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Hajimirzaei P, Tabatabaei FSA, Nasibi-Sis H, Razavian RS, Nasirinezhad F. Schwann cell transplantation for remyelination, regeneration, tissue sparing, and functional recovery in spinal cord injury: A systematic review and meta-analysis of animal studies. Exp Neurol 2025; 384:115062. [PMID: 39579959 DOI: 10.1016/j.expneurol.2024.115062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/02/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024]
Abstract
INTRODUCTION Spinal cord injury (SCI) is a significant global health challenge that results in profound physical and neurological impairments. Despite progress in medical care, the treatment options for SCI are still restricted and often focus on symptom management rather than promoting neural repair and functional recovery. This study focused on clarifying the impact of Schwann cell (SC) transplantation on the molecular, cellular, and functional basis of recovery in animal models of SCI. MATERIAL AND METHODS Relevant studies were identified by conducting searches across multiple databases, which included PubMed, Web of Science, Scopus, and ProQuest. The data were analyzed via comprehensive meta-analysis software. We assessed the risk of bias via the SYRCLE method. RESULTS The analysis included 59 studies, 48 of which provided quantitative data. The results revealed significant improvements in various outcome variables, including protein zero structures (SMD = 1.66, 95 %CI: 0.96-2.36; p < 0.001; I2 = 49.8 %), peripherally myelinated axons (SMD = 1.81, 95 %CI: 0.99-2.63; p < 0.001; I2 = 39.3 %), biotinylated dextran amine-labeled CST only rostral (SMD = 1.31, 95 % CI: 0.50-2.12, p < 0.01, I2 = 49.7 %), fast blue-labeled reticular formation (SMD = 0.96, 95 %CI: 0.43-1.49, p < 0.001, I2 = 0.0 %), 5-hydroxytryptamine caudally (SMD = 0.83, 95 %CI: 0.36-1.29, p < 0.001, I2 = 17.2 %) and epicenter (SMD = 0.85, 95 %CI: 0.17-1.53, p < 0.05, I2 = 62.7 %), tyrosine hydroxylase caudally (SMD = 1.86, 95 %CI: 1.14-2.59, p < 0.001, I2 = 0.0 %) and epicenter (SMD = 1.82, 95 %CI: 1.18-2.47, p < 0.001, I2 = 0.0 %), cavity volume (SMD = -2.07, 95 %CI: -2.90 - -1.24, p < 0.001, I2 = 67.2 %), and Basso, Beattie, and Bresnahan (SMD = 1.26, 95 %CI: 0.93-1.58; p < 0.001; I2 = 79.4 %). CONCLUSIONS This study demonstrates the promising potential of SC transplantation as a therapeutic approach for SCI, clarifying its impact on various biological processes critical for recovery.
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Affiliation(s)
- Pooya Hajimirzaei
- Department of Radiation Sciences, Allied Medicine Faculty, Iran University of Medical Sciences, Tehran, Iran; Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Hamed Nasibi-Sis
- Department of Medical Library and Information Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Farinaz Nasirinezhad
- Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Physiology Research Center, Iran University of Medical sciences, Tehran, Iran; Center of Experimental and Comparative Study, Iran University of Medical sciences, Tehran, Iran.
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Guest JD, Santamaria AJ, Solano JP, de Rivero Vaccari JP, Dietrich WD, Pearse DD, Khan A, Levi AD. Challenges in advancing Schwann cell transplantation for spinal cord injury repair. Cytotherapy 2025; 27:36-50. [PMID: 39387736 DOI: 10.1016/j.jcyt.2024.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 08/05/2024] [Accepted: 08/09/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND AIMS In this article we aimed to provide an expert synthesis of the current status of Schwann cell (SC)therapeutics and potential steps to increase their clinical utility. METHODS We provide an expert synthesis based on preclinical, clinical and manufacturing experience. RESULTS Schwann cells (SCs) are essential for peripheral nerve regeneration and are of interest in supporting axonal repair after spinal cord injury (SCI). SCs can be isolated and cultivated in tissue culture from adult nerve biopsies or generated from precursors and neural progenitors using specific differentiation protocols leading to expanded quantities. In culture, they undergo dedifferentiation to a state similar to "repair" SCs. The known repertoire of SC functions is increasing beyond axon maintenance, myelination, and axonal regeneration to include immunologic regulation and the release of potentially therapeutic extracellular vesicles. Recently, autologous human SC cultures purified under cGMP conditions have been tested in both nerve repair and subacute and chronic SCI clinical trials. Although the effects of SCs to support nerve regeneration are indisputable, their efficacy for clinical SCI has been limited according to the outcomes examined. CONCLUSIONS This review discusses the current limitations of transplanted SCs within the damaged spinal cord environment. Limitations include limited post-transplant cell survival, the inability of SCs to migrate within astrocytic parenchyma, and restricted axonal regeneration out of SC-rich graft regions. We describe steps to amplify the survival and integration of transplanted SCs and to expand the repertoire of uses of SCs, including SC-derived extracellular vesicles. The relative merits of transplanting autologous versus allogeneic SCs and the role that endogenous SCs play in spinal cord repair are described. Finally, we briefly describe the issues requiring solutions to scale up SC manufacturing for commercial use.
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Affiliation(s)
- James D Guest
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Andrea J Santamaria
- The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Juan P Solano
- Pediatric Critical Care, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Juan P de Rivero Vaccari
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - William D Dietrich
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Damien D Pearse
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Aisha Khan
- The Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Allan D Levi
- The Miami Project to Cure Paralysis and Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
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Dill-Macky AS, Lee EN, Wertheim JA, Koss KM. Glia in tissue engineering: From biomaterial tools to transplantation. Acta Biomater 2024; 190:24-49. [PMID: 39396630 DOI: 10.1016/j.actbio.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 10/01/2024] [Accepted: 10/10/2024] [Indexed: 10/15/2024]
Abstract
Glia are imperative in nearly every function of the nervous system, including neurotransmission, neuronal repair, development, immunity, and myelination. Recently, the reparative roles of glia in the central and peripheral nervous systems have been elucidated, suggesting a tremendous potential for these cells as novel treatments to central nervous system disorders. Glial cells often behave as 'double-edged swords' in neuroinflammation, ultimately deciding the life or death of resident cells. Compared to glia, neuronal cells have limited mobility, lack the ability to divide and self-renew, and are generally more delicate. Glia have been candidates for therapeutic use in many successful grafting studies, which have been largely focused on restoring myelin with Schwann cells, olfactory ensheathing glia, and oligodendrocytes with support from astrocytes. However, few therapeutics of this class have succeeded past clinical trials. Several tools and materials are being developed to understand and re-engineer these grafting concepts for greater success, such as extra cellular matrix-based scaffolds, bioactive peptides, biomolecular delivery systems, biomolecular discovery for neuroinflammatory mediation, composite microstructures such as artificial channels for cell trafficking, and graft enhanced electrical stimulation. Furthermore, advances in stem cell-derived cortical/cerebral organoid differentiation protocols have allowed for the generation of patient-derived glia comparable to those acquired from tissues requiring highly invasive procedures or are otherwise inaccessible. However, research on bioengineered tools that manipulate glial cells is nowhere near as comprehensive as that for systems of neurons and neural stem cells. This article explores the therapeutic potential of glia in transplantation with an emphasis on novel bioengineered tools for enhancement of their reparative properties. STATEMENT OF SIGNIFICANCE: Neural glia are responsible for a host of developmental, homeostatic, and reparative roles in the central nervous system but are often a major cause of tissue damage and cellular loss in insults and degenerative pathologies. Most glial grafts have employed Schwann cells for remyelination, but other glial with novel biomaterials have been employed, emphasizing their diverse functionality. Promising strategies have emerged, including neuroimmune mediation of glial scar tissues and facilitated migration and differentiation of stem cells for neural replacement. Herein, a comprehensive review of biomaterial tools for glia in transplantation is presented, highlighting Schwann cells, astrocytes, olfactory ensheating glia, oligodendrocytes, microglia, and ependymal cells.
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Affiliation(s)
- A S Dill-Macky
- Department of Surgery, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, United States
| | - E N Lee
- Department of Surgery, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, United States
| | - J A Wertheim
- Department of Surgery, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, United States
| | - K M Koss
- Department of Neurobiology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0625, United States; Sealy Institute for Drug Discovery, University of Texas Medical Branch, 105 11th Street Galveston, TX 77555-1110, United States.
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Doulames VM, Marquardt LM, Hefferon ME, Baugh NJ, Suhar RA, Wang AT, Dubbin KR, Weimann JM, Palmer TD, Plant GW, Heilshorn SC. Custom-engineered hydrogels for delivery of human iPSC-derived neurons into the injured cervical spinal cord. Biomaterials 2024; 305:122400. [PMID: 38134472 PMCID: PMC10846596 DOI: 10.1016/j.biomaterials.2023.122400] [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: 06/23/2023] [Revised: 09/18/2023] [Accepted: 11/11/2023] [Indexed: 12/24/2023]
Abstract
Cervical damage is the most prevalent type of spinal cord injury clinically, although few preclinical research studies focus on this anatomical region of injury. Here we present a combinatorial therapy composed of a custom-engineered, injectable hydrogel and human induced pluripotent stem cell (iPSC)-derived deep cortical neurons. The biomimetic hydrogel has a modular design that includes a protein-engineered component to allow customization of the cell-adhesive peptide sequence and a synthetic polymer component to allow customization of the gel mechanical properties. In vitro studies with encapsulated iPSC-neurons were used to select a bespoke hydrogel formulation that maintains cell viability and promotes neurite extension. Following injection into the injured cervical spinal cord in a rat contusion model, the hydrogel biodegraded over six weeks without causing any adverse reaction. Compared to cell delivery using saline, the hydrogel significantly improved the reproducibility of cell transplantation and integration into the host tissue. Across three metrics of animal behavior, this combinatorial therapy significantly improved sensorimotor function by six weeks post transplantation. Taken together, these findings demonstrate that design of a combinatorial therapy that includes a gel customized for a specific fate-restricted cell type can induce regeneration in the injured cervical spinal cord.
