lipid accumulation in microglia/macrophages. Cultured neonatal Hri -/- OLs showed lower ISR cytotoxicity. Moreover, cell autonomous reduction in neuroinflammatory potential was observed in microglia and bone marrow-derived macrophages derived from Hri -/- mice. These data identify HRI as a major positive regulator of SCI-associated secondary injury. In addition, targeting HRI may enable multimodal neuroprotection to enhance functional recovery after SCI.
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Affiliation(s)
- Sujata Saraswat Ohri
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Scott A Myers
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Benjamin Rood
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Biochemistry & Molecular Genetics, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Brandon L Brown
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Anatomical Sciences & Neurobiology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Pharmacology & Toxicology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Paula M Chilton
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Norton Neuroscience Institute, Louisville, Kentucky, USA
| | - Lukasz Slomnicki
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Yu Liu
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - George Z Wei
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Interdisciplinary Program in Translational Neuroscience, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Kariena R Andres
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Divya Mohan
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Russell M Howard
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Scott R Whittemore
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Biochemistry & Molecular Genetics, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Anatomical Sciences & Neurobiology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Pharmacology & Toxicology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Interdisciplinary Program in Translational Neuroscience, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Michal Hetman
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Biochemistry & Molecular Genetics, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Anatomical Sciences & Neurobiology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Pharmacology & Toxicology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Department of Interdisciplinary Program in Translational Neuroscience, University of Louisville, School of Medicine, Louisville, Kentucky, USA
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Saraswat Ohri S, Forston MD, Myers SA, Brown BL, Andres KR, Howard RM, Gao Y, Liu Y, Cavener DR, Hetman M, Whittemore SR. Oligodendrocyte-selective deletion of the eIF2α kinase Perk/Eif2ak3 limits functional recovery after spinal cord injury. Glia 2024; 72:1259-1272. [PMID: 38587137 DOI: 10.1002/glia.24525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/13/2024] [Accepted: 03/04/2024] [Indexed: 04/09/2024]
Abstract
After spinal cord injury (SCI), re-establishing cellular homeostasis is critical to optimize functional recovery. Central to that response is PERK signaling, which ultimately initiates a pro-apoptotic response if cellular homeostasis cannot be restored. Oligodendrocyte (OL) loss and white matter damage drive functional consequences and determine recovery potential after thoracic contusive SCI. We examined acute (<48 h post-SCI) and chronic (6 weeks post-SCI) effects of conditionally deleting Perk from OLs prior to SCI. While Perk transcript is expressed in many types of cells in the adult spinal cord, its levels are disproportionately high in OL lineage cells. Deletion of OL-Perk prior to SCI resulted in: (1) enhanced acute phosphorylation of eIF2α, a major PERK substrate and the critical mediator of the integrated stress response (ISR), (2) enhanced acute expression of the downstream ISR genes Atf4, Ddit3/Chop, and Tnfrsf10b/Dr5, (3) reduced acute OL lineage-specific Olig2 mRNA, but not neuronal or astrocytic mRNAs, (4) chronically decreased OL content in the spared white matter at the injury epicenter, (5) impaired hindlimb locomotor recovery, and (6) reduced chronic epicenter white matter sparing. Cultured primary OL precursor cells with reduced PERK expression and activated ER stress response showed: (1) unaffected phosphorylation of eIF2α, (2) enhanced ISR gene induction, and (3) increased cytotoxicity. Therefore, OL-Perk deficiency exacerbates ISR signaling and potentiates white matter damage after SCI. The latter effect is likely mediated by increased loss of Perk-/- OLs.
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Affiliation(s)
- Sujata Saraswat Ohri
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Interdisciplinary Program in Translational Neuroscience, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Michael D Forston
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Scott A Myers
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
| | - Brandon L Brown
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
- Department of Interdisciplinary Program in Translational Neuroscience, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Kariena R Andres
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
| | - Russell M Howard
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
| | - Yonglin Gao
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
| | - Yu Liu
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
| | - Douglas R Cavener
- Department of Biology, Penn State University, University Park, Pennsylvania, USA
| | - Michal Hetman
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Interdisciplinary Program in Translational Neuroscience, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- M.D./Ph.D. Program, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Scott R Whittemore
- Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky, USA
- Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Interdisciplinary Program in Translational Neuroscience, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Department of Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- M.D./Ph.D. Program, University of Louisville School of Medicine, Louisville, Kentucky, USA
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Wu C, Pan Y, Wang L, Liu M, Tu P, Chen S, Shi L, Yan D, Ma Y, Guo Y. Inhibition of HDAC6 promotes microvascular endothelial cells to phagocytize myelin debris and reduces inflammatory response to accelerate the repair of spinal cord injury. CNS Neurosci Ther 2024; 30:e14439. [PMID: 37641882 PMCID: PMC10916453 DOI: 10.1111/cns.14439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 05/31/2023] [Accepted: 08/16/2023] [Indexed: 08/31/2023] Open
Abstract
AIMS To identify an effective strategy for promoting microvascular endothelial cells (MECs) to phagocytize myelin debris and reduce secretion of inflammatory factors following spinal cord injury (SCI). METHODS We established a coculture model of myelin debris and vascular-like structures. The efficiency with which MECs phagocytize myelin debris under different conditions was examined via ELISA, flow cytometry, and immunofluorescence. Tubastatin-A was used to interfere with the coculture model. The anti-inflammatory effects of Tubastatin-A were observed by HE staining, flow cytometry, immunofluorescence, and ELISA. RESULTS MECs phagocytized myelin debris via IgM opsonization, and phagocytosis promoted the secretion of inflammatory factors, whereas IgG-opsonized myelin debris had no effect on inflammatory factors. Application of the HDAC6 inhibitor Tubastatin-A increased the IgG levels and decreased the IgM levels by regulating the proliferation and differentiation of B cells. Tubastatin-A exerted a regulatory effect on the HDAC6-mediated autophagy-lysosome pathway, promoting MECs to phagocytize myelin debris, reducing the secretion of inflammatory factors, and accelerating the repair of SCI. CONCLUSIONS Inhibition of HDAC6 to regulate the immune-inflammatory response and promote MECs to phagocytize myelin debris may represent a novel strategy in the treatment of SCI.
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Affiliation(s)
- Chengjie Wu
- Department of Traumatology and OrthopedicsAffiliated Hospital of Nanjing University of Chinese MedicineNanjingChina
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & OrthopedicsNanjing University of Chinese MedicineNanjingChina
| | - Yalan Pan
- Laboratory of Chinese Medicine Nursing Intervention for Chronic DiseasesNanjing University of Chinese MedicineNanjingChina
| | - Lining Wang
- School of Chinese Medicine, School of Integrated Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Mengmin Liu
- School of Chinese Medicine, School of Integrated Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Pengcheng Tu
- Department of Traumatology and OrthopedicsAffiliated Hospital of Nanjing University of Chinese MedicineNanjingChina
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & OrthopedicsNanjing University of Chinese MedicineNanjingChina
| | - Sixian Chen
- School of Chinese Medicine, School of Integrated Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Lei Shi
- School of Chinese Medicine, School of Integrated Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Danqing Yan
- Department of Traumatology and OrthopedicsAffiliated Hospital of Nanjing University of Chinese MedicineNanjingChina
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & OrthopedicsNanjing University of Chinese MedicineNanjingChina
| | - Yong Ma
- Department of Traumatology and OrthopedicsAffiliated Hospital of Nanjing University of Chinese MedicineNanjingChina
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & OrthopedicsNanjing University of Chinese MedicineNanjingChina
- School of Chinese Medicine, School of Integrated Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Yang Guo
- Department of Traumatology and OrthopedicsAffiliated Hospital of Nanjing University of Chinese MedicineNanjingChina
- Laboratory of New Techniques of Restoration & Reconstruction, Institute of Traumatology & OrthopedicsNanjing University of Chinese MedicineNanjingChina
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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.
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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
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Saraswat Ohri S, Andres KR, Howard RM, Brown BL, Forston MD, Hetman M, Whittemore SR. Acute Pharmacological Inhibition of Protein Kinase R-Like Endoplasmic Reticulum Kinase Signaling After Spinal Cord Injury Spares Oligodendrocytes and Improves Locomotor Recovery. J Neurotrauma 2023; 40:1007-1019. [PMID: 36503284 PMCID: PMC10162120 DOI: 10.1089/neu.2022.0177] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a major signal transducer of the endoplasmic reticulum stress response (ERSR) pathway. Outcomes of PERK activation range from abrogating ER stress to induction of cell death, dependent on its level, duration, and cellular context. Current data demonstrate that after mouse spinal cord injury (SCI), acute inhibition of PERK (0-72 h) with the small molecule inhibitor GSK2656157 reduced ERSR while improving white matter sparing and hindlimb locomotion recovery. GSK2656157-treated mice showed increased numbers of oligodendrocytes at the injury epicenter. Moreover, GSK2656157 protected cultured primary mouse oligodendrocyte precursor cells from ER stress-induced cytotoxicity. These findings suggest that in the context of SCI, excessive acute activation of PERK contributes to functionally relevant white matter damage. Pharmacological inhibition of PERK is a potential strategy to protect central nervous system (CNS) white matter following acute injuries, including SCI.