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Affiliation(s)
- V M Doulames
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - L M Marquardt
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - M E Hefferon
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - N J Baugh
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - R A Suhar
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - A T Wang
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - K R Dubbin
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA
| | - J M Weimann
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - T D Palmer
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - G W Plant
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.
| | - S C Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA.
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Dutta D, Pirolli NH, Levy D, Tsao J, Seecharan N, Wang Z, Xu X, Jia X, Jay SM. Differentiation state and culture conditions impact neural stem/progenitor cell-derived extracellular vesicle bioactivity. Biomater Sci 2023; 11:5474-5489. [PMID: 37367824 PMCID: PMC10529403 DOI: 10.1039/d3bm00340j] [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] [Indexed: 06/28/2023]
Abstract
Extracellular vesicles (EVs) derived from neural progenitor/stem cells (NPSCs) have shown promising efficacy in a variety of preclinical models. However, NPSCs lack critical neuroregenerative functionality such as myelinating capacity. Further, culture conditions used in NPSC EV production lack standardization, limiting reproducibility challenging and potentially potency of the overall approach via lack of optimization. Here, we assessed whether oligodendrocyte precursor cells (OPCs) and immature oligodendrocytes (iOLs), which are further differentiated than NPSCs and which both give rise to mature myelinating oligodendrocytes, could yield EVs with neurotherapeutic properties comparable or superior to those from NPSCs. We additionally examined the effects of extracellular matrix (ECM) coating materials and the presence or absence of growth factors in cell culture on the ultimate properties of EVs. The data show that OPC EVs and iOL EVs performed similarly to NPSC EVs in cell proliferation and anti-inflammatory assays, but NPSC EVs performed better in a neurite outgrowth assay. Additionally, the presence of nerve growth factor (NGF) in culture was found to maximize NPSC EV bioactivity among the conditions tested. NPSC EVs produced under rationally-selected culture conditions (fibronectin + NGF) enhanced axonal regeneration and muscle reinnervation in a rat nerve crush injury model. These results highlight the need for standardization of culture conditions for neurotherapeutic NPSC EV production.
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Affiliation(s)
- Dipankar Dutta
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
| | - Nicholas H Pirolli
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
| | - Daniel Levy
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
| | - Jeffrey Tsao
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
| | - Nicholas Seecharan
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
| | - Zihui Wang
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Xiang Xu
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.
| | - Xiaofeng Jia
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.
- Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Steven M Jay
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
- Program in Molecular and Cell Biology, University of Maryland, College Park, MD, USA
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6
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Ou YC, Huang CC, Kao YL, Ho PC, Tsai KJ. Stem Cell Therapy in Spinal Cord Injury-Induced Neurogenic Lower Urinary Tract Dysfunction. Stem Cell Rev Rep 2023; 19:1691-1708. [PMID: 37115409 DOI: 10.1007/s12015-023-10547-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2023] [Indexed: 04/29/2023]
Abstract
Spinal cord injury (SCI) is a devastating condition that enormously affects an individual's health and quality of life. Neurogenic lower urinary tract dysfunction (NLUTD) is one of the most important sequelae induced by SCI, causing complications including urinary tract infection, renal function deterioration, urinary incontinence, and voiding dysfunction. Current therapeutic methods for SCI-induced NLUTD mainly target on the urinary bladder, but the outcomes are still far from satisfactory. Stem cell therapy has gained increasing attention for years for its ability to rescue the injured spinal cord directly. Stem cell differentiation and their paracrine effects, including exosomes, are the proposed mechanisms to enhance the recovery from SCI. Several animal studies have demonstrated improvement in bladder function using mesenchymal stem cells (MSCs) and neural stem cells (NSCs). Human clinical trials also provide promising results in urodynamic parameters after MSC therapy. However, there is still uncertainty about the ideal treatment window and application protocol for stem cell therapy. Besides, data on the therapeutic effects regarding NSCs and stem cell-derived exosomes in SCI-related NLUTD are scarce. Therefore, there is a pressing need for further well-designed human clinical trials to translate the stem cell therapy into a formal therapeutic option for SCI-induced NLUTD.
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Affiliation(s)
- Yin-Chien Ou
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Chen Huang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yao-Lin Kao
- Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Chuan Ho
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan
| | - Kuen-Jer Tsai
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701, Taiwan.
- Research Center of Clinical Medicine, National Cheng Kung University Hospital , College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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David BT, Curtin JJ, Brown JL, Scorpio K, Kandaswamy V, Coutts DJC, Vivinetto A, Bianchimano P, Karuppagounder SS, Metcalfe M, Cave JW, Hill CE. Temporary induction of hypoxic adaptations by preconditioning fails to enhance Schwann cell transplant survival after spinal cord injury. Glia 2023; 71:648-666. [PMID: 36565279 PMCID: PMC11848738 DOI: 10.1002/glia.24302] [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: 04/19/2022] [Revised: 10/26/2022] [Accepted: 11/01/2022] [Indexed: 12/25/2022]
Abstract
Hypoxic preconditioning is protective in multiple models of injury and disease, but whether it is beneficial for cells transplanted into sites of spinal cord injury (SCI) is largely unexplored. In this study, we analyzed whether hypoxia-related preconditioning protected Schwann cells (SCs) transplanted into the contused thoracic rat spinal cord. Hypoxic preconditioning was induced in SCs prior to transplantation by exposure to either low oxygen (1% O2 ) or pharmacological agents (deferoxamine or adaptaquin). All preconditioning approaches induced hypoxic adaptations, including increased expression of HIF-1α and its target genes. These adaptations, however, were transient and resolved within 24 h of transplantation. Pharmacological preconditioning attenuated spinal cord oxidative stress and enhanced transplant vascularization, but it did not improve either transplanted cell survival or recovery of sensory or motor function. Together, these experiments show that hypoxia-related preconditioning is ineffective at augmenting either cell survival or the functional outcomes of SC-SCI transplants. They also reveal that the benefits of hypoxia-related adaptations induced by preconditioning for cell transplant therapies are not universal.
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Affiliation(s)
- Brian T. David
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Jessica J. Curtin
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Jennifer L. Brown
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Kerri Scorpio
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Veena Kandaswamy
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - David J. C. Coutts
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Ana Vivinetto
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Paola Bianchimano
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Saravanan S. Karuppagounder
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - Mariajose Metcalfe
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
| | - John W. Cave
- InVitro Cell Research, LLC, Englewood, NJ, United States
| | - Caitlin E. Hill
- Burke Neurological Institute, White Plains, NY, United States
- Weill Cornell Medicine, Feil Family Brain and Mind Research Institute, New York, NY, United States
- Neural Stem Cell Institute, Rensselaer, NY, United States
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Gant KL, Guest JD, Palermo AE, Vedantam A, Jimsheleishvili G, Bunge MB, Brooks AE, Anderson KD, Thomas CK, Santamaria AJ, Perez MA, Curiel R, Nash MS, Saraf-Lavi E, Pearse DD, Widerström-Noga E, Khan A, Dietrich WD, Levi AD. Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury. J Neurotrauma 2022; 39:285-299. [PMID: 33757304 PMCID: PMC9360180 DOI: 10.1089/neu.2020.7590] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (n = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI.
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Affiliation(s)
- Katie L. Gant
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
| | - James D. Guest
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
- Department of Neuroscience, University of Miami, Miami, Florida, USA
| | - Anne E. Palermo
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
| | - Aditya Vedantam
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
| | - George Jimsheleishvili
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
| | - Mary Bartlett Bunge
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
- Department of Neuroscience, University of Miami, Miami, Florida, USA
- Department of Cell Biology, University of Miami, Miami, Florida, USA
- Department of Neurology, University of Miami, Miami, Florida, USA
- Department of Interdisciplinary Stem Cell Institute, University of Miami, Miami, Florida, USA
| | - Adriana E. Brooks
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Interdisciplinary Stem Cell Institute, University of Miami, Miami, Florida, USA
| | - Kim D. Anderson
- Department of Physical Medicine and Rehabilitation, Case Western Reserve University, Metrohealth Medical Center, Cleveland, Ohio, USA
| | - Christine K. Thomas
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
| | - Andrea J. Santamaria
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
| | - Monica A. Perez
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
- Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida, USA
- Shirley Ryan AbilityLab, Northwestern University, Edward Hines Jr, VA Hospital, Chicago, Illinois, USA
| | - Rosie Curiel
- Department of Psychiatry, University of Miami, Miami, Florida, USA
| | - Mark S. Nash
- Department of Rehabilitation Medicine, University of Miami, Miami, Florida, USA
| | - Efrat Saraf-Lavi
- Department of Radiology, University of Miami, Miami, Florida, USA
| | - Damien D. Pearse
- Department of Neuroscience, University of Miami, Miami, Florida, USA
- Department of Interdisciplinary Stem Cell Institute, University of Miami, Miami, Florida, USA
- Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida, USA
- Shirley Ryan AbilityLab, Northwestern University, Edward Hines Jr, VA Hospital, Chicago, Illinois, USA
| | - Eva Widerström-Noga
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
- Department of Neuroscience, University of Miami, Miami, Florida, USA
- Department of Rehabilitation Medicine, University of Miami, Miami, Florida, USA
- Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida, USA
| | - Aisha Khan
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Interdisciplinary Stem Cell Institute, University of Miami, Miami, Florida, USA
| | - W. Dalton Dietrich
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
- Department of Neuroscience, University of Miami, Miami, Florida, USA
- Department of Cell Biology, University of Miami, Miami, Florida, USA
- Department of Neurology, University of Miami, Miami, Florida, USA
- Department of Interdisciplinary Stem Cell Institute, University of Miami, Miami, Florida, USA
| | - Allan D. Levi
- The Miami Project to Cure Paralysis, University of Miami, Miami, Florida, USA
- Department of Neurological Surgery, University of Miami, Miami, Florida, USA
- Department of Neuroscience, University of Miami, Miami, Florida, USA
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9
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Murtaza M, Mohanty L, Ekberg JAK, St John JA. Designing Olfactory Ensheathing Cell Transplantation Therapies: Influence of Cell Microenvironment. Cell Transplant 2022; 31:9636897221125685. [PMID: 36124646 PMCID: PMC9490465 DOI: 10.1177/09636897221125685] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Olfactory ensheathing cell (OEC) transplantation is emerging as a promising treatment option for injuries of the nervous system. OECs can be obtained relatively easily from nasal biopsies, and exhibit several properties such as secretion of trophic factors, and phagocytosis of debris that facilitate neural regeneration and repair. But a major limitation of OEC-based cell therapies is the poor survival of transplanted cells which subsequently limit their therapeutic efficacy. There is an unmet need for approaches that enable the in vitro production of OECs in a state that will optimize their survival and integration after transplantation into the hostile injury site. Here, we present an overview of the strategies to modulate OECs focusing on oxygen levels, stimulating migratory, phagocytic, and secretory properties, and on bioengineering a suitable environment in vitro.
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Affiliation(s)
- Mariyam Murtaza
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.,Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia.,Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
| | - Lipsa Mohanty
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.,Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
| | - Jenny A K Ekberg
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.,Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia.,Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
| | - James A St John
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia.,Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia.,Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
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10
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Miah M, Ferretti P, Choi D. Considering the Cellular Composition of Olfactory Ensheathing Cell Transplants for Spinal Cord Injury Repair: A Review of the Literature. Front Cell Neurosci 2021; 15:781489. [PMID: 34867207 PMCID: PMC8635789 DOI: 10.3389/fncel.2021.781489] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022] Open
Abstract
Olfactory ensheathing cells (OECs) are specialized glia cells of the olfactory system that support the continual regeneration of olfactory neurons throughout adulthood. Owing to their pro-regenerative properties, OECs have been transplanted in animal models of spinal cord injuries (SCI) and trialed in clinical studies on SCI patients. Although these studies have provided convincing evidence to support the continued development of OEC transplantation as a treatment option for the repair of SCI, discrepancies in the reported outcome has shown that OEC transplantation requires further improvement. Much of the variability in the reparative potential of OEC transplants is due to the variations in the cell composition of transplants between studies. As a result, the optimal cell preparation is currently a subject of debate. Here we review, the characterization as well as the effect of the cell composition of olfactory cell transplantation on therapeutic outcome in SCI. Firstly, we summarize and review the cell composition of olfactory cell preparations across the different species studied prior to transplantation. Since the purity of cells in olfactory transplants might affect the study outcome we also examine the effect of the proportions of OECs and the different cell types identified in the transplant on neuroregeneration. Finally, we consider the effect of the yield of cells on neuroregeneration by assessing the cell dose of transplants on therapeutic outcome.
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Affiliation(s)
- Mahjabeen Miah
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Patrizia Ferretti
- Developmental Biology and Cancer Department, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - David Choi
- Spinal Repair Unit, Department of Brain Repair and Rehabilitation, UCL Queen Square Institute of Neurology, London, United Kingdom
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11
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Assunção Silva RC, Pinto L, Salgado AJ. Cell transplantation and secretome based approaches in spinal cord injury regenerative medicine. Med Res Rev 2021; 42:850-896. [PMID: 34783046 DOI: 10.1002/med.21865] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 07/12/2021] [Accepted: 10/07/2021] [Indexed: 01/01/2023]
Abstract
The axonal growth-restrictive character of traumatic spinal cord injury (SCI) makes finding a therapeutic strategy a very demanding task, due to the postinjury events impeditive to spontaneous axonal outgrowth and regeneration. Considering SCI pathophysiology complexity, it has been suggested that an effective therapy should tackle all the SCI-related aspects and provide sensory and motor improvement to SCI patients. Thus, the current aim of any therapeutic approach for SCI relies in providing neuroprotection and support neuroregeneration. Acknowledging the current SCI treatment paradigm, cell transplantation is one of the most explored approaches for SCI with mesenchymal stem cells (MSCs) being in the forefront of many of these. Studies showing the beneficial effects of MSC transplantation after SCI have been proposing a paracrine action of these cells on the injured tissues, through the secretion of protective and trophic factors, rather than attributing it to the action of cells itself. This manuscript provides detailed information on the most recent data regarding the neuroregenerative effect of the secretome of MSCs as a cell-free based therapy for SCI. The main challenge of any strategy proposed for SCI treatment relies in obtaining robust preclinical evidence from in vitro and in vivo models, before moving to the clinics, so we have specifically focused on the available vertebrate and mammal models of SCI currently used in research and how can SCI field benefit from them.
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Affiliation(s)
- Rita C Assunção Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - Luísa Pinto
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal.,BnML, Behavioral and Molecular Lab, Braga, Portugal
| | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal.,ICVS/3B's e PT Government Associate Laboratory, Braga/Guimarães, Portugal
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12
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Zhang Y, Al Mamun A, Yuan Y, Lu Q, Xiong J, Yang S, Wu C, Wu Y, Wang J. Acute spinal cord injury: Pathophysiology and pharmacological intervention (Review). Mol Med Rep 2021; 23:417. [PMID: 33846780 PMCID: PMC8025476 DOI: 10.3892/mmr.2021.12056] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 11/12/2020] [Indexed: 12/12/2022] Open
Abstract
Spinal cord injury (SCI) is one of the most debilitating of all the traumatic conditions that afflict individuals. For a number of years, extensive studies have been conducted to clarify the molecular mechanisms of SCI. Experimental and clinical studies have indicated that two phases, primary damage and secondary damage, are involved in SCI. The initial mechanical damage is caused by local impairment of the spinal cord. In addition, the fundamental mechanisms are associated with hyperflexion, hyperextension, axial loading and rotation. By contrast, secondary injury mechanisms are led by systemic and cellular factors, which may also be initiated by the primary injury. Although significant advances in supportive care have improved clinical outcomes in recent years, a number of studies continue to explore specific pharmacological therapies to minimize SCI. The present review summarized some important pathophysiologic mechanisms that are involved in SCI and focused on several pharmacological and non‑pharmacological therapies, which have either been previously investigated or have a potential in the management of this debilitating injury in the near future.
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Affiliation(s)
- Yi Zhang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, P.R. China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Abdullah Al Mamun
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Yuan Yuan
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Qi Lu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Jun Xiong
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Shulin Yang
- School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, P.R. China
| | - Chengbiao Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Yanqing Wu
- Institute of Life Sciences, Wenzhou University, Wenzhou, Zhejiang 325035, P.R. China
| | - Jian Wang
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
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13
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Pearse DD, Rao SNR, Morales AA, Wakarchuk W, Rutishauser U, El-Maarouf A, Ghosh M. Engineering polysialic acid on Schwann cells using polysialyltransferase gene transfer or purified enzyme exposure for spinal cord injury transplantation. Neurosci Lett 2021; 748:135690. [PMID: 33540059 DOI: 10.1016/j.neulet.2021.135690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 12/23/2020] [Accepted: 01/25/2021] [Indexed: 11/29/2022]
Abstract
Polysialic acid (PolySia) is a critical post-translational modification on the neural cell adhesion molecule (NCAM, a.k.a., CD56), important for cell migration and axon growth during nervous system development, plasticity and repair. PolySia induction on Schwann cells (SCs) enhances their migration, axon growth support and ability to improve functional recovery after spinal cord injury (SCI) transplantation. In the current investigation two methods of PolySia induction on SCs, lentiviral vector transduction of the mouse polysialytransferase gene ST8SIA4 (LV-PST) or enzymatic engineering with a recombinant bacterial PST (PSTNm), were examined comparatively for their effects on PolySia induction, SC migration, the innate immune response and axon growth after acute SCI. PSTNm produced significant PolySia induction and a greater diversity of surface molecule polysialylation on SCs as evidenced by immunoblot. In the scratch wound assay, PSTNm was superior to LV-PST in the promotion of SC migration and gap closure. At 24 h after SCI transplantation, PolySia induction on SCs was most pronounced with LV-PST. Co-delivery of PSTNm with SCs, but not transient cell exposure, led to broader induction of PolySia within the injured spinal cord due to polysialylation upon both host cells and transplanted SCs. The innate immune response after SCI, measured by CD68 immunoreactivity, was similar among PolySia induction methods. LV-PST or PSTNm co-delivery with SCs provided a similar enhancement of SC migration and axon growth support above that of unmodified SCs. These studies demonstrate that LV-PST and PSTNm provide comparable acute effects on SC polysialation, the immune response and neurorepair after SCI.
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Affiliation(s)
- Damien D Pearse
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; The Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Veterans Affairs, Veterans Affairs Medical Center, Miami, FL, 33136, USA.
| | - Sudheendra N R Rao
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Alejo A Morales
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Warren Wakarchuk
- Department of Biological Sciences, University of Alberta, Edmonton, AB, TG6 2E9, Canada
| | - Urs Rutishauser
- Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, USA
| | | | - Mousumi Ghosh
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; The Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA; Department of Veterans Affairs, Veterans Affairs Medical Center, Miami, FL, 33136, USA.
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14
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Ahuja CS, Mothe A, Khazaei M, Badhiwala JH, Gilbert EA, van der Kooy D, Morshead CM, Tator C, Fehlings MG. The leading edge: Emerging neuroprotective and neuroregenerative cell-based therapies for spinal cord injury. Stem Cells Transl Med 2020; 9:1509-1530. [PMID: 32691994 PMCID: PMC7695641 DOI: 10.1002/sctm.19-0135] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/01/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
Spinal cord injuries (SCIs) are associated with tremendous physical, social, and financial costs for millions of individuals and families worldwide. Rapid delivery of specialized medical and surgical care has reduced mortality; however, long-term functional recovery remains limited. Cell-based therapies represent an exciting neuroprotective and neuroregenerative strategy for SCI. This article summarizes the most promising preclinical and clinical cell approaches to date including transplantation of mesenchymal stem cells, neural stem cells, oligodendrocyte progenitor cells, Schwann cells, and olfactory ensheathing cells, as well as strategies to activate endogenous multipotent cell pools. Throughout, we emphasize the fundamental biology of cell-based therapies, critical features in the pathophysiology of spinal cord injury, and the strengths and limitations of each approach. We also highlight salient completed and ongoing clinical trials worldwide and the bidirectional translation of their findings. We then provide an overview of key adjunct strategies such as trophic factor support to optimize graft survival and differentiation, engineered biomaterials to provide a support scaffold, electrical fields to stimulate migration, and novel approaches to degrade the glial scar. We also discuss important considerations when initiating a clinical trial for a cell therapy such as the logistics of clinical-grade cell line scale-up, cell storage and transportation, and the delivery of cells into humans. We conclude with an outlook on the future of cell-based treatments for SCI and opportunities for interdisciplinary collaboration in the field.