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Affiliation(s)
- Sujata Saraswat Ohri
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Interdisciplinary Program in Translational Neuroscience, and Department of University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Kariena R. Andres
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Russell M. Howard
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Brandon L. Brown
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Interdisciplinary Program in Translational Neuroscience, and Department of University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Anatomical Sciences and Neurobiology, and University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Michael D. Forston
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Anatomical Sciences and Neurobiology, and University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Michal Hetman
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Interdisciplinary Program in Translational Neuroscience, and Department of University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Anatomical Sciences and Neurobiology, and University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Pharmacology and Toxicology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
| | - Scott R. Whittemore
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Interdisciplinary Program in Translational Neuroscience, and Department of University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Neurological Surgery, University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Anatomical Sciences and Neurobiology, and University of Louisville, School of Medicine, Louisville, Kentucky, USA
- Pharmacology and Toxicology, University of Louisville, School of Medicine, Louisville, Kentucky, USA
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Hu Y, Wang Y, Liu S, Wang H. The Potential Roles of Ferroptosis in Pathophysiology and Treatment of Musculoskeletal Diseases—Opportunities, Challenges, and Perspectives. J Clin Med 2023; 12:jcm12062125. [PMID: 36983130 PMCID: PMC10051297 DOI: 10.3390/jcm12062125] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
Ferroptosis is different from other forms of cell death, such as apoptosis, autophagy, pyroptosis, and cuproptosis, mainly involving iron metabolism and lipid peroxidation. Ferroptosis plays an important role in various disease, such as malignant tumors, neuron-degenerative diseases, and cardiovascular diseases, and has become the focus of current research. Both iron overload and lipid peroxide accumulation contribute to the occurrence, development, and treatment of musculoskeletal diseases, such as osteoporosis, osteoarthritis, osteosarcoma, intervertebral disc degeneration, and spinal cord injury. For a better understanding of the potential roles ferroptosis may play in pathophysiology and treatment of common musculoskeletal disorders, this article briefly reviewed the relationship and possible mechanisms. Through an investigation of ferroptosis’ role in musculoskeletal diseases’ occurrence, development, and treatment, ferroptosis could offer new opportunities for clinical diagnosis and treatment.
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Affiliation(s)
- Yunxiang Hu
- Department of Orthopedics, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, No. 826, Southwestern Road, Shahekou District, Dalian 116021, China
- School of Graduates, Dalian Medical University, No. 9, West Section of South Lvshun Road, Dalian 116044, China
| | - Yufei Wang
- School of Graduates, Dalian Medical University, No. 9, West Section of South Lvshun Road, Dalian 116044, China
- Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian 110623, China
| | - Sanmao Liu
- Department of Orthopedics, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, No. 826, Southwestern Road, Shahekou District, Dalian 116021, China
- School of Graduates, Dalian Medical University, No. 9, West Section of South Lvshun Road, Dalian 116044, China
| | - Hong Wang
- Department of Orthopedics, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, No. 826, Southwestern Road, Shahekou District, Dalian 116021, China
- School of Graduates, Dalian Medical University, No. 9, West Section of South Lvshun Road, Dalian 116044, China
- Correspondence:
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Zawadzka M, Yeghiazaryan M, Niedziółka S, Miazga K, Kwaśniewska A, Bekisz M, Sławińska U. Forced Remyelination Promotes Axon Regeneration in a Rat Model of Spinal Cord Injury. Int J Mol Sci 2022; 24:ijms24010495. [PMID: 36613945 PMCID: PMC9820536 DOI: 10.3390/ijms24010495] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/22/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022] Open
Abstract
Spinal cord injuries result in the loss of motor and sensory functions controlled by neurons located at the site of the lesion and below. We hypothesized that experimentally enhanced remyelination supports axon preservation and/or growth in the total spinal cord transection in rats. Multifocal demyelination was induced by injection of ethidium bromide (EB), either at the time of transection or twice during transection and at 5 days post-injury. We demonstrated that the number of oligodendrocyte progenitor cells (OPCs) significantly increased 14 days after demyelination. Most OPCs differentiated into mature oligodendrocytes by 60-90 dpi in double-EB-injected rats; however, most axons were remyelinated by Schwann cells. A significant number of axons passed the injury epicenter and entered the distant segments of the spinal cord in the double-EB-injected rats. Moreover, some serotoninergic fibers, not detected in control animals, grew caudally through the injury site. Behavioral tests performed at 60-90 dpi revealed significant improvement in locomotor function recovery in double-EB-injected rats, which was impaired by the blockade of serotonin receptors, confirming the important role of restored serotonergic fibers in functional recovery. Our findings indicate that enhanced remyelination per se, without substantial inhibition of glial scar formation, is an important component of spinal cord injury regeneration.
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Zhao Q, Zhu Y, Ren Y, Yin S, Yu L, Huang R, Song S, Hu X, Zhu R, Cheng L, Xie N. Neurogenesis potential of oligodendrocyte precursor cells from oligospheres and injured spinal cord. Front Cell Neurosci 2022; 16:1049562. [PMID: 36619671 PMCID: PMC9813964 DOI: 10.3389/fncel.2022.1049562] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
Severe traumatic spinal cord injury (SCI) leads to long-lasting oligodendrocyte death and extensive demyelination in the lesion area. Oligodendrocyte progenitor cells (OPCs) are the reservoir of new mature oligodendrocytes during damaged myelin regeneration, which also have latent potential for neurogenic regeneration and oligospheres formation. Whether oligospheres derived OPCs can differentiate into neurons and the neurogenesis potential of OPCs after SCI remains unclear. In this study, primary OPCs cultures were used to generate oligospheres and detect the differentiation and neurogenesis potential of oligospheres. In vivo, SCI models of juvenile and adult mice were constructed. Combining the single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), bioinformatics analysis, immunofluorescence staining, and molecular experiment, we investigated the neurogenesis potential and mechanisms of OPCs in vitro and vivo. We found that OPCs differentiation and oligodendrocyte morphology were significantly different between brain and spinal cord. Intriguingly, we identify a previously undescribed findings that OPCs were involved in oligospheres formation which could further differentiate into neuron-like cells. We also firstly detected the intermediate states of oligodendrocytes and neurons during oligospheres differentiation. Furthermore, we found that OPCs were significantly activated after SCI. Combining scRNA-seq and bulk RNA-seq data from injured spinal cord, we confirmed the neurogenesis potential of OPCs and the activation of endoplasmic reticulum stress after SCI. Inhibition of endoplasmic reticulum stress could effectively attenuate OPCs death. Additionally, we also found that endoplasmic reticulum may regulate the stemness and differentiation of oligospheres. These findings revealed the neurogenesis potential of OPCs from oligospheres and injured spinal cord, which may provide a new source and a potential target for spinal cord repair.
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Affiliation(s)
- Qing Zhao
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China,Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Yanjing Zhu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yilong Ren
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China,Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Shuai Yin
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China,Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Liqun Yu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Ruiqi Huang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Simin Song
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Xiao Hu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China,Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China
| | - Rongrong Zhu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China,*Correspondence: Rongrong Zhu,
| | - Liming Cheng
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China,Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China,Liming Cheng,
| | - Ning Xie
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Medicine, School of Life Sciences and Technology, Tongji University, Shanghai, China,Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, China,Ning Xie,
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9
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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: 14] [Impact Index Per Article: 4.7] [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.
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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.
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10
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The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury. Nat Commun 2022; 13:5786. [PMID: 36184639 PMCID: PMC9527244 DOI: 10.1038/s41467-022-33463-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 09/16/2022] [Indexed: 01/18/2023] Open
Abstract
Spinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)-1α is produced by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induces neutrophil infiltration and OL death throughout the spinal cord, mimicking the injury cascade seen in SCI sites. These effects are abolished through co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which demonstrate enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restores IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduces OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes results in toxicity for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS), and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, inducing astrocyte- and EC-mediated OL degeneration.
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11
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Li N, Yao M, Liu J, Zhu Z, Lam TL, Zhang P, Kiang KMY, Leung GKK. Vitamin D Promotes Remyelination by Suppressing c-Myc and Inducing Oligodendrocyte Precursor Cell Differentiation after Traumatic Spinal Cord Injury. Int J Biol Sci 2022; 18:5391-5404. [PMID: 36147469 PMCID: PMC9461656 DOI: 10.7150/ijbs.73673] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/13/2022] [Indexed: 11/22/2022] Open
Abstract
Demyelination due to oligodendrocytes loss occurs after traumatic spinal cord injury (TSCI). Several studies have suggested the therapeutic potential of vitamin D (VitD) in demyelinating diseases. However, experimental evidence in the context of TSCI is limited, particularly in the presence of prior VitD-deficiency. In the present study, a contusion and a transection TSCI rat model were used, representing mild and severe injury, respectively. Motor recovery was assessed in rats with normal VitD level or with VitD-deficiency after 8 weeks' treatment post-TSCI (Cholecalciferol, 500 IU/kg/day). The impact on myelin integrity was examined by transmission electron microscopy and studied in vitro using primary culture of oligodendrocytes. We found that VitD treatment post-TSCI effectively improved hindlimb movement in rats with normal VitD level irrespective of injury severity. However, cord-transected rats with prior deficiency did not seem to benefit from VitD supplementation. Our data further suggested that having sufficient VitD was essential for persevering myelin integrity after injury. VitD rescued oligodendrocytes from apoptotic cell death in vitro and enhanced their myelinating ability towards dorsal root axons. Enhanced myelination was mediated by increased oligodendrocyte precursor cells (OPCs) differentiation into oligodendrocytes in concert with c-Myc downregulation and suppressed OPCs proliferation. Our study provides novel insights into the functioning of VitD as a regulator of OPCs differentiation as well as strong preclinical evidence supporting future clinical testing of VitD for TSCI.
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Affiliation(s)
- Ning Li
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,Department of Neurosurgery, Zhongda Hospital, Southeast University, Nanjing, China
| | - Min Yao
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,School of Pharmaceutical Sciences, Health Science Centre, Shenzhen University, Shenzhen, China
| | - Jiaxin Liu
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Zhiyuan Zhu
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.,Department of Functional Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Tsz-Lung Lam
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Pingde Zhang
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Karrie Mei-Yee Kiang
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Gilberto Ka-Kit Leung
- Department of Surgery, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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12
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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.
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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.
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13
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Wang R, Zhou R, Chen Z, Gao S, Zhou F. The Glial Cells Respond to Spinal Cord Injury. Front Neurol 2022; 13:844497. [PMID: 35599739 PMCID: PMC9120539 DOI: 10.3389/fneur.2022.844497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
It is been over 100 years since glial cells were discovered by Virchow. Since then, a great deal of research was carried out to specify these further roles and properties of glial cells in central nervous system (CNS). As it is well-known that glial cells, such as astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte progenitor cells (OPCs) play an important role in supporting and enabling the effective nervous system function in CNS. After spinal cord injury (SCI), these glial cells play different roles in SCI and repair. In this review, we will discuss in detail about the role of glial cells in the healthy CNS and how they respond to SCI.