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Affiliation(s)
- Christopher S. Ahuja
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Andrea Mothe
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Mohamad Khazaei
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Jetan H. Badhiwala
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - Emily A. Gilbert
- Division of Anatomy, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
| | - Derek van der Kooy
- Department of Molecular GeneticsUniversity of TorontoTorontoOntarioCanada
| | - Cindi M. Morshead
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Division of Anatomy, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Biomaterials and Biomedical EngineeringUniversity of TorontoTorontoOntarioCanada
| | - Charles Tator
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
| | - Michael G. Fehlings
- Division of Neurosurgery, Department of SurgeryUniversity of TorontoTorontoOntarioCanada
- Institute of Medical ScienceUniversity of TorontoTorontoOntarioCanada
- Department of Genetics and DevelopmentKrembil Research Institute, UHNTorontoOntarioCanada
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15
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Assinck P, Sparling JS, Dworski S, Duncan GJ, Wu DL, Liu J, Kwon BK, Biernaskie J, Miller FD, Tetzlaff W. Transplantation of Skin Precursor-Derived Schwann Cells Yields Better Locomotor Outcomes and Reduces Bladder Pathology in Rats with Chronic Spinal Cord Injury. Stem Cell Reports 2020; 15:140-155. [PMID: 32559459 PMCID: PMC7363874 DOI: 10.1016/j.stemcr.2020.05.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 12/20/2022] Open
Abstract
Cell transplantation for spinal cord injury (SCI) has largely been studied in sub-acute settings within 1–2 weeks of injury. In contrast, here we transplanted skin-derived precursors differentiated into Schwann cells (SKP-SCs) into the contused rat spinal cord 8 weeks post-injury (wpi). Twenty-one weeks later (29 wpi), SKP-SCs were found to have survived transplantation, integrated with host tissue, and mitigated the formation of a dense glial scar. Furthermore, transplanted SKP-SCs filled much of the lesion sites and greatly enhanced the presence of endogenous SCs, which myelinated thousands of sprouting/spared host axons in and around the injury site. In addition, SKP-SC transplantation improved locomotor outcomes and decreased pathological thickening of bladder wall. To date, functional improvements have very rarely been observed with cell transplantation beyond the sub-acute stage of injury. Hence, these findings indicate that skin-derived SCs are a promising candidate cell type for the treatment of chronic SCI.
SKP-SCs injected 8 weeks after SCI survive long-term and integrate with host tissue SKP-SC transplants boosted the presence of endogenous SCs in the chronic SCI site Treated spinal cords showed enhanced growth and SC myelination of axons Treated rats displayed better locomotor outcomes with reduced bladder pathologies
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Affiliation(s)
- Peggy Assinck
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada
| | - Joseph S Sparling
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Shaalee Dworski
- Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada
| | - Greg J Duncan
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Zoology, University of British Columbia, Vancouver, BC, Canada
| | - Di L Wu
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada
| | - Jie Liu
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada
| | - Brian K Kwon
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Orthopaedics, University of British Columbia, Vancouver, BC, Canada
| | - Jeff Biernaskie
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Freda D Miller
- Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Wolfram Tetzlaff
- International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada; Department of Zoology, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
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16
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Hypoxia-Inducible Factor 1α (HIF-1α) Counteracts the Acute Death of Cells Transplanted into the Injured Spinal Cord. eNeuro 2020; 7:ENEURO.0092-19.2019. [PMID: 31488552 PMCID: PMC7215587 DOI: 10.1523/eneuro.0092-19.2019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 08/10/2019] [Accepted: 08/19/2019] [Indexed: 01/13/2023] Open
Abstract
Cellular transplantation is in clinical testing for a number of central nervous system disorders, including spinal cord injury (SCI). One challenge is acute transplanted cell death. To prevent this death, there is a need to both establish when the death occurs and develop approaches to mitigate its effects. Here, using luciferase (luc) and green fluorescent protein (GFP) expressing Schwann cell (SC) transplants in the contused thoracic rat spinal cord 7 d postinjury, we establish via in vivo bioluminescent (IVIS) imaging and stereology that cell death occurs prior to 2–3 d postimplantation. We then test an alternative approach to the current paradigm of enhancing transplant survival by including multiple factors along with the cells. To stimulate multiple cellular adaptive pathways concurrently, we activate the hypoxia-inducible factor 1α (HIF-1α) transcriptional pathway. Retroviral expression of VP16-HIF-1α in SCs increased HIF-α by 5.9-fold and its target genes implicated in oxygen transport and delivery (VEGF, 2.2-fold) and cellular metabolism (enolase, 1.7-fold). In cell death assays in vitro, HIF-1α protected cells from H2O2-induced oxidative damage. It also provided some protection against camptothecin-induced DNA damage, but not thapsigargin-induced endoplasmic reticulum stress or tunicamycin-induced unfolded protein response. Following transplantation, VP16-HIF-1α increased SC survival by 34.3%. The increase in cell survival was detectable by stereology, but not by in vivo luciferase or ex vivo GFP IVIS imaging. The results support the hypothesis that activating adaptive cellular pathways enhances transplant survival and identifies an alternative pro-survival approach that, with optimization, could be amenable to clinical translation.
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17
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Reshamwala R, Shah M, Belt L, Ekberg JAK, St John JA. Reliable cell purification and determination of cell purity: crucial aspects of olfactory ensheathing cell transplantation for spinal cord repair. Neural Regen Res 2020; 15:2016-2026. [PMID: 32394949 PMCID: PMC7716040 DOI: 10.4103/1673-5374.282218] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Transplantation of olfactory ensheathing cells, the glia of the primary olfactory nervous system, has been trialed for spinal cord injury repair with promising but variable outcomes in animals and humans. Olfactory ensheathing cells can be harvested either from the lamina propria beneath the neuroepithelium in the nasal cavity, or from the olfactory bulb in the brain. As these areas contain several other cell types, isolating and purifying olfactory ensheathing cells is a critical part of the process. It is largely unknown how contaminating cells such as fibroblasts, other glial cell types and supporting cells affect olfactory ensheathing cell function post-transplantation; these cells may also cause unwanted side-effects. It is also, however, possible that the presence of some of the contaminant cells can improve outcomes. Here, we reviewed the last decade of olfactory ensheathing cell transplantation studies in rodents, with a focus on olfactory ensheathing cell purity. We analyzed how purification methods and resultant cell purity differed between olfactory mucosa- and olfactory bulb-derived cell preparations. We analyzed how the studies reported on olfactory ensheathing cell purity and which criteria were used to define cells as olfactory ensheathing cells. Finally, we analyzed the correlation between cell purity and transplantation outcomes. We found that olfactory bulb-derived olfactory ensheathing cell preparations are typically purer than mucosa-derived preparations. We concluded that there is an association between high olfactory ensheathing cell purity and favourable outcomes, but the lack of olfactory ensheathing cell-specific markers severely hampers the field.
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Affiliation(s)
- Ronak Reshamwala
- Griffith Institute for Drug Discovery, Griffith University, Brisbane; Menzies Health Institute Queensland, Griffith University, Southport; Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
| | - Megha Shah
- Menzies Health Institute Queensland, Griffith University, Southport; Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
| | - Lucy Belt
- Menzies Health Institute Queensland, Griffith University, Southport; Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
| | - Jenny A K Ekberg
- Griffith Institute for Drug Discovery, Griffith University, Brisbane; Menzies Health Institute Queensland, Griffith University, Southport; Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
| | - James A St John
- Griffith Institute for Drug Discovery, Griffith University, Brisbane; Menzies Health Institute Queensland, Griffith University, Southport; Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, QLD, Australia
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18
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Reshamwala R, Shah M, St John J, Ekberg J. Survival and Integration of Transplanted Olfactory Ensheathing Cells are Crucial for Spinal Cord Injury Repair: Insights from the Last 10 Years of Animal Model Studies. Cell Transplant 2019; 28:132S-159S. [PMID: 31726863 PMCID: PMC7016467 DOI: 10.1177/0963689719883823] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/03/2019] [Accepted: 09/27/2019] [Indexed: 12/15/2022] Open
Abstract
Olfactory ensheathing cells (OECs), the glial cells of the primary olfactory nervous system, support the natural regeneration of the olfactory nerve that occurs throughout life. OECs thus exhibit unique properties supporting neuronal survival and growth. Transplantation of OECs is emerging as a promising treatment for spinal cord injury; however, outcomes in both animals and humans are variable and the method needs improvement and standardization. A major reason for the discrepancy in functional outcomes is the variability in survival and integration of the transplanted cells, key factors for successful spinal cord regeneration. Here, we review the outcomes of OEC transplantation in rodent models over the last 10 years, with a focus on survival and integration of the transplanted cells. We identify the key factors influencing OEC survival: injury type, source of transplanted cells, co-transplantation with other cell types, number and concentration of cells, method of delivery, and time of transplantation after the injury. We found that two key issues are hampering optimization and standardization of OEC transplantation: lack of (1) reliable methods for identifying transplanted cells, and (2) three-dimensional systems for OEC delivery. To develop OEC transplantation as a successful and standardized therapy for spinal cord injury, we must address these issues and increase our understanding of the complex parameters influencing OEC survival.
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Affiliation(s)
- Ronak Reshamwala
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia
- Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia
- Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, Queensland, Australia
| | - Megha Shah
- Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia
- Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, Queensland, Australia
| | - James St John
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia
- Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia
- Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, Queensland, Australia
| | - Jenny Ekberg
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland, Australia
- Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia
- Clem Jones Centre for Neurobiology and Stem Cell Research, Griffith University, Brisbane, Queensland, Australia
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19
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Duncan GJ, Manesh SB, Hilton BJ, Assinck P, Plemel JR, Tetzlaff W. The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury. Glia 2019; 68:227-245. [PMID: 31433109 DOI: 10.1002/glia.23706] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 07/24/2019] [Accepted: 08/01/2019] [Indexed: 12/27/2022]
Abstract
Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed population of progenitor cells in the adult central nervous system, which allows these cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after traumatic spinal cord injury (SCI), compromising efficient conduction and, potentially, the long-term health of axons. In response, OPCs proliferate and then differentiate into new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in highly efficient remyelination following experimental SCI in which nearly all intact demyelinated axons are remyelinated in rodent models. However, myelin regeneration comprises only one role of OPCs following SCI. OPCs contribute to scar formation after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter their gene expression following demyelination, express cytokines and perpetuate the immune response. Here, we review the functional contribution of myelin regeneration and other recently uncovered roles of OPCs and their progeny to repair following SCI.
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Affiliation(s)
- Greg J Duncan
- Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, Oregon
| | - Sohrab B Manesh
- Graduate Program in Neuroscience, International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), Vancouver, British Columbia, Canada
| | - Brett J Hilton
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Peggy Assinck
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Jason R Plemel
- Department of Medicine, Division of Neurology, Neuroscience and Mental Health Institute, University of Alberta, Calgary, Alberta, Canada
| | - Wolfram Tetzlaff
- Graduate Program in Neuroscience, International Collaboration on Repair Discoveries (ICORD), University of British Columbia (UBC), Vancouver, British Columbia, Canada.,Departments of Zoology and Surgery, University of British Columbia, Vancouver, British Columbia, Canada
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20
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Ruzicka J, Romanyuk N, Jirakova K, Hejcl A, Janouskova O, Machova LU, Bochin M, Pradny M, Vargova L, Jendelova P. The Effect of iPS-Derived Neural Progenitors Seeded on Laminin-Coated pHEMA-MOETACl Hydrogel with Dual Porosity in a Rat Model of Chronic Spinal Cord Injury. Cell Transplant 2019; 28:400-412. [PMID: 30654639 PMCID: PMC6628561 DOI: 10.1177/0963689718823705] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Spinal cord injury (SCI), is a devastating condition leading to the loss of locomotor and sensory function below the injured segment. Despite some progress in acute SCI treatment using stem cells and biomaterials, chronic SCI remains to be addressed. We have assessed the use of laminin-coated hydrogel with dual porosity, seeded with induced pluripotent stem cell-derived neural progenitors (iPSC-NPs), in a rat model of chronic SCI. iPSC-NPs cultured for 3 weeks in hydrogel in vitro were positive for nestin, glial fibrillary acidic protein (GFAP) and microtubule-associated protein 2 (MAP2). These cell-polymer constructs were implanted into a balloon compression lesion, 5 weeks after lesion induction. Animals were behaviorally tested, and spinal cord tissue was immunohistochemically analyzed 28 weeks after SCI. The implanted iPSC-NPs survived in the scaffold for the entire experimental period. Host axons, astrocytes and blood vessels grew into the implant and an increased sprouting of host TH+ fibers was observed in the lesion vicinity. The implantation of iPSC-NP-LHM cell-polymer construct into the chronic SCI led to the integration of material into the injured spinal cord, reduced cavitation and supported the iPSC-NPs survival, but did not result in a statistically significant improvement of locomotor recovery.
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Affiliation(s)
- Jiri Ruzicka
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic
| | - Nataliya Romanyuk
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic
| | - Klara Jirakova
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic
| | - Ales Hejcl
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic
| | - Olga Janouskova
- 2 Department of Polymer Networks and Gels, Institute of Macromolecular Chemistry, CAS, Prague, Czech Republic
| | - Lucia Urdzikova Machova
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic
| | - Marcel Bochin
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic.,3 Department of Neurosciences, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Martin Pradny
- 2 Department of Polymer Networks and Gels, Institute of Macromolecular Chemistry, CAS, Prague, Czech Republic
| | - Lydia Vargova
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic.,3 Department of Neurosciences, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Pavla Jendelova
- 1 Department of Tissue Culture and Stem Cells, Institute of Experimental Medicine, CAS, Prague, Czech Republic.,3 Department of Neurosciences, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
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21
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Cerqueira SR, Lee YS, Cornelison RC, Mertz MW, Wachs RA, Schmidt CE, Bunge MB. Decellularized peripheral nerve supports Schwann cell transplants and axon growth following spinal cord injury. Biomaterials 2018; 177:176-185. [PMID: 29929081 PMCID: PMC6034707 DOI: 10.1016/j.biomaterials.2018.05.049] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 05/25/2018] [Accepted: 05/28/2018] [Indexed: 01/10/2023]
Abstract
Schwann cell (SC) transplantation has been comprehensively studied as a strategy for spinal cord injury (SCI) repair. SCs are neuroprotective and promote axon regeneration and myelination. Nonetheless, substantial SC death occurs post-implantation, which limits therapeutic efficacy. The use of extracellular matrix (ECM)-derived matrices, such as Matrigel, supports transplanted SC survival and axon growth, resulting in improved motor function. Because appropriate matrices are needed for clinical translation, we test here the use of an acellular injectable peripheral nerve (iPN) matrix. Implantation of SCs in iPN into a contusion lesion did not alter immune cell infiltration compared to injury only controls. iPN implants were larger and contained twice as many SC-myelinated axons as Matrigel grafts. SC/iPN animals performed as well as the SC/Matrigel group in the BBB locomotor test, and made fewer errors on the grid walk at 4 weeks, equalizing at 8 weeks. The fact that this clinically relevant iPN matrix is immunologically tolerated and supports SC survival and axon growth within the graft offers a highly translational possibility for improving efficacy of SC treatment after SCI. To our knowledge, it is the first time that an injectable PN matrix is being evaluated to improve the efficacy of SC transplantation in SCI repair.
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Affiliation(s)
- Susana R Cerqueira
- The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, FL, USA.
| | - Yee-Shuan Lee
- The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Robert C Cornelison
- Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA
| | - Michaela W Mertz
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Rebecca A Wachs
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Christine E Schmidt
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Mary Bartlett Bunge
- The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Cell Biology, University of Miami, Miller School of Medicine, Miami, FL, USA; Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA.
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22
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Pearse DD, Bastidas J, Izabel SS, Ghosh M. Schwann Cell Transplantation Subdues the Pro-Inflammatory Innate Immune Cell Response after Spinal Cord Injury. Int J Mol Sci 2018; 19:E2550. [PMID: 30154346 PMCID: PMC6163303 DOI: 10.3390/ijms19092550] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 08/20/2018] [Accepted: 08/22/2018] [Indexed: 12/12/2022] Open
Abstract
The transplantation of Schwann cells (SCs) has been shown to provide tissue preservation and support axon growth and remyelination as well as improve functional recovery across a diverse range of experimental spinal cord injury (SCI) paradigms. The autologous use of SCs has progressed to Phase 1 SCI clinical trials in humans where their use has been shown to be both feasible and safe. The contribution of immune modulation to the protective and reparative actions of SCs within the injured spinal cord remains largely unknown. In the current investigation, the ability of SC transplants to alter the innate immune response after contusive SCI in the rat was examined. SCs were intraspinally transplanted into the lesion site at 1 week following a thoracic (T8) contusive SCI. Multicolor flow cytometry and immunohistochemical analysis of specific phenotypic markers of pro- and anti-inflammatory microglia and macrophages as well as cytokines at 1 week after SC transplantation was employed. The introduction of SCs significantly attenuated the numbers of cluster of differentiation molecule 11B (CD11b)⁺, cluster of differentiation molecule 68 (CD68)⁺, and ionized calcium-binding adapter molecule 1 (Iba1)⁺ immune cells within the lesion implant site, particularly those immunoreactive for the pro-inflammatory marker, inducible nitric oxide synthase (iNOS). Whereas numbers of anti-inflammatory CD68⁺ Arginase-1 (Arg1⁺) iNOS- cells were not altered by SC transplantation, CD68⁺ cells of an intermediate, Arg1⁺ iNOS⁺ phenotype were increased by the introduction of SCs into the injured spinal cord. The morphology of Iba1⁺ immune cells was also markedly altered in the SC implant, being elongated and in alignment with SCs and in-growing axons versus their amoeboid form after SCI alone. Examination of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and anti-inflammatory cytokines, interleukin-4 (IL-4) and interleukin-10 (IL-10), by multicolor flow cytometry analysis showed that their production in CD11b⁺ cells was unaltered by SC transplantation at 1 week post-transplantation. The ability of SCs to subdue the pro-inflammatory iNOS⁺ microglia and macrophage phenotype after intraspinal transplantation may provide an important contribution to the neuroprotective effects of SCs within the sub-acute SCI setting.
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Affiliation(s)
- Damien D Pearse
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Veterans Affairs, Veterans Affairs Medical Center, Miami, FL 33136, USA.
| | - Johana Bastidas
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Sarah S Izabel
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Mousumi Ghosh
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Veterans Affairs, Veterans Affairs Medical Center, Miami, FL 33136, USA.
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23
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Abstract
Adult Schwann cells (SCs) can provide both a permissive substrate for axonal growth and a source of cells to ensheath and myelinate axons when transplanted into the injured spinal cord. Multiple studies have demonstrated that SC transplants can be used as part of a combinatorial approach to repairing the injured spinal cord. Here, we describe the protocols for collection and transplantation of adult rat primary SCs into the injured spinal cord. Protocols are included for the tissue culture procedures necessary for collection, quantification, and suspension of the cells for transplantation and for the surgical procedures for spinal cord injury at thoracic level nine (T9), reexposure of the injury site for delayed transplantation, and injection of the cells into the spinal cord.