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14
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Salvador AFM, Kipnis J. Immune response after central nervous system injury. Semin Immunol 2022; 59:101629. [PMID: 35753867 DOI: 10.1016/j.smim.2022.101629] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/07/2022] [Accepted: 06/13/2022] [Indexed: 01/15/2023]
Abstract
Traumatic injuries of the central nervous system (CNS) affect millions of people worldwide, and they can lead to severely damaging consequences such as permanent disability and paralysis. Multiple factors can obstruct recovery after CNS injury. One of the most significant is the progressive neuronal death that follows the initial mechanical impact, leading to the loss of undamaged cells via a process termed secondary neurodegeneration. Efforts to define treatments that limit the spread of damage, while important, have been largely ineffectual owing to gaps in the mechanistic understanding that underlies the persisting neuronal cell death. Inflammation, with its influx of immune cells that occurs shortly after injury, has been associated with secondary neurodegeneration. However, the role of the immune system after CNS injury is far more complex. Studies have indicated that the immune response after CNS injury is detrimental, owing to immune cell-produced factors (e.g., pro-inflammatory cytokines, free radicals, neurotoxic glutamate) that worsen tissue damage. Our lab and others have also demonstrated the beneficial immune response that occurs after CNS injury, with the release of growth factors such as brain-derived growth factor (BDNF) and interleukin (IL-10) and the clearance of apoptotic and myelin debris by immune cells1-4. In this review, we first discuss the multifaceted roles of the immune system after CNS injury. We then speculate on how advancements in single-cell RNA technologies can dramatically change our understanding of the immune response, how the spinal cord meninges serve as an important site for hosting immunological processes critical for recovery, and how the origin of peripherally recruited immune cells impacts their function in the injured CNS.
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Affiliation(s)
- Andrea Francesca M Salvador
- Department of Pathology & Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA.
| | - Jonathan Kipnis
- Department of Pathology & Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
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15
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Zhang Y, Yang S, Liu C, Han X, Gu X, Zhou S. Deciphering glial scar after spinal cord injury. BURNS & TRAUMA 2021; 9:tkab035. [PMID: 34761050 PMCID: PMC8576268 DOI: 10.1093/burnst/tkab035] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/26/2021] [Indexed: 12/25/2022]
Abstract
Spinal cord injury (SCI) often leads to permanent disability, which is mainly caused by the loss of functional recovery. In this review, we aimed to investigate why the healing process is interrupted. One of the reasons for this interruption is the formation of a glial scar around the severely damaged tissue, which is usually covered by reactive glia, macrophages and fibroblasts. Aiming to clarify this issue, we summarize the latest research findings pertaining to scar formation, tissue repair, and the divergent roles of blood-derived monocytes/macrophages, ependymal cells, fibroblasts, microglia, oligodendrocyte progenitor cells (OPCs), neuron-glial antigen 2 (NG2) and astrocytes during the process of scar formation, and further analyse the contribution of these cells to scar formation. In addition, we recapitulate the development of therapeutic treatments targeting glial scar components. Altogether, we aim to present a comprehensive decoding of the glial scar and explore potential therapeutic strategies for improving functional recovery after SCI.
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Affiliation(s)
- Yu Zhang
- Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210000, China
| | - Shuhai Yang
- Medical College of Nantong University, Nantong, 226001, China
| | - Chang Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Xiaoxiao Han
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Xiaosong Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Songlin Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
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16
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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.
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17
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Liu S, Zhang W, Yang L, Zhou F, Liu P, Wang Y. Overexpression of bone morphogenetic protein 7 reduces oligodendrocytes loss and promotes functional recovery after spinal cord injury. J Cell Mol Med 2021; 25:8764-8774. [PMID: 34390115 PMCID: PMC8435414 DOI: 10.1111/jcmm.16832] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/03/2021] [Accepted: 07/22/2021] [Indexed: 12/04/2022] Open
Abstract
Spinal cord injury (SCI), as a severe disease with no effective therapeutic measures, has always been a hot topic for scientists. Bone morphogenetic protein 7 (BMP7), as a multifunctional cytokine, has been reported to exert protective effects on the nervous system. The present study aimed to investigate the neuroprotective effect and the potential mechanisms of BMP7 on rats that suffered SCI. Rat models of SCI were established by the modified Allen's method. Adeno‐associated virus (AAV) was injected at T9 immediately before SCI to overexpress BMP7. Results showed that the expression of BMP7 decreased in the injured spinal cords that were at the same time demyelinated. AAV‐BMP7 partly reversed oligodendrocyte (OL) loss, and it was beneficial to maintain the normal structure of myelin. The intervention group showed an increase in the number of axons and Basso‐Beattie‐Bresnahan scores. Moreover, double‐labelled immunofluorescence images indicated p‐Smad1/5/9 and p‐STAT3 in OLs induced by BMP7 might be involved in the protective effects of BMP7. These findings suggest that BMP7 may be a feasible therapy for SCI to reduce demyelination and promote functional recovery.
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Affiliation(s)
- Shuxin Liu
- Department of Pain Management and Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Wei Zhang
- Department of Pain Management and Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lin Yang
- Department of Pain Management and Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Fan Zhou
- Department of Pain Management and Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Peng Liu
- Department of Disease Prevention and Control, People's Liberation Army Joint Logistic Support Force 921th Hospital, Changsha, China
| | - Yaping Wang
- Department of Pain Management and Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China
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18
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Tai W, Wu W, Wang LL, Ni H, Chen C, Yang J, Zang T, Zou Y, Xu XM, Zhang CL. In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury. Cell Stem Cell 2021; 28:923-937.e4. [PMID: 33675690 PMCID: PMC8106641 DOI: 10.1016/j.stem.2021.02.009] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 12/04/2020] [Accepted: 02/05/2021] [Indexed: 12/19/2022]
Abstract
Adult neurogenesis plays critical roles in maintaining brain homeostasis and responding to neurogenic insults. However, the adult mammalian spinal cord lacks an intrinsic capacity for neurogenesis. Here we show that spinal cord injury (SCI) unveils a latent neurogenic potential of NG2+ glial cells, which can be exploited to produce new neurons and promote functional recovery after SCI. Although endogenous SOX2 is required for SCI-induced transient reprogramming, ectopic SOX2 expression is necessary and sufficient to unleash the full neurogenic potential of NG2 glia. Ectopic SOX2-induced neurogenesis proceeds through an expandable ASCL1+ progenitor stage and generates excitatory and inhibitory propriospinal neurons, which make synaptic connections with ascending and descending spinal pathways. Importantly, SOX2-mediated reprogramming of NG2 glia reduces glial scarring and promotes functional recovery after SCI. These results reveal a latent neurogenic potential of somatic glial cells, which can be leveraged for regenerative medicine.
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Affiliation(s)
- Wenjiao Tai
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Wei Wu
- Department of Neurological Surgery, Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Lei-Lei Wang
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
| | - Haoqi Ni
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Chunhai Chen
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jianjing Yang
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Tong Zang
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yuhua Zou
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xiao-Ming Xu
- Department of Neurological Surgery, Spinal Cord and Brain Injury Research Group, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Chun-Li Zhang
- Department of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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19
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Olmsted ZT, Paluh JL. Stem Cell Neurodevelopmental Solutions for Restorative Treatments of the Human Trunk and Spine. Front Cell Neurosci 2021; 15:667590. [PMID: 33981202 PMCID: PMC8107236 DOI: 10.3389/fncel.2021.667590] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 03/29/2021] [Indexed: 12/21/2022] Open
Abstract
The ability to reliably repair spinal cord injuries (SCI) will be one of the greatest human achievements realized in regenerative medicine. Until recently, the cellular path to this goal has been challenging. However, as detailed developmental principles are revealed in mouse and human models, their application in the stem cell community brings trunk and spine embryology into efforts to advance human regenerative medicine. New models of posterior embryo development identify neuromesodermal progenitors (NMPs) as a major bifurcation point in generating the spinal cord and somites and is leading to production of cell types with the full range of axial identities critical for repair of trunk and spine disorders. This is coupled with organoid technologies including assembloids, circuitoids, and gastruloids. We describe a paradigm for applying developmental principles towards the goal of cell-based restorative therapies to enable reproducible and effective near-term clinical interventions.
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20
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Hassanzadeh S, Jalessi M, Jameie SB, Khanmohammadi M, Bagher Z, Namjoo Z, Davachi SM. More attention on glial cells to have better recovery after spinal cord injury. Biochem Biophys Rep 2021; 25:100905. [PMID: 33553683 PMCID: PMC7844125 DOI: 10.1016/j.bbrep.2020.100905] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 12/29/2020] [Accepted: 12/29/2020] [Indexed: 01/01/2023] Open
Abstract
Functional improvement after spinal cord injury remains an unsolved difficulty. Glial scars, a major component of SCI lesions, are very effective in improving the rate of this recovery. Such scars are a result of complex interaction mechanisms involving three major cells, namely, astrocytes, oligodendrocytes, and microglia. In recent years, scientists have identified two subtypes of reactive astrocytes, namely, A1 astrocytes that induce the rapid death of neurons and oligodendrocytes, and A2 astrocytes that promote neuronal survival. Moreover, recent studies have suggested that the macrophage polarization state is more of a continuum between M1 and M2 macrophages. M1 macrophages that encourage the inflammation process kill their surrounding cells and inhibit cellular proliferation. In contrast, M2 macrophages promote cell proliferation, tissue growth, and regeneration. Furthermore, the ability of oligodendrocyte precursor cells to differentiate into adult oligodendrocytes or even neurons has been reviewed. Here, we first scrutinize recent findings on glial cell subtypes and their beneficial or detrimental effects after spinal cord injury. Second, we discuss how we may be able to help the functional recovery process after injury.