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Affiliation(s)
- Ying Dai
- Burke Medical Research Institute, White Plains, NY, USA.,Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Caitlin E Hill
- Burke Medical Research Institute, White Plains, NY, USA. .,Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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24
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Abstract
Cell transplant-mediated tissue repair of the damaged spinal cord is being tested in several clinical trials. The current candidates are neural stem cells, stromal cells, and autologous Schwann cells (aSC). Due to their peripheral origin and limited penetration of astrocytic regions, aSC are transplanted intralesionally as compared to neural stem cells that are transplanted into intact spinal cord. Injections into either location can cause iatrogenic injury, and thus technical precision is important in the therapeutic risk-benefit equation. In this chapter, we discuss how we bridged from transplant studies in large animals to human application for two Phase 1 aSC transplant studies, one subacute and one chronic. Preclinical SC transplant studies conducted at the University of Miami in 2009-2012 in rodents, minipigs, and primates supported a successful Investigational New Drug (IND) submission for a Phase 1 trial in subacute complete spinal cord injury (SCI). Our studies optimized the safety and efficiency of intralesional cell delivery for subacute human SCI and led to the development of new simpler techniques for cell delivery into subjects with chronic SCI. Key parameters of delivery methodology include precision localization of the injury site, stereotaxic devices to control needle trajectory, method of entry into the spinal cord, spinal cord motion reduction, the volume and density of the cell suspension, rate of delivery, and control of shear stresses on cells.
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25
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Steffensen N, Lehmbecker A, Gerhauser I, Wang Y, Carlson R, Tipold A, Baumgärtner W, Stein VM. Generation and characterization of highly purified canine Schwann cells from spinal nerve dorsal roots as potential new candidates for transplantation strategies. J Tissue Eng Regen Med 2017; 12:e422-e437. [DOI: 10.1002/term.2478] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 05/06/2017] [Accepted: 05/09/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Nicole Steffensen
- Department of Small Animal Medicine and Surgery; University of Veterinary Medicine; Hannover Germany
| | - Annika Lehmbecker
- Department of Pathology; University of Veterinary Medicine; Hannover Germany
- Center for Systems Neuroscience; Hannover Germany
| | - Ingo Gerhauser
- Department of Pathology; University of Veterinary Medicine; Hannover Germany
| | - Yimin Wang
- Department of Pathology; University of Veterinary Medicine; Hannover Germany
- Center for Systems Neuroscience; Hannover Germany
| | - Regina Carlson
- Department of Small Animal Medicine and Surgery; University of Veterinary Medicine; Hannover Germany
| | - Andrea Tipold
- Department of Small Animal Medicine and Surgery; University of Veterinary Medicine; Hannover Germany
- Center for Systems Neuroscience; Hannover Germany
| | - Wolfgang Baumgärtner
- Department of Pathology; University of Veterinary Medicine; Hannover Germany
- Center for Systems Neuroscience; Hannover Germany
| | - Veronika M. Stein
- Department of Small Animal Medicine and Surgery; University of Veterinary Medicine; Hannover Germany
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26
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DePaul MA, Lin CY, Silver J, Lee YS. Combinatory repair strategy to promote axon regeneration and functional recovery after chronic spinal cord injury. Sci Rep 2017; 7:9018. [PMID: 28827771 PMCID: PMC5567101 DOI: 10.1038/s41598-017-09432-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 07/26/2017] [Indexed: 01/08/2023] Open
Abstract
Eight weeks post contusive spinal cord injury, we built a peripheral nerve graft bridge (PNG) through the cystic cavity and treated the graft/host interface with acidic fibroblast growth factor (aFGF) and chondroitinase ABC (ChABC). This combinatorial strategy remarkably enhanced integration between host astrocytes and graft Schwann cells, allowing for robust growth, especially of catecholaminergic axons, through the graft and back into the distal spinal cord. In the absence of aFGF+ChABC fewer catecholaminergic axons entered the graft, no axons exited, and Schwann cells and astrocytes failed to integrate. In sharp contrast with the acutely bridge-repaired cord, in the chronically repaired cord only low levels of serotonergic axons regenerated into the graft, with no evidence of re-entry back into the spinal cord. The failure of axons to regenerate was strongly correlated with a dramatic increase of SOCS3 expression. While regeneration was more limited overall than at acute stages, our combinatorial strategy in the chronically injured animals prevented a decline in locomotor behavior and bladder physiology outcomes associated with an invasive repair strategy. These results indicate that PNG+aFGF+ChABC treatment of the chronically contused spinal cord can provide a permissive substrate for the regeneration of certain neuronal populations that retain a growth potential over time, and lead to functional improvements.
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Affiliation(s)
- Marc A DePaul
- Case Western Reserve Univ., Dept. of Neurosciences, 10900 Euclid Ave., SOM E654, Cleveland, OH, 44106, USA
| | - Ching-Yi Lin
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA
| | - Jerry Silver
- Case Western Reserve Univ., Dept. of Neurosciences, 10900 Euclid Ave., SOM E654, Cleveland, OH, 44106, USA
| | - Yu-Shang Lee
- Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
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27
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Eve DJ, Sanberg PR. Article Commentary: Regenerative Medicine: An Analysis of Cell Transplantation's Impact. Cell Transplant 2017; 16:751-764. [DOI: 10.3727/000000007783465136] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- David J. Eve
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, University of South Florida College of Medicine, Tampa, FL 33612, USA
| | - Paul R. Sanberg
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, University of South Florida College of Medicine, Tampa, FL 33612, USA
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28
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Schaal SM, Kitay BM, Cho KS, Lo TP, Barakat DJ, Marcillo AE, Sanchez AR, Andrade CM, Pearse DD. Schwann Cell Transplantation Improves Reticulospinal Axon Growth and Forelimb Strength after Severe Cervical Spinal Cord Contusion. Cell Transplant 2017; 16:207-28. [PMID: 17503734 DOI: 10.3727/000000007783464768] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Schwann cell (SC) implantation alone has been shown to promote the growth of propriospinal and sensory axons, but not long-tract descending axons, after thoracic spinal cord injury (SCI). In the current study, we examined if an axotomy close to the cell body of origin (so as to enhance the intrinsic growth response) could permit supraspinal axons to grow onto SC grafts. Adult female Fischer rats received a severe (C5) cervical contusion (1.1 mm displacement, 3 KDyn). At 1 week postinjury, 2 million SCs ex vivo transduced with lentiviral vector encoding enhanced green fluorescent protein (EGFP) were implanted within media into the injury epicenter; injury-only animals served as controls. Animals were tested weekly using the BBB score for 7 weeks postimplantation and received at end point tests for upper body strength: self-supported forelimb hanging, forearm grip force, and the incline plane. Following behavioral assessment, animals were anterogradely traced bilaterally from the reticular formation using BDA-Texas Red. Stereological quantification revealed a twofold increase in the numbers of preserved NeuN+ neurons rostral and caudal to the injury/graft site in SC implanted animals, corroborating previous reports of their neuroprotective efficacy. Examination of labeled reticulospinal axon growth revealed that while rarely an axon was present within the lesion site of injury-only controls, numerous reticulospinal axons had penetrated the SC implant/lesion milieu. This has not been observed following implantation of SCs alone into the injured thoracic spinal cord. Significant behavioral improvements over injury-only controls in upper limb strength, including an enhanced grip strength (a 296% increase) and an increased self-supported forelimb hanging, accompanied SC-mediated neuroprotection and reticulospinal axon growth. The current study further supports the neuroprotective efficacy of SC implants after SCI and demonstrates that SCs alone are capable of supporting modest supraspinal axon growth when the site of axon injury is closer to the cell body of the axotomized neuron.
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Affiliation(s)
- S M Schaal
- The Miami Project to Cure Paralysis, University of Miami School of Medicine, Miami, FL 33101, USA
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29
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Bickford PC. Frontiers in Neural Transplantation and Repair: A Special Issue Based on the 11th ASNTR Meeting. Cell Transplant 2017; 14:171-172. [PMID: 28876088 DOI: 10.3727/000000005783983151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Paula C Bickford
- ASNTR 2005 James A Haley VA Hospital Center of Excellence for Aging and Brain Repair, USF Tampa, FL
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30
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SanMartin A, Borlongan CV. Article Commentary: Cell Transplantation: Toward Cell Therapy. Cell Transplant 2017; 15:665-73. [PMID: 17176618 DOI: 10.3727/000000006783981666] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Affiliation(s)
- Agneta SanMartin
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery, University of South Florida, Tampa, FL 33612, USA.
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31
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Nardone R, Florea C, Höller Y, Brigo F, Versace V, Lochner P, Golaszewski S, Trinka E. Rodent, large animal and non-human primate models of spinal cord injury. ZOOLOGY 2017; 123:101-114. [PMID: 28720322 DOI: 10.1016/j.zool.2017.06.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Revised: 06/02/2017] [Accepted: 06/02/2017] [Indexed: 01/05/2023]
Abstract
In this narrative review we aimed to assess the usefulness of the different animal models in identifying injury mechanisms and developing therapies for humans suffering from spinal cord injury (SCI). Results obtained from rodent studies are useful but, due to the anatomical, molecular and functional differences, confirmation of these findings in large animals or non-human primates may lead to basic discoveries that cannot be made in rodent models and that are more useful for developing treatment strategies in humans. SCI in dogs can be considered as intermediate between rodent models and human clinical trials, but the primate models could help to develop appropriate methods that might be more relevant to humans. Ideally, an animal model should meet the requirements of availability and repeatability as well as reproduce the anatomical features and the clinical pathological changing process of SCI. An animal model that completely simulates SCI in humans does not exist. The different experimental models of SCI have advantages and disadvantages for investigating the different aspects of lesion development, recovery mechanisms and potential therapeutic interventions. The potential advantages of non-human primate models include genetic similarities, similar caliber/length of the spinal cord as well as biological and physiological responses to injury which are more similar to humans. Among the potential disadvantages, high operating costs, infrastructural requirements and ethical concerns should be considered. The translation from experimental repair strategies to clinical applications needs to be investigated in future carefully designed studies.
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Affiliation(s)
- Raffaele Nardone
- Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020, Salzburg, Austria; Department of Neurology, Franz Tappeiner Hospital, Via Rossini 5, I-39012, Merano, Italy; Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020, Salzburg, Austria.
| | - Cristina Florea
- Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020, Salzburg, Austria
| | - Yvonne Höller
- Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020, Salzburg, Austria
| | - Francesco Brigo
- Department of Neurology, Franz Tappeiner Hospital, Via Rossini 5, I-39012, Merano, Italy; Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Piazzale L.A. Scuro, I-37134 Verona, Italy
| | - Viviana Versace
- Department of Neurorehabilitation, Hospital of Vipiteno, Via Santa Margherita 24, I-39049, Italy
| | - Piergiorgio Lochner
- Department of Neurology, Saarland University Medical Center, Kirrberger-Str. 100, D-66421 Homburg, Germany
| | - Stefan Golaszewski
- Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020, Salzburg, Austria
| | - Eugen Trinka
- Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center, Paracelsus Medical University, Ignaz-Harrer-Str. 79, A-5020, Salzburg, Austria
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32
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Bastidas J, Athauda G, De La Cruz G, Chan WM, Golshani R, Berrocal Y, Henao M, Lalwani A, Mannoji C, Assi M, Otero PA, Khan A, Marcillo AE, Norenberg M, Levi AD, Wood PM, Guest JD, Dietrich WD, Bartlett Bunge M, Pearse DD. Human Schwann cells exhibit long-term cell survival, are not tumorigenic and promote repair when transplanted into the contused spinal cord. Glia 2017; 65:1278-1301. [PMID: 28543541 DOI: 10.1002/glia.23161] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Revised: 04/07/2017] [Accepted: 04/10/2017] [Indexed: 12/26/2022]
Abstract
The transplantation of rodent Schwann cells (SCs) provides anatomical and functional restitution in a variety of spinal cord injury (SCI) models, supporting the recent translation of SCs to phase 1 clinical trials for human SCI. Whereas human (Hu)SCs have been examined experimentally in a complete SCI transection paradigm, to date the reported behavior of SCs when transplanted after a clinically relevant contusive SCI has been restricted to the use of rodent SCs. Here, in a xenotransplant, contusive SCI paradigm, the survival, biodistribution, proliferation and tumorgenicity as well as host responses to HuSCs, cultured according to a protocol analogous to that developed for clinical application, were investigated. HuSCs persisted within the contused nude rat spinal cord through 6 months after transplantation (longest time examined), exhibited low cell proliferation, displayed no evidence of tumorigenicity and showed a restricted biodistribution to the lesion. Neuropathological examination of the CNS revealed no adverse effects of HuSCs. Animals exhibiting higher numbers of surviving HuSCs within the lesion showed greater volumes of preserved white matter and host rat SC and astrocyte ingress as well as axon ingrowth and myelination. These results demonstrate the safety of HuSCs when employed in a clinically relevant experimental SCI paradigm. Further, signs of a potentially positive influence of HuSC transplants on host tissue pathology were observed. These findings show that HuSCs exhibit a favorable toxicity profile for up to 6 months after transplantation into the contused rat spinal cord, an important outcome for FDA consideration of their use in human clinical trials.
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Affiliation(s)
- Johana Bastidas
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Gagani Athauda
- The Department of Cellular Biology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, 33199.,The Department of Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, 33199
| | - Gabriela De La Cruz
- Translational Pathology Laboratory, Lineberger Comprehensive Cancer Center, Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 27599
| | - Wai-Man Chan
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Roozbeh Golshani
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Yerko Berrocal
- The Department of Cellular Biology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, 33199.,The Department of Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, 33199
| | - Martha Henao
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Anil Lalwani
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Chikato Mannoji
- The Department of Orthopedic Surgery, Chiba University School of Medicine, Chiba, Japan
| | - Mazen Assi
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - P Anthony Otero
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Aisha Khan
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Alexander E Marcillo
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Michael Norenberg
- The Department of Pathology, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Allan D Levi
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Patrick M Wood
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - James D Guest
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - W Dalton Dietrich
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Neurology, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Neuroscience Program, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Interdisciplinary Stem Cell Institute, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Cell Biology, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Mary Bartlett Bunge
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Neuroscience Program, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Interdisciplinary Stem Cell Institute, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Cell Biology, The University of Miami Miller School of Medicine, Miami, Florida, 33136
| | - Damien D Pearse
- The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Neuroscience Program, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,The Interdisciplinary Stem Cell Institute, The University of Miami Miller School of Medicine, Miami, Florida, 33136.,Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, Florida, 33136
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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: 608] [Impact Index Per Article: 76.0] [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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Anderson KD, Guest JD, Dietrich WD, Bartlett Bunge M, Curiel R, Dididze M, Green BA, Khan A, Pearse DD, Saraf-Lavi E, Widerström-Noga E, Wood P, Levi AD. Safety of Autologous Human Schwann Cell Transplantation in Subacute Thoracic Spinal Cord Injury. J Neurotrauma 2017; 34:2950-2963. [PMID: 28225648 DOI: 10.1089/neu.2016.4895] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The rationale for implantation of autologous human Schwann cells (SCs) in persons with subacute spinal cord injury (SCI) is based on evidence that transplanted SCs are neuroprotective, support local axonal plasticity, and are capable of myelinating axons. A Phase I clinical trial was conducted to evaluate the safety of autologous human SC transplantation into the injury epicenter of six subjects with subacute SCI. The trial was an open-label, unblinded, non-randomized, non-placebo controlled study with a dose escalation design and standard medical rehabilitation. Participants were paraplegics with neurologically complete, trauma-induced spinal lesions. Autologous SCs were cultured in vitro from a sural nerve harvested from each participant and injected into the epicenter of the spinal lesion. Outcome measures for safety were protocol compliance, feasibility, adverse events, stability of neurological level, absence of detectable mass lesion, and the emergence of clinically significant neuropathic pain or muscle spasticity no greater than expected for a natural course cohort. One year post-transplantation, there were no surgical, medical, or neurological complications to indicate that the timing or procedure for the cell transplantation was unsafe. There were no adverse events or serious adverse events related to the cell therapy. There was no evidence of additional spinal cord damage, mass lesion, or syrinx formation. We conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5-30 days of injury, and perform an intra-spinal transplantation of highly purified autologous SCs within 4-7 weeks of injury.
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Affiliation(s)
- Kim D Anderson
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida
| | - James D Guest
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida.,3 The Neuroscience Program, The University of Miami Miller School of Medicine , Miami, Florida
| | - W Dalton Dietrich
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida.,3 The Neuroscience Program, The University of Miami Miller School of Medicine , Miami, Florida.,4 Department of Cell Biology, The University of Miami Miller School of Medicine , Miami, Florida.,5 Department of Neurology, The University of Miami Miller School of Medicine , Miami, Florida.,6 Department of The Interdisciplinary Stem Cell Institute, The University of Miami Miller School of Medicine , Miami, Florida
| | - Mary Bartlett Bunge
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida.,3 The Neuroscience Program, The University of Miami Miller School of Medicine , Miami, Florida.,4 Department of Cell Biology, The University of Miami Miller School of Medicine , Miami, Florida.,5 Department of Neurology, The University of Miami Miller School of Medicine , Miami, Florida.,6 Department of The Interdisciplinary Stem Cell Institute, The University of Miami Miller School of Medicine , Miami, Florida
| | - Rosie Curiel
- 7 Department of Psychiatry, The University of Miami Miller School of Medicine , Miami, Florida
| | - Marine Dididze
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida
| | - Barth A Green
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida.,5 Department of Neurology, The University of Miami Miller School of Medicine , Miami, Florida.,8 Department of Orthopaedics, The University of Miami Miller School of Medicine , Miami, Florida.,9 Department of Rehabilitation Medicine, The University of Miami Miller School of Medicine , Miami, Florida
| | - Aisha Khan
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,6 Department of The Interdisciplinary Stem Cell Institute, The University of Miami Miller School of Medicine , Miami, Florida
| | - Damien D Pearse
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida.,3 The Neuroscience Program, The University of Miami Miller School of Medicine , Miami, Florida.,6 Department of The Interdisciplinary Stem Cell Institute, The University of Miami Miller School of Medicine , Miami, Florida.,11 Bruce W. Carter Department of Veterans Affairs Medical Center , Miami, Florida
| | - Efrat Saraf-Lavi
- 10 Department of Radiology, The University of Miami Miller School of Medicine , Miami, Florida
| | - Eva Widerström-Noga
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida.,3 The Neuroscience Program, The University of Miami Miller School of Medicine , Miami, Florida.,9 Department of Rehabilitation Medicine, The University of Miami Miller School of Medicine , Miami, Florida.,11 Bruce W. Carter Department of Veterans Affairs Medical Center , Miami, Florida
| | - Patrick Wood
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida
| | - Allan D Levi
- 1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.,2 Department of Neurological Surgery, The University of Miami Miller School of Medicine , Miami, Florida.,8 Department of Orthopaedics, The University of Miami Miller School of Medicine , Miami, Florida
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Gu M, Gao Z, Li X, Guo L, Lu T, Li Y, He X. Conditioned medium of olfactory ensheathing cells promotes the functional recovery and axonal regeneration after contusive spinal cord injury. Brain Res 2017; 1654:43-54. [DOI: 10.1016/j.brainres.2016.10.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 10/05/2016] [Accepted: 10/22/2016] [Indexed: 01/15/2023]
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Hosseini M, Yousefifard M, Baikpour M, Rahimi-Movaghar V, Nasirinezhad F, Younesian S, Safari S, Ghelichkhani P, Moghadas Jafari A. The efficacy of Schwann cell transplantation on motor function recovery after spinal cord injuries in animal models: A systematic review and meta-analysis. J Chem Neuroanat 2016; 78:102-111. [PMID: 27609084 DOI: 10.1016/j.jchemneu.2016.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 07/09/2016] [Accepted: 09/04/2016] [Indexed: 12/31/2022]
Abstract
AIM This article aimed to assess the efficacy of Schwann cell transplantation on motor function recovery in animal model of spinal cord injuries via meta-analysis. METHODS An extended search was carried out in the electronic databases of Medline (via PubMed), EMBASE (via OvidSP), CENTRAL, SCOPUS, Web of Science (BIOSIS), and ProQuest. Finally, 41 eligible studies conducted on 1046 animals including 517 control animals and 529 transplanted animals were included in the meta-analysis. Pooled standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (95% CI) were reported. RESULTS The findings showed that treatment with Schwann cells leads to a modest motor function recovery after spinal cord injury (SMD=0.85; 95% CI: 0.63-1.07; p<0.001). Transplantation of these cells in acute phase of the injury (immediately after the injury) (OR=4.30; 95% CI: 1.53-12.05; p=0.007), application of mesenchymal/skin-derived precursors (OR=2.34; 95% CI: 1.28-4.29; p=0.008), and cells with human sources are associated with an increase in efficacy of Schwann cells (OR=10.96; 95% CI: 1.49-80.77; p=0.02). Finally, it seems that the efficacy of Schwann cells in mice is significantly lower than rats (OR=0.03; 95% CI: 0.003-0.41; p=0.009). CONCLUSION Transplantation of Schwann cells can moderately improve motor function recovery. It seems that inter-species differences might exist regarding the efficacy of this cells. Therefore, this should be taken into account when using Schwann cells in clinical trials regarding spinal cord injuries.