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Affiliation(s)
- Sajad Hassanzadeh
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Jalessi
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Behnamedin Jameie
- Neuroscience Research Center (NRC), Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Basic Sciences, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Khanmohammadi
- Skull Base Research Center, Hazrat Rasoul Hospital, The Five Senses Health Institute, Iran University of Medical Sciences, Tehran, Iran
| | - Zohre Bagher
- ENT and Head & Neck Research Center and Department, The Five Senses Health Institute, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Zeinab Namjoo
- Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Seyed Mohammad Davachi
- Department of Food Science, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, USA
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21
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Ohri SS, Howard RM, Liu Y, Andres KR, Hetman M, Whittemore SR. Oligodendrocyte-specific deletion of Xbp1 exacerbates the endoplasmic reticulum stress response and restricts locomotor recovery after thoracic spinal cord injury. Glia 2021; 69:424-435. [PMID: 32926479 PMCID: PMC8931742 DOI: 10.1002/glia.23907] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Revised: 08/21/2020] [Accepted: 08/23/2020] [Indexed: 12/31/2022]
Abstract
The endoplasmic reticulum stress response (ERSR) is activated in various neurodegenerative diseases and/or after CNS traumatic injuries. The ERSR is comprised of three major arms, PERK, IRE-1, and activating transcription factor-6, with the latter two contributing to the unfolded protein response (UPR). PERK activity overlaps with the integrated stress response (ISR) kinases, PKR, HRI, and GCN2 which all signal through, eukaryotic initiation factor 2α, ATF4, and CHOP. All initially attempt to restore endoplasmic reticulum (ER) homeostasis, but if ER stress is unresolved, ATF4/CHOP-mediated cell death is initiated. Here, we investigate the contribution of the inositol-requiring protein-1α-X-box binding protein-1 (XBP1)-mediated UPR signaling pathway to the pathogenesis of spinal cord injury (SCI). We demonstrate that deletion of Xbp1 caused an exacerbated ATF4/CHOP signaling in cultured mouse oligodendrocyte (OL) progenitor cells and enhanced their sensitivity to ER stress. Similar effects were also observed with the Xbp1 pathway inhibitor toyocamycin. Furthermore, OL lineage-specific loss of Xbp1 resulted in enhanced ISR in mice that underwent moderate contusive SCI at the T9 level. Consistently, post-injury recovery of hindlimb locomotion and white matter sparing were reduced in OL Xbp1-deficient mice, which correlated with chronically decreased relative density of OPCs and OLs at the injury epicenter at 6 weeks post-SCI. We conclude that the IRE1-XBP1-mediated UPR signaling pathway contributes to restoration of ER homeostasis in OLs and is necessary for enhanced white matter sparing and functional recovery post-SCI.
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Affiliation(s)
- Sujata Saraswat Ohri
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
| | - Russell M. Howard
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
| | - Yu Liu
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
| | - Kariena R. Andres
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
| | - Michal Hetman
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Pharmacology & Toxicology, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Anatomical Sciences & Neurobiology, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
| | - Scott R. Whittemore
- Kentucky Spinal Cord Injury Research Center, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Neurological Surgery, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Pharmacology & Toxicology, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
- Departments of Anatomical Sciences & Neurobiology, University of Louisville, School of Medicine, 511 S. Floyd St., MDR 616, Louisville, KY 40202, USA
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22
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Fan BY, Pang YL, Li WX, Zhao CX, Zhang Y, Wang X, Ning GZ, Kong XH, Liu C, Yao X, Feng SQ. Liproxstatin-1 is an effective inhibitor of oligodendrocyte ferroptosis induced by inhibition of glutathione peroxidase 4. Neural Regen Res 2021; 16:561-566. [PMID: 32985488 PMCID: PMC7996026 DOI: 10.4103/1673-5374.293157] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Our previous studies showed that ferroptosis plays an important role in the acute and subacute stages of spinal cord injury. High intracellular iron levels and low glutathione levels make oligodendrocytes vulnerable to cell death after central nervous system trauma. In this study, we established an oligodendrocyte (OLN-93 cell line) model of ferroptosis induced by RSL-3, an inhibitor of glutathione peroxidase 4 (GPX4). RSL-3 significantly increased intracellular concentrations of reactive oxygen species and malondialdehyde. RSL-3 also inhibited the main anti-ferroptosis pathway, i.e., SLC7A11/glutathione/glutathione peroxidase 4 (xCT/GSH/GPX4), and downregulated acyl-coenzyme A synthetase long chain family member 4. Furthermore, we evaluated the ability of several compounds to rescue oligodendrocytes from ferroptosis. Liproxstatin-1 was more potent than edaravone or deferoxamine. Liproxstatin-1 not only inhibited mitochondrial lipid peroxidation, but also restored the expression of GSH, GPX4 and ferroptosis suppressor protein 1. These findings suggest that GPX4 inhibition induces ferroptosis in oligodendrocytes, and that liproxstatin-1 is a potent inhibitor of ferroptosis. Therefore, liproxstatin-1 may be a promising drug for the treatment of central nervous system diseases.
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Affiliation(s)
- Bao-You Fan
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yi-Lin Pang
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Wen-Xiang Li
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Chen-Xi Zhao
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yan Zhang
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Xu Wang
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Guang-Zhi Ning
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | | | - Chang Liu
- School of Medicine, Nankai University, Tianjin, China
| | - Xue Yao
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
| | - Shi-Qing Feng
- International Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, China
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23
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Distinct oligodendrocyte populations have spatial preference and different responses to spinal cord injury. Nat Commun 2020; 11:5860. [PMID: 33203872 PMCID: PMC7673029 DOI: 10.1038/s41467-020-19453-x] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 10/14/2020] [Indexed: 12/23/2022] Open
Abstract
Mature oligodendrocytes (MOLs) show transcriptional heterogeneity, the functional consequences of which are unclear. MOL heterogeneity might correlate with the local environment or their interactions with different neuron types. Here, we show that distinct MOL populations have spatial preference in the mammalian central nervous system (CNS). We found that MOL type 2 (MOL2) is enriched in the spinal cord when compared to the brain, while MOL types 5 and 6 (MOL5/6) increase their contribution to the OL lineage with age in all analyzed regions. MOL2 and MOL5/6 also have distinct spatial preference in the spinal cord regions where motor and sensory tracts run. OL progenitor cells (OPCs) are not specified into distinct MOL populations during development, excluding a major contribution of OPC intrinsic mechanisms determining MOL heterogeneity. In disease, MOL2 and MOL5/6 present different susceptibility during the chronic phase following traumatic spinal cord injury. Our results demonstrate that the distinct MOL populations have different spatial preference and different responses to disease. The oligodendrocyte lineage is known for its transcriptional heterogeneity, but the functional consequences of this are unclear. Here, the authors show that distinct populations of mature oligodendrocytes have spatial preferences in the brain and spinal cord and show different responses to spinal cord injury.
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24
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Slomnicki LP, Myers SA, Saraswat Ohri S, Parsh MV, Andres KR, Chariker JH, Rouchka EC, Whittemore SR, Hetman M. Improved locomotor recovery after contusive spinal cord injury in Bmal1 -/- mice is associated with protection of the blood spinal cord barrier. Sci Rep 2020; 10:14212. [PMID: 32848194 PMCID: PMC7450087 DOI: 10.1038/s41598-020-71131-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/10/2020] [Indexed: 11/09/2022] Open
Abstract
The transcription factor BMAL1/ARNTL is a non-redundant component of the clock pathway that regulates circadian oscillations of gene expression. Loss of BMAL1 perturbs organismal homeostasis and usually exacerbates pathological responses to many types of insults by enhancing oxidative stress and inflammation. Surprisingly, we observed improved locomotor recovery and spinal cord white matter sparing in Bmal1-/- mice after T9 contusive spinal cord injury (SCI). While acute loss of neurons and oligodendrocytes was unaffected, Bmal1 deficiency reduced the chronic loss of oligodendrocytes at the injury epicenter 6 weeks post SCI. At 3 days post-injury (dpi), decreased expression of genes associated with cell proliferation, neuroinflammation and disruption of the blood spinal cord barrier (BSCB) was also observed. Moreover, intraspinal extravasation of fibrinogen and immunoglobulins was decreased acutely at dpi 1 and subacutely at dpi 7. Subacute decrease of hemoglobin deposition was also observed. Finally, subacutely reduced levels of the leukocyte marker CD45 and even greater reduction of the pro-inflammatory macrophage receptor CD36 suggest not only lower numbers of those cells but also their reduced inflammatory potential. These data indicate that Bmal1 deficiency improves SCI outcome, in part by reducing BSCB disruption and hemorrhage decreasing cytotoxic neuroinflammation and attenuating the chronic loss of oligodendrocytes.
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Affiliation(s)
- Lukasz P Slomnicki
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40202, USA
- Department of Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA
| | - Scott A Myers
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40202, USA
- Department of Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA
| | - Sujata Saraswat Ohri
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40202, USA.
- Department of Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA.
- Kentucky Spinal Cord Injury Research Center, University of Louisville, 511 S. Floyd St., MDR616, Louisville, KY, 40292, USA.
| | - Molly V Parsh
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40202, USA
- Department of Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA
| | - Kariena R Andres
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40202, USA
- Department of Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA
| | - Julia H Chariker
- Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY, 40202, USA
- Kentucky Biomedical Research Infrastructure Network Bioinformatics Core, University of Louisville, Louisville, KY, 40202, USA
| | - Eric C Rouchka
- Department of Computer Engineering and Computer Science, University of Louisville, Louisville, KY, 40202, USA
- Kentucky Biomedical Research Infrastructure Network Bioinformatics Core, University of Louisville, Louisville, KY, 40202, USA
| | - Scott R Whittemore
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40202, USA
- Department of Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, 40202, USA
| | - Michal Hetman
- Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY, 40202, USA.
- Department of Neurological Surgery, University of Louisville, Louisville, KY, 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA.
- Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY, 40202, USA.
- Kentucky Spinal Cord Injury Research Center, University of Louisville, 511 S. Floyd St., MDR616, Louisville, KY, 40292, USA.
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25
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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.
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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.
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26
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Abbaszadeh F, Fakhri S, Khan H. Targeting apoptosis and autophagy following spinal cord injury: Therapeutic approaches to polyphenols and candidate phytochemicals. Pharmacol Res 2020; 160:105069. [PMID: 32652198 DOI: 10.1016/j.phrs.2020.105069] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/28/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022]
Abstract
Spinal cord injury (SCI) is a neurological disorder associated with the loss of sensory and motor function. Understanding the precise dysregulated signaling pathways, especially apoptosis and autophagy following SCI, is of vital importance in developing innovative therapeutic targets and treatments. The present study lies in the fact that it reveals the precise dysregulated signaling mediators of apoptotic and autophagic pathways following SCI and also examines the effects of polyphenols and other candidate phytochemicals. It provides new insights to develop new treatments for post-SCI complications. Accordingly, a comprehensive review was conducted using electronic databases including, Scopus, Web of Science, PubMed, and Medline, along with the authors' expertise in apoptosis and autophagy as well as their knowledge about the effects of polyphenols and other phytochemicals on SCI pathogenesis. The primary mechanical injury to spinal cord is followed by a secondary cascade of apoptosis and autophagy that play critical roles during SCI. In terms of pharmacological mechanisms, caspases, Bax/Bcl-2, TNF-α, and JAK/STAT in apoptosis along with LC3 and Beclin-1 in autophagy have shown a close interconnection with the inflammatory pathways mainly glutamatergic, PI3K/Akt/mTOR, ERK/MAPK, and other cross-linked mediators. Besides, apoptotic pathways have been shown to regulate autophagy mediators and vice versa. Prevailing evidence has highlighted the importance of modulating these signaling mediators/pathways by polyphenols and other candidate phytochemicals post-SCI. The present review provides dysregulated signaling mediators and therapeutic targets of apoptotic and autophagic pathways following SCI, focusing on the modulatory effects of polyphenols and other potential phytochemical candidates.
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Affiliation(s)
- Fatemeh Abbaszadeh
- Department of Neuroscience, Faculty of Advanced Technologies in Medical Sciences, Iran University of Medical Sciences, Tehran, Iran; Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan.
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27
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Li G, Fan ZK, Gu GF, Jia ZQ, Zhang QQ, Dai JY, He SS. Epidural Spinal Cord Stimulation Promotes Motor Functional Recovery by Enhancing Oligodendrocyte Survival and Differentiation and by Protecting Myelin after Spinal Cord Injury in Rats. Neurosci Bull 2019; 36:372-384. [PMID: 31732865 DOI: 10.1007/s12264-019-00442-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Epidural spinal cord stimulation (ESCS) markedly improves motor and sensory function after spinal cord injury (SCI), but the underlying mechanisms are unclear. Here, we investigated whether ESCS affects oligodendrocyte differentiation and its cellular and molecular mechanisms in rats with SCI. ESCS improved hindlimb motor function at 7 days, 14 days, 21 days, and 28 days after SCI. ESCS also significantly increased the myelinated area at 28 days, and reduced the number of apoptotic cells in the spinal white matter at 7 days. SCI decreased the expression of 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase, an oligodendrocyte marker) at 7 days and that of myelin basic protein at 28 days. ESCS significantly upregulated these markers and increased the percentage of Sox2/CNPase/DAPI-positive cells (newly differentiated oligodendrocytes) at 7 days. Recombinant human bone morphogenetic protein 4 (rhBMP4) markedly downregulated these factors after ESCS. Furthermore, ESCS significantly decreased BMP4 and p-Smad1/5/9 expression after SCI, and rhBMP4 reduced this effect of ESCS. These findings indicate that ESCS enhances the survival and differentiation of oligodendrocytes, protects myelin, and promotes motor functional recovery by inhibiting the BMP4-Smad1/5/9 signaling pathway after SCI.
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Affiliation(s)
- Gang Li
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Spinal Pain Research Institute, Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhong-Kai Fan
- Department of Orthopaedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Guang-Fei Gu
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
- Spinal Pain Research Institute, Tongji University School of Medicine, Shanghai, 200072, China
| | - Zhi-Qiang Jia
- Department of Spinal Surgery, The Second Affiliated Hospital, Henan University of Science and Technology, Luoyang, 471003, China
| | - Qiang-Qiang Zhang
- Department of Orthopaedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Jun-Yu Dai
- Department of Orthopaedics, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Shi-Sheng He
- Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
- Spinal Pain Research Institute, Tongji University School of Medicine, Shanghai, 200072, China.
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28
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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: 62] [Impact Index Per Article: 10.3] [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.
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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
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29
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Zhao X, Li Z, Liang S, Li S, Ren J, Li B, Zhu Y, Xia M. Different epidermal growth factor receptor signaling pathways in neurons and astrocytes activated by extracellular matrix after spinal cord injury. Neurochem Int 2019; 129:104500. [PMID: 31295509 DOI: 10.1016/j.neuint.2019.104500] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 06/25/2019] [Accepted: 07/07/2019] [Indexed: 12/26/2022]
Abstract
Spinal cord injury (SCI) is a serious central nervous system (CNS) trauma that results in permanent and severe disability. The extracellular matrix (ECM) can affect the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) by interacting with the ERK integrin subunits. In this study, we built a model of SCI with glial fibrillary acidic protein-green fluorescent protein (GFAP-GFP) and thymus cell antigen 1-yellow fluorescent protein-H (Thy1-YFPH) in mice that express specific transgenes in their astrocytes or neurons. Then, we collected spinal cord neurons or astrocytes by fluorescence-activated cell sorting (FACS). In this way, we investigated the SCI-induced phosphorylation of ERK1/2 and epidermal growth factor receptor (EGFR) in neurons and astrocytes, and we discovered that the SCI-induced EGFR signaling pathways differed between neurons and astrocytes. In the present study, we found that the Src-dependent phosphorylation of EGFR induced by SCI occurred only in neurons, not in astrocytes. This phenomenon may be due to the involvement of Thy-1, which promoted the binding between Src and EGFR in neurons after SCI. In addition, the expression of the integrin subunits after SCI differed between neurons and astrocytes. Our present study shows that the EGFR signaling pathway triggered by SCI in neurons differed from the EGFR signaling pathway triggered in astrocytes, a finding that may help to pave the way for clinical trials of therapies that inhibit EGFR signaling pathways after SCI.
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Affiliation(s)
- Xin Zhao
- Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China; Department of Operating Room, First Affiliated Hospital, China Medical University, Shenyang, People's Republic of China
| | - Zexiong Li
- Practical Teaching Center, School of Forensic Medicine, China Medical University, Shenyang, People's Republic of China
| | - Shanshan Liang
- Practical Teaching Center, School of Forensic Medicine, China Medical University, Shenyang, People's Republic of China
| | - Shuai Li
- Practical Teaching Center, School of Forensic Medicine, China Medical University, Shenyang, People's Republic of China
| | - Jiaan Ren
- Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Baoman Li
- Practical Teaching Center, School of Forensic Medicine, China Medical University, Shenyang, People's Republic of China. http://
| | - Yue Zhu
- Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China. http://
| | - Maosheng Xia
- Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People's Republic of China.
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30
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Transplantation of miR‐219 overexpressed human endometrial stem cells encapsulated in fibrin hydrogel in spinal cord injury. J Cell Physiol 2019; 234:18887-18896. [DOI: 10.1002/jcp.28527] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 02/09/2019] [Accepted: 02/14/2019] [Indexed: 12/31/2022]
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31
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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.
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32
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Smith DR, Margul DJ, Dumont CM, Carlson MA, Munsell MK, Johnson M, Cummings BJ, Anderson AJ, Shea LD. Combinatorial lentiviral gene delivery of pro-oligodendrogenic factors for improving myelination of regenerating axons after spinal cord injury. Biotechnol Bioeng 2019; 116:155-167. [PMID: 30229864 PMCID: PMC6289889 DOI: 10.1002/bit.26838] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 08/30/2018] [Accepted: 09/12/2018] [Indexed: 12/12/2022]
Abstract
Spinal cord injury (SCI) results in paralysis below the injury and strategies are being developed that support axonal regrowth, yet recovery lags, in part, because many axons are not remyelinated. Herein, we investigated strategies to increase myelination of regenerating axons by overexpression of platelet-derived growth factor (PDGF)-AA and noggin either alone or in combination in a mouse SCI model. Noggin and PDGF-AA have been identified as factors that enhance recruitment and differentiation of endogenous progenitors to promote myelination. Lentivirus encoding for these factors was delivered from a multichannel bridge, which we have previously shown creates a permissive environment and supports robust axonal growth through channels. The combination of noggin+PDGF enhanced total myelination of regenerating axons relative to either factor alone, and importantly, enhanced functional recovery relative to the control condition. The increase in myelination was consistent with an increase in oligodendrocyte-derived myelin, which was also associated with a greater density of cells of an oligodendroglial lineage relative to each factor individually and control conditions. These results suggest enhanced myelination of regenerating axons by noggin+PDGF that act on oligodendrocyte-lineage cells post-SCI, which ultimately led to improved functional outcomes.
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Affiliation(s)
- Dominique R. Smith
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Daniel J. Margul
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | - Courtney M. Dumont
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Mitchell A. Carlson
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Mary K. Munsell
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Mitchell Johnson
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Brian J. Cummings
- Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, CA, USA
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA
- Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA
- Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA
| | - Aileen J. Anderson
- Institute for Memory Impairments and Neurological Disorders (iMIND), University of California, Irvine, CA, USA
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA, USA
- Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA
- Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA
| | - Lonnie D. Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
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33
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Lesteberg KE, Beckham JD. Immunology of West Nile Virus Infection and the Role of Alpha-Synuclein as a Viral Restriction Factor. Viral Immunol 2018; 32:38-47. [PMID: 30222521 DOI: 10.1089/vim.2018.0075] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
West Nile virus (WNV) is a single-stranded RNA flavivirus and is a major cause of viral encephalitis worldwide. Experimental models of WNV infection in mice are commonly used to define acute neuroinflammatory responses in the brain. Alpha-synuclein (Asyn) is a protein of primarily neuronal origin and is a major cause of Parkinson's disease (PD), a disorder characterized by loss of dopaminergic neurons. Both WNV and PD pathologies are largely mediated by inflammation of the central nervous system (neuroinflammation) and have overlapping inflammatory pathways. In this review, we highlight the roles of the immune system in both diseases while comparing and contrasting both protective and pathogenic roles of immune cells and their effector proteins. Additionally, we review the current literature showing that Asyn is an important mediator of the immune response with diverging roles in PD (pathogenic) and WNV disease (neuroprotective).
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Affiliation(s)
- Kelsey E Lesteberg
- 1 Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine , Aurora, Colorado
| | - John David Beckham
- 1 Division of Infectious Diseases, Department of Medicine, University of Colorado School of Medicine , Aurora, Colorado.,2 Division of Neuroimmunology and Neurological Infections, Department of Neurology, University of Colorado School of Medicine , Aurora, Colorado.,3 Veterans Administration, Eastern Colorado Health System , Denver, Colorado
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34
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Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Liu J, Moulson A, Plemel JR, Tetzlaff W. Locomotor recovery following contusive spinal cord injury does not require oligodendrocyte remyelination. Nat Commun 2018; 9:3066. [PMID: 30076300 PMCID: PMC6076268 DOI: 10.1038/s41467-018-05473-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 06/28/2018] [Indexed: 12/16/2022] Open
Abstract
Remyelination occurs after spinal cord injury (SCI) but its functional relevance is unclear. We assessed the necessity of myelin regulatory factor (Myrf) in remyelination after contusive SCI by deleting the gene from platelet-derived growth factor receptor alpha positive (PDGFRα-positive) oligodendrocyte progenitor cells (OPCs) in mice prior to SCI. While OPC proliferation and density are not altered by Myrf inducible knockout after SCI, the accumulation of new oligodendrocytes is largely prevented. This greatly inhibits myelin regeneration, resulting in a 44% reduction in myelinated axons at the lesion epicenter. However, spontaneous locomotor recovery after SCI is not altered by remyelination failure. In controls with functional MYRF, locomotor recovery precedes the onset of most oligodendrocyte myelin regeneration. Collectively, these data demonstrate that MYRF expression in PDGFRα-positive cell derived oligodendrocytes is indispensable for myelin regeneration following contusive SCI but that oligodendrocyte remyelination is not required for spontaneous recovery of stepping.
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Affiliation(s)
- Greg J Duncan
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), 818 West 10th Avenue, V5Z 1M9, Vancouver, BC, Canada
- Department of Zoology, University of British Columbia, 4200-6270 University Blvd, Vancouver, V6T 1Z4, BC, Canada
| | - Sohrab B Manesh
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), 818 West 10th Avenue, V5Z 1M9, Vancouver, BC, Canada
- Graduate Program in Neuroscience, University of British Columbia, 3402-2215 Wesbrook Mall, Vancouver, V6T 1Z3, BC, Canada
| | - Brett J Hilton
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), 818 West 10th Avenue, V5Z 1M9, Vancouver, BC, Canada
- Department of Zoology, University of British Columbia, 4200-6270 University Blvd, Vancouver, V6T 1Z4, BC, Canada
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Sigmund-Freud-Straße 27, 53127, Bonn, Germany
| | - Peggy Assinck
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), 818 West 10th Avenue, V5Z 1M9, Vancouver, BC, Canada
- Graduate Program in Neuroscience, University of British Columbia, 3402-2215 Wesbrook Mall, Vancouver, V6T 1Z3, BC, Canada
| | - Jie Liu
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), 818 West 10th Avenue, V5Z 1M9, Vancouver, BC, Canada
| | - Aaron Moulson
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), 818 West 10th Avenue, V5Z 1M9, Vancouver, BC, Canada
- Department of Zoology, University of British Columbia, 4200-6270 University Blvd, Vancouver, V6T 1Z4, BC, Canada
| | - Jason R Plemel
- The Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, T2N 4N1, Calgary, AB, Canada
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), 818 West 10th Avenue, V5Z 1M9, Vancouver, BC, Canada.
- Department of Zoology, University of British Columbia, 4200-6270 University Blvd, Vancouver, V6T 1Z4, BC, Canada.
- Department of Surgery, University of British Columbia, 2775 Laurel Street, Vancouver, V5Z 1M9, BC, Canada.
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35
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Muñoz-Galdeano T, Reigada D, Del Águila Á, Velez I, Caballero-López MJ, Maza RM, Nieto-Díaz M. Cell Specific Changes of Autophagy in a Mouse Model of Contusive Spinal Cord Injury. Front Cell Neurosci 2018; 12:164. [PMID: 29946241 PMCID: PMC6005838 DOI: 10.3389/fncel.2018.00164] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 05/28/2018] [Indexed: 12/15/2022] Open
Abstract
Autophagy is an essential process of cellular waist clearance that becomes altered following spinal cord injury (SCI). Details on these changes, including timing after injury, underlying mechanisms, and affected cells, remain controversial. Here we present a characterization of autophagy in the mice spinal cord before and after a contusive SCI. In the undamaged spinal cord, analysis of LC3 and Beclin 1 autophagic markers reveals important differences in basal autophagy between neurons, oligodendrocytes, and astrocytes and even within cell populations. Following moderate contusion, western blot analyses of LC3 indicates that autophagy increases to a maximum at 7 days post injury (dpi), whereas unaltered Beclin 1 expression and increase of p62 suggests a possible blockage of autophagosome clearance. Immunofluorescence analyses of LC3 and Beclin 1 provide additional details that reveal a complex, cell-specific scenario. Autophagy is first activated (1 dpi) in the severed axons, followed by a later (7 dpi) accumulation of phagophores and/or autophagosomes in the neuronal soma without signs of increased initiation. Oligodendrocytes and reactive astrocytes also accumulate phagophores and autophagosomes at 7 dpi, but whereas the accumulation in astrocytes is associated with an increased autophagy initiation, it seems to result from a blockage of the autophagic flux in oligodendrocytes. Comparison with previous studies highlights the complex and heterogeneous autophagic responses induced by the SCI, leading in many cases to contradictory results and interpretations. Future studies should consider this complexity in the design of therapeutic interventions based on the modulation of autophagy to treat SCI.
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Affiliation(s)
- Teresa Muñoz-Galdeano
- Laboratory of Molecular Neuroprotection, UDI-HNP, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain
| | - David Reigada
- Laboratory of Molecular Neuroprotection, UDI-HNP, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain
| | - Ángela Del Águila
- Laboratory of Molecular Neuroprotection, UDI-HNP, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain.,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Irene Velez
- Laboratory of Molecular Neuroprotection, UDI-HNP, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain
| | - Marcos J Caballero-López
- Laboratory of Molecular Neuroprotection, UDI-HNP, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain
| | - Rodrigo M Maza
- Laboratory of Molecular Neuroprotection, UDI-HNP, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain
| | - Manuel Nieto-Díaz
- Laboratory of Molecular Neuroprotection, UDI-HNP, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain
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36
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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.
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37
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Halford J, Shen S, Itamura K, Levine J, Chong AC, Czerwieniec G, Glenn TC, Hovda DA, Vespa P, Bullock R, Dietrich WD, Mondello S, Loo JA, Wanner IB. New astroglial injury-defined biomarkers for neurotrauma assessment. J Cereb Blood Flow Metab 2017; 37:3278-3299. [PMID: 28816095 PMCID: PMC5624401 DOI: 10.1177/0271678x17724681] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 05/01/2017] [Accepted: 05/25/2017] [Indexed: 01/08/2023]
Abstract
Traumatic brain injury (TBI) is an expanding public health epidemic with pathophysiology that is difficult to diagnose and thus treat. TBI biomarkers should assess patients across severities and reveal pathophysiology, but currently, their kinetics and specificity are unclear. No single ideal TBI biomarker exists. We identified new candidates from a TBI CSF proteome by selecting trauma-released, astrocyte-enriched proteins including aldolase C (ALDOC), its 38kD breakdown product (BDP), brain lipid binding protein (BLBP), astrocytic phosphoprotein (PEA15), glutamine synthetase (GS) and new 18-25kD-GFAP-BDPs. Their levels increased over four orders of magnitude in severe TBI CSF. First post-injury week, ALDOC levels were markedly high and stable. Short-lived BLBP and PEA15 related to injury progression. ALDOC, BLBP and PEA15 appeared hyper-acutely and were similarly robust in severe and mild TBI blood; 25kD-GFAP-BDP appeared overnight after TBI and was rarely present after mild TBI. Using a human culture trauma model, we investigated biomarker kinetics. Wounded (mechanoporated) astrocytes released ALDOC, BLBP and PEA15 acutely. Delayed cell death corresponded with GFAP release and proteolysis into small GFAP-BDPs. Associating biomarkers with cellular injury stages produced astroglial injury-defined (AID) biomarkers that facilitate TBI assessment, as neurological deficits are rooted not only in death of CNS cells, but also in their functional compromise.
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Affiliation(s)
- Julia Halford
- Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
| | - Sean Shen
- Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
| | - Kyohei Itamura
- Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
| | - Jaclynn Levine
- Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
| | - Albert C Chong
- Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
| | - Gregg Czerwieniec
- Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
| | - Thomas C Glenn
- Department of Neurosurgery, Brain Injury Research Center, Department of Molecular and Medical Pharmacology
| | - David A Hovda
- Department of Neurosurgery, Brain Injury Research Center, Department of Molecular and Medical Pharmacology
| | - Paul Vespa
- Department of Neurology, UCLA-David Geffen School of Medicine, Los Angeles, CA, USA
| | - Ross Bullock
- Department of Neurological Surgery, Jackson Memorial Hospital, Miami, FL, USA
| | - W Dalton Dietrich
- The Miami Project to Cure Paralysis, University of Miami-Miller School of Medicine, Miami, FL, USA
| | - Stefania Mondello
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy
| | - Joseph A Loo
- Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA
- Department of Biological Chemistry, UCLA Molecular Biology Institute, and UCLA/DOE Institute for Genomics and Proteomics, University of California, Los Angeles, CA, USA
| | - Ina-Beate Wanner
- Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA
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38
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Li Q, Houdayer T, Liu S, Belegu V. Induced Neural Activity Promotes an Oligodendroglia Regenerative Response in the Injured Spinal Cord and Improves Motor Function after Spinal Cord Injury. J Neurotrauma 2017; 34:3351-3361. [PMID: 28474539 DOI: 10.1089/neu.2016.4913] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
Myelination in the central nervous system (CNS) is a dynamic process that includes birth of oligodendrocyte progenitor cells (OPCs), their differentiation into oligodendrocytes, and ensheathment of axons. Regulation of myelination by neuronal activity has emerged as a new mechanism of CNS plasticity. Activity-dependent myelination has been shown to regulate sensory, motor, and cognitive functions. In this work, we aimed to employ this mechanism of CNS plasticity by utilizing induced neuronal activity to promote remyelination and functional recovery in a subchronic model of spinal cord injury (SCI). We used a mild contusive SCI at T10, which demyelinates surviving axons of the dorsal corticospinal tract (dCST), to investigate the effects of induced neuronal activity on oligodendrogenesis, remyelination, and motor function after SCI. Neuronal activity was induced through epidural electrodes that were implanted over the primary motor (M1) cortex. Induced neuronal activity increased the number of proliferating OPCs. Additionally, induced neuronal activity in the subchronic stages of SCI increased the number of oligodendrocytes, and enhanced myelin basic protein (MBP) expression and myelin sheath formation in dCST. The oligodendroglia regenerative response could have been mediated by axon-OPC synapses, the number of which increased after induced neuronal activity. Further, M1-induced neuronal activation promoted recovery of hindlimb motor function after SCI. Our work is a proof of principle demonstration that epidural electrical stimulation as a mode of inducing neuronal activity throughout white matter tracts of the CNS could be used to promote remyelination and functional recovery after CNS injuries and demyelination disorders.
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Affiliation(s)
- Qun Li
- 1 The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger , Baltimore, Maryland
| | - Thierry Houdayer
- 1 The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger , Baltimore, Maryland
| | - Su Liu
- 1 The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger , Baltimore, Maryland
| | - Visar Belegu
- 1 The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger , Baltimore, Maryland.,2 Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, Maryland.,3 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland
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39
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Cell transplantation therapy for spinal cord injury. Nat Neurosci 2017; 20:637-647. [DOI: 10.1038/nn.4541] [Citation(s) in RCA: 435] [Impact Index Per Article: 54.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 02/22/2017] [Indexed: 02/07/2023]
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40
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Shultz RB, Wang Z, Nong J, Zhang Z, Zhong Y. Local delivery of thyroid hormone enhances oligodendrogenesis and myelination after spinal cord injury. J Neural Eng 2017; 14:036014. [PMID: 28358726 DOI: 10.1088/1741-2552/aa6450] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Traumatic spinal cord injury (SCI) causes apoptosis of myelin-forming oligodendrocytes (OLs) and demyelination of surviving axons, resulting in conduction failure. Remyelination of surviving denuded axons provides a promising therapeutic target for spinal cord repair. While cell transplantation has demonstrated efficacy in promoting remyelination and functional recovery, the lack of ideal cell sources presents a major obstacle to clinical application. The adult spinal cord contains oligodendrocyte precursor cells and multipotent neural stem/progenitor cells that have the capacity to differentiate into mature, myelinating OLs. However, endogenous oligodendrogenesis and remyelination processes are limited by the upregulation of remyelination-inhibitory molecules in the post-injury microenvironment. Multiple growth factors/molecules have been shown to promote OL differentiation and myelination. APPROACH In this study we screened these therapeutics and found that 3, 3', 5-triiodothyronine (T3) is the most effective in promoting oligodendrogenesis and OL maturation in vitro. However, systemic administration of T3 to achieve therapeutic doses in the injured spinal cord is likely to induce hyperthyroidism, resulting in serious side effects. MAIN RESULTS In this study we developed a novel hydrogel-based drug delivery system for local delivery of T3 to the injury site without eliciting systemic toxicity. SIGNIFICANCE Using a clinically relevant cervical contusion injury model, we demonstrate that local delivery of T3 at doses comparable to safe human doses promoted new mature OL formation and myelination after SCI.
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Affiliation(s)
- Robert B Shultz
- School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, United States of America
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41
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Pharmacological inhibition of spinal cord injury-stimulated ribosomal biogenesis does not affect locomotor outcome. Neurosci Lett 2017; 642:153-157. [PMID: 28188847 DOI: 10.1016/j.neulet.2017.02.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 01/20/2017] [Accepted: 02/06/2017] [Indexed: 12/20/2022]
Abstract
After unresolved endoplasmic reticulum stress, recovery of protein synthesis including increased expression of ribosomal components and translation factors may induce cell death. Using a mouse model of moderate contusive spinal cord injury (SCI) at the T9 level, upregulation of ribosomal biogenesis was observed in the injury epicenter at 24h after trauma. Such upregulation coincided with endoplasmic reticulum stress response as previously reported in this model. It was also accompanied by changes in expression of many other genes associated with translational regulation. Systemic treatment with a pharmacological inhibitor of RNA-Polymerase-1, BMH-21 reduced rRNA transcription in the spinal cord. Moreover, in the injury epicenter, treatment with BMH-21 increased expression of oligodendrocyte-specific transcripts including Mbp and Cldn11 at 3days post injury. Although such findings may suggest at least transient reduction of oligodendrocyte death, locomotor outcome was mostly unaffected except slightly accelerated recovery of hindlimb function at week 2 post-injury. Therefore, at least in mice, RNA-Polymerase-1 does not appear to be a robust target for therapies to protect spinal cord tissue after contusion. However, these findings raise an interesting possibility that altered rate of ribosomal biogenesis contributes to the apparent translational reprogramming after contusive SCI. Such a reprogramming could be a major regulator of SCI-induced gene expression.
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Hackett AR, Lee JK. Understanding the NG2 Glial Scar after Spinal Cord Injury. Front Neurol 2016; 7:199. [PMID: 27895617 PMCID: PMC5108923 DOI: 10.3389/fneur.2016.00199] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 10/31/2016] [Indexed: 01/05/2023] Open
Abstract
NG2 cells, also known as oligodendrocyte progenitor cells, are located throughout the central nervous system and serve as a pool of progenitors to differentiate into oligodendrocytes. In response to spinal cord injury (SCI), NG2 cells increase their proliferation and differentiation into remyelinating oligodendrocytes. While astrocytes are typically associated with being the major cell type in the glial scar, many NG2 cells also accumulate within the glial scar but their function remains poorly understood. Similar to astrocytes, these cells hypertrophy, upregulate expression of chondroitin sulfate proteoglycans, inhibit axon regeneration, contribute to the glial-fibrotic scar border, and some even differentiate into astrocytes. Whether NG2 cells also have a role in other astrocyte functions, such as preventing the spread of infiltrating leukocytes and expression of inflammatory cytokines, is not yet known. Thus, NG2 cells are not only important for remyelination after SCI but are also a major component of the glial scar with functions that overlap with astrocytes in this region. In this review, we describe the signaling pathways important for the proliferation and differentiation of NG2 cells, as well as the role of NG2 cells in scar formation and tissue repair.
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Affiliation(s)
- Amber R. Hackett
- Miami Project to Cure Paralysis, The Neuroscience Graduate Program, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jae K. Lee
- Miami Project to Cure Paralysis, The Neuroscience Graduate Program, Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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Duan H, Song W, Zhao W, Gao Y, Yang Z, Li X. Endogenous neurogenesis in adult mammals after spinal cord injury. SCIENCE CHINA-LIFE SCIENCES 2016; 59:1313-1318. [PMID: 27796638 DOI: 10.1007/s11427-016-0205-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 08/19/2016] [Indexed: 01/19/2023]
Abstract
During the whole life cycle of mammals, new neurons are constantly regenerated in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles. Thanks to emerging methodologies, great progress has been made in the characterization of spinal cord endogenous neural stem cells (ependymal cells) and identification of their role in adult spinal cord development. As recently evidenced, both the intrinsic and extrinsic molecular mechanisms of ependymal cells control the sequential steps of the adult spinal cord neurogenesis. This review introduces the concept of adult endogenous neurogenesis, the reaction of ependymal cells after adult spinal cord injury (SCI), the heterogeneity and markers of ependymal cells, the factors that regulate ependymal cells, and the niches that impact the activation or differentiation of ependymal cells.
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Affiliation(s)
- Hongmei Duan
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Wei Song
- School of Rehabilitation Medinice, China Rehabilitation Research Centre, Capital Medical University, Beijing, 100069, China
| | - Wen Zhao
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Yudan Gao
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China
| | - Zhaoyang Yang
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
| | - Xiaoguang Li
- Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
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Zhang S, Ju P, Tjandra E, Yeap Y, Owlanj H, Feng Z. Inhibition of Epidermal Growth Factor Receptor Improves Myelination and Attenuates Tissue Damage of Spinal Cord Injury. Cell Mol Neurobiol 2016; 36:1169-78. [PMID: 26883518 PMCID: PMC11482360 DOI: 10.1007/s10571-015-0313-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 11/24/2015] [Indexed: 12/11/2022]
Abstract
Preventing demyelination and promoting remyelination of denuded axons are promising therapeutic strategies for spinal cord injury (SCI). Epidermal growth factor receptor (EGFR) inhibition was reported to benefit the neural functional recovery and the axon regeneration after SCI. However, its role in de- and remyelination of axons in injured spinal cord is unclear. In the present study, we evaluated the effects of EGFR inhibitor, PD168393 (PD), on the myelination in mouse contusive SCI model. We found that expression of myelin basic protein (MBP) in the injured spinal cords of PD treated mice was remarkably elevated. The density of glial precursor cells and oligodendrocytes (OLs) was increased and the cell apoptosis in lesions was attenuated after PD168393 treatment. Moreover, PD168393 treatment reduced both the numbers of OX42 + microglial cells and glial fibrillary acidic protein + astrocytes in damaged area of spinal cords. We thus conclude that the therapeutic effects of EGFR inhibition after SCI involves facilitating remyelination of the injured spinal cord, increasing of oligodendrocyte precursor cells and OLs, as well as suppressing the activation of astrocytes and microglia/macrophages.
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Affiliation(s)
- Si Zhang
- School of Life Science and Technology, Xinxiang Medical University, Jinsui Road, Xinxiang, 453003, Henan, China
- Brain Research Center, Faculty of Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada
| | - Peijun Ju
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 201108, China
| | - Editha Tjandra
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Yeeshan Yeap
- Cytogenetics Laboratory, Singapore General Hospital, Singapore, Singapore
| | - Hamed Owlanj
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Zhiwei Feng
- School of Life Science and Technology, Xinxiang Medical University, Jinsui Road, Xinxiang, 453003, Henan, China.
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Ghosh S, Hui SP. Regeneration of Zebrafish CNS: Adult Neurogenesis. Neural Plast 2016; 2016:5815439. [PMID: 27382491 PMCID: PMC4921647 DOI: 10.1155/2016/5815439] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Accepted: 04/18/2016] [Indexed: 12/13/2022] Open
Abstract
Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. Among vertebrates, fish and amphibians are capable of regenerating a variety of complex organs through epimorphosis. Zebrafish is an excellent animal model, which can repair several organs like damaged retina, severed spinal cord, injured brain and heart, and amputated fins. The focus of the present paper is on spinal cord regeneration in adult zebrafish. We intend to discuss our current understanding of the cellular and molecular mechanism(s) that allows formation of proliferating progenitors and controls neurogenesis, which involve changes in epigenetic and transcription programs. Unlike mammals, zebrafish retains radial glia, a nonneuronal cell type in their adult central nervous system. Injury induced proliferation involves radial glia which proliferate, transcribe embryonic genes, and can give rise to new neurons. Recent technological development of exquisite molecular tools in zebrafish, such as cell ablation, lineage analysis, and novel and substantial microarray, together with advancement in stem cell biology, allowed us to investigate how progenitor cells contribute to the generation of appropriate structures and various underlying mechanisms like reprogramming.
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Affiliation(s)
- Sukla Ghosh
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, 92 A. P. C. Road, Kolkata 700009, India
| | - Subhra Prakash Hui
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, 92 A. P. C. Road, Kolkata 700009, India
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Rao SNR, Pearse DD. Regulating Axonal Responses to Injury: The Intersection between Signaling Pathways Involved in Axon Myelination and The Inhibition of Axon Regeneration. Front Mol Neurosci 2016; 9:33. [PMID: 27375427 PMCID: PMC4896923 DOI: 10.3389/fnmol.2016.00033] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/02/2016] [Indexed: 01/06/2023] Open
Abstract
Following spinal cord injury (SCI), a multitude of intrinsic and extrinsic factors adversely affect the gene programs that govern the expression of regeneration-associated genes (RAGs) and the production of a diversity of extracellular matrix molecules (ECM). Insufficient RAG expression in the injured neuron and the presence of inhibitory ECM at the lesion, leads to structural alterations in the axon that perturb the growth machinery, or form an extraneous barrier to axonal regeneration, respectively. Here, the role of myelin, both intact and debris, in antagonizing axon regeneration has been the focus of numerous investigations. These studies have employed antagonizing antibodies and knockout animals to examine how the growth cone of the re-growing axon responds to the presence of myelin and myelin-associated inhibitors (MAIs) within the lesion environment and caudal spinal cord. However, less attention has been placed on how the myelination of the axon after SCI, whether by endogenous glia or exogenously implanted glia, may alter axon regeneration. Here, we examine the intersection between intracellular signaling pathways in neurons and glia that are involved in axon myelination and axon growth, to provide greater insight into how interrogating this complex network of molecular interactions may lead to new therapeutics targeting SCI.
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Affiliation(s)
- Sudheendra N R Rao
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine Miami, FL, USA
| | - Damien D Pearse
- The Miami Project to Cure Paralysis, University of Miami Miller School of MedicineMiami, FL, USA; The Department of Neurological Surgery, University of Miami Miller School of MedicineMiami, FL, USA; The Neuroscience Program, University of Miami Miller School of MedicineMiami, FL, USA; The Interdisciplinary Stem Cell Institute, University of Miami Miller School of MedicineMiami, FL, USA; Bruce W. Carter Department of Veterans Affairs Medical CenterMiami, FL, USA
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Hackett AR, Lee DH, Dawood A, Rodriguez M, Funk L, Tsoulfas P, Lee JK. STAT3 and SOCS3 regulate NG2 cell proliferation and differentiation after contusive spinal cord injury. Neurobiol Dis 2016; 89:10-22. [PMID: 26804026 PMCID: PMC4785033 DOI: 10.1016/j.nbd.2016.01.017] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/18/2016] [Accepted: 01/20/2016] [Indexed: 10/22/2022] Open
Abstract
NG2 cells, also known as oligodendrocyte progenitors or polydendrocytes, are a major component of the glial scar that forms after spinal cord injury. NG2 cells react to injury by proliferating around the lesion site and differentiating into oligodendrocytes and astrocytes, but the molecular mechanism is poorly understood. In this study, we tested the role of the transcription factor STAT3, and its suppressor SOCS3, in NG2 cell proliferation and differentiation after spinal cord injury. Using knockout mice in which STAT3 or SOCS3 are genetically deleted specifically in NG2 cells, we found that deletion of STAT3 led to a reduction in oligodendrogenesis, while deletion of SOCS3 led to enhanced proliferation of NG2 cells within the glial scar after spinal cord injury. Additionally, STAT3 and SOCS3 were not required for astrogliogenesis from NG2 cells after spinal cord injury. Interestingly, genetic deletion of STAT3 and SOCS3 did not have opposing effects, suggesting that SOCS3 may have targets other than the STAT3 pathway in NG2 cells after spinal cord injury. Altogether, our data show that both STAT3 and SOCS3 play important, yet unexpected, roles in NG2 cell proliferation and differentiation after spinal cord injury.
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Affiliation(s)
- Amber R Hackett
- Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA
| | - Do-Hun Lee
- Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA
| | - Abdul Dawood
- Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA
| | - Mario Rodriguez
- Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA
| | - Lucy Funk
- Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA
| | - Pantelis Tsoulfas
- Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA
| | - Jae K Lee
- Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL 33136, USA.
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Zhu Z, Ding L, Qiu WF, Wu HF, Li R. Salvianolic acid B protects the myelin sheath around injured spinal cord axons. Neural Regen Res 2016; 11:487-92. [PMID: 27127491 PMCID: PMC4829017 DOI: 10.4103/1673-5374.179068] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Salvianolic acid B, an active pharmaceutical compound present in Salvia miltiorrhiza, exerts a neuroprotective effect in animal models of brain and spinal cord injury. Salvianolic acid B can promote recovery of neurological function; however, its protective effect on the myelin sheath after spinal cord injury remains poorly understood. Thus, in this study, in vitro tests showed that salvianolic acid B contributed to oligodendrocyte precursor cell differentiation, and the most effective dose was 20 μg/mL. For in vivo investigation, rats with spinal cord injury were intraperitoneally injected with 20 mg/kg salvianolic acid B for 8 weeks. The amount of myelin sheath and the number of regenerating axons increased, neurological function recovered, and caspase-3 expression was decreased in the spinal cord of salvianolic acid B-treated animals compared with untreated control rats. These results indicate that salvianolic acid B can protect axons and the myelin sheath, and can promote the recovery of neurological function. Its mechanism of action is likely to be associated with inhibiting apoptosis and promoting the differentiation and maturation of oligodendrocyte precursor cells.
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Affiliation(s)
- Zhe Zhu
- Hand & Foot Surgery and Reparative & Reconstruction Surgery Center, the Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lu Ding
- Department of Physiology, Guangdong Medical University, Dongguan, Guangdong Province, China
| | - Wen-Feng Qiu
- Department of Physiology, Guangdong Medical University, Dongguan, Guangdong Province, China
| | - Hong-Fu Wu
- Department of Physiology, Guangdong Medical University, Dongguan, Guangdong Province, China
| | - Rui Li
- Hand & Foot Surgery and Reparative & Reconstruction Surgery Center, the Second Hospital of Jilin University, Changchun, Jilin Province, China
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Tumor necrosis factor superfamily member APRIL contributes to fibrotic scar formation after spinal cord injury. J Neuroinflammation 2016; 13:87. [PMID: 27098833 PMCID: PMC4839088 DOI: 10.1186/s12974-016-0552-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 04/14/2016] [Indexed: 12/28/2022] Open
Abstract
Background Fibrotic scar formation contributes to the axon growth-inhibitory environment that forms following spinal cord injury (SCI). We recently demonstrated that depletion of hematogenous macrophages led to a reduction in fibrotic scar formation and increased axon growth after SCI. These changes were associated with decreased TNFSF13 (a proliferation inducing ligand (APRIL)) expression, but the role of APRIL in fibrotic scar formation after SCI has not been directly investigated. Thus, the goal of this study was to determine the role of APRIL in fibrotic scar formation after SCI. Methods APRIL knockout and wild-type mice received contusive SCI and were assessed for inflammatory cytokine/chemokine expression, leukocyte infiltration, fibrotic scar formation, axon growth, and cell proliferation. Results Expression of APRIL and its receptor BCMA is increased following SCI, and genetic deletion of APRIL led to reduced fibrotic scar formation and increased axon growth. However, the fibrotic scar reduction in APRIL KO mice was not a result of changes in fibroblast or astrocyte proliferation. Rather, APRIL knockout mice displayed reduced TNFα and CCL2 expression and less macrophage and B cell infiltration at the injury site. Conclusions Our data indicate that APRIL contributes to fibrotic scar formation after SCI by mediating the inflammatory response.
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50
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Yonan JM, Binder DK. Aquaporin-4 and spinal cord injury. World J Neurol 2016; 6:1-13. [DOI: 10.5316/wjn.v6.i1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 12/25/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023] Open
Abstract
Edema formation is a major problem following traumatic spinal cord injury (SCI) that acts to exacerbate secondary damage. Severity of edema correlates with reduced neurological outcome in human patients. To date, there are no effective treatments to directly resolve edema within the spinal cord. The aquaporin-4 (AQP4) water channel is found on membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid and ependyma around the central canal. Being so locally expressed at the interface between fluid and tissue allow AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma. With the need to better understand the pathophysiology underlying the devastating cellular events in SCI, animal models have become an integral part of exploration. Inevitably, several injury models have been developed (contusion, compression, transection) resulting in difficult interpretation between studies with conflicting results. This is true in the case of understanding the role of AQP4 in the progression and resolution of edema following SCI, whose role is still not completely understood and is highly dependent on the type of edema present (vasogenic vs cytotoxic). Here, we discuss regulation of AQP4 in varying injury models and the effects of potential therapeutic interventions on expression, edema formation and functional recovery. Better understanding of the precise role of AQP4 following a wide range of injuries will help to understand optimal treatment timing following human SCI for prime therapeutic benefit and enhanced neurological outcome.
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