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Affiliation(s)
- Mostafa Hosseini
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Yousefifard
- Physiology Research Center and Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Masoud Baikpour
- Department of Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Vafa Rahimi-Movaghar
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Farinaz Nasirinezhad
- Physiology Research Center and Department of Physiology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Somaye Younesian
- Department of Emergency Medicine, Qom University of Medical Sciences, Qom, Iran
| | - Saeed Safari
- Department of Emergency Medicine, Shohadaye Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Ghelichkhani
- Department of Intensive Care Nursing, School of Nursing and Midwifery, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Moghadas Jafari
- Department of Emergency Medicine, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
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Differential regenerative ability of sensory and motor neurons. Neurosci Lett 2016; 652:35-40. [PMID: 27818349 DOI: 10.1016/j.neulet.2016.11.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 10/24/2016] [Accepted: 11/01/2016] [Indexed: 11/22/2022]
Abstract
After injury, the adult mammalian central nervous system (CNS) lacks long-distance axon regeneration. This review discusses the similarities and differences of sensory and motor neurons, seeking to understand how to achieve functional sensory and motor regeneration. As these two types of neurons respond differently to axotomy, growth environment and treatment, the future challenge will be on how to achieve full recovery in a way that allows regeneration of both types of fibres simultaneously.
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Yahata K, Kanno H, Ozawa H, Yamaya S, Tateda S, Ito K, Shimokawa H, Itoi E. Low-energy extracorporeal shock wave therapy for promotion of vascular endothelial growth factor expression and angiogenesis and improvement of locomotor and sensory functions after spinal cord injury. J Neurosurg Spine 2016; 25:745-755. [PMID: 27367940 DOI: 10.3171/2016.4.spine15923] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Extracorporeal shock wave therapy (ESWT) is widely used to treat various human diseases. Low-energy ESWT increases expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. The VEGF stimulates not only endothelial cells to promote angiogenesis but also neural cells to induce neuroprotective effects. A previous study by these authors demonstrated that low-energy ESWT promoted expression of VEGF in damaged neural tissue and improved locomotor function after spinal cord injury (SCI). However, the neuroprotective mechanisms in the injured spinal cord produced by low-energy ESWT are still unknown. In the present study, the authors investigated the cell specificity of VEGF expression in injured spinal cords and angiogenesis induced by low-energy ESWT. They also examined the neuroprotective effects of low-energy ESWT on cell death, axonal damage, and white matter sparing as well as the therapeutic effect for improvement of sensory function following SCI. METHODS Adult female Sprague-Dawley rats were divided into the SCI group (SCI only) and SCI-SW group (low-energy ESWT applied after SCI). Thoracic SCI was produced using a New York University Impactor. Low-energy ESWT was applied to the injured spinal cord 3 times a week for 3 weeks after SCI. Locomotor function was evaluated using the Basso, Beattie, and Bresnahan open-field locomotor score for 42 days after SCI. Mechanical and thermal allodynia in the hindpaw were evaluated for 42 days. Double staining for VEGF and various cell-type markers (NeuN, GFAP, and Olig2) was performed at Day 7; TUNEL staining was also performed at Day 7. Immunohistochemical staining for CD31, α-SMA, and 5-HT was performed on spinal cord sections taken 42 days after SCI. Luxol fast blue staining was performed at Day 42. RESULTS Low-energy ESWT significantly improved not only locomotion but also mechanical and thermal allodynia following SCI. In the double staining, expression of VEGF was observed in NeuN-, GFAP-, and Olig2-labeled cells. Low-energy ESWT significantly promoted CD31 and α-SMA expressions in the injured spinal cords. In addition, low-energy ESWT significantly reduced the TUNEL-positive cells in the injured spinal cords. Furthermore, the immunodensity of 5-HT-positive axons was significantly higher in the animals treated by low-energy ESWT. The areas of spared white matter were obviously larger in the SCI-SW group than in the SCI group, as indicated by Luxol fast blue staining. CONCLUSIONS The results of this study suggested that low-energy ESWT promotes VEGF expression in various neural cells and enhances angiogenesis in damaged neural tissue after SCI. Furthermore, the neuroprotective effect of VEGF induced by low-energy ESWT can suppress cell death and axonal damage and consequently improve locomotor and sensory functions after SCI. Thus, low-energy ESWT can be a novel therapeutic strategy for treatment of SCI.
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Affiliation(s)
| | | | | | | | | | - Kenta Ito
- Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroaki Shimokawa
- Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Eiji Itoi
- Departments of 1 Orthopaedic Surgery and
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Myers SA, Bankston AN, Burke DA, Ohri SS, Whittemore SR. Does the preclinical evidence for functional remyelination following myelinating cell engraftment into the injured spinal cord support progression to clinical trials? Exp Neurol 2016; 283:560-72. [PMID: 27085393 DOI: 10.1016/j.expneurol.2016.04.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 04/06/2016] [Accepted: 04/07/2016] [Indexed: 02/08/2023]
Abstract
This article reviews all historical literature in which rodent-derived myelinating cells have been engrafted into the contused adult rodent spinal cord. From 2500 initial PubMed citations identified, human cells grafts, bone mesenchymal stem cells, olfactory ensheathing cells, non-myelinating cell grafts, and rodent grafts into hemisection or transection models were excluded, resulting in the 67 studies encompassed in this review. Forty five of those involved central nervous system (CNS)-derived cells, including neural stem progenitor cells (NSPCs), neural restricted precursor cells (NRPs) or oligodendrocyte precursor cells (OPCs), and 22 studies involved Schwann cells (SC). Of the NSPC/NPC/OPC grafts, there was no consistency with respect to the types of cells grafted and/or the additional growth factors or cells co-grafted. Enhanced functional recovery was reported in 31/45 studies, but only 20 of those had appropriate controls making conclusive interpretation of the remaining studies impossible. Of those 20, 19 were properly powered and utilized appropriate statistical analyses. Ten of those 19 studies reported the presence of graft-derived myelin, 3 reported evidence of endogenous remyelination or myelin sparing, and 2 reported both. For the SC grafts, 16/21 reported functional improvement, with 11 having appropriate cellular controls and 9/11 using proper statistical analyses. Of those 9, increased myelin was reported in 6 studies. The lack of consistency and replication among these preclinical studies are discussed with respect to the progression of myelinating cell transplantation therapies into the clinic.
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Affiliation(s)
- Scott A Myers
- 511 S. Floyd St., MDR 623, Kentucky Spinal Cord Injury Research Center and Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, KY 40202, USA
| | - Andrew N Bankston
- 511 S. Floyd St., MDR 623, Kentucky Spinal Cord Injury Research Center and Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, KY 40202, USA
| | - Darlene A Burke
- 511 S. Floyd St., MDR 623, Kentucky Spinal Cord Injury Research Center and Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, KY 40202, USA
| | - Sujata Saraswat Ohri
- 511 S. Floyd St., MDR 623, Kentucky Spinal Cord Injury Research Center and Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, KY 40202, USA
| | - Scott R Whittemore
- 511 S. Floyd St., MDR 623, Kentucky Spinal Cord Injury Research Center and Department of Neurological Surgery, University of Louisville, School of Medicine, Louisville, KY 40202, USA.
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Jin Y, Bouyer J, Shumsky JS, Haas C, Fischer I. Transplantation of neural progenitor cells in chronic spinal cord injury. Neuroscience 2016; 320:69-82. [PMID: 26852702 DOI: 10.1016/j.neuroscience.2016.01.066] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Revised: 01/07/2016] [Accepted: 01/29/2016] [Indexed: 01/24/2023]
Abstract
Previous studies demonstrated that neural progenitor cells (NPCs) transplanted into a subacute contusion injury improve motor, sensory, and bladder function. In this study we tested whether transplanted NPCs can also improve functional recovery after chronic spinal cord injury (SCI) alone or in combination with the reduction of glial scar and neurotrophic support. Adult rats received a T10 moderate contusion. Thirteen weeks after the injury they were divided into four groups and received either: 1. Medium (control), 2. NPC transplants, 3. NPC+lentivirus vector expressing chondroitinase, or 4. NPC+lentivirus vectors expressing chondroitinase and neurotrophic factors. During the 8 weeks post-transplantation the animals were tested for functional recovery and eventually analyzed by anatomical and immunohistochemical assays. The behavioral tests for motor and sensory function were performed before and after injury, and weekly after transplantation, with some animals also tested for bladder function at the end of the experiment. Transplant survival in the chronic injury model was variable and showed NPCs at the injury site in 60% of the animals in all transplantation groups. The NPC transplants comprised less than 40% of the injury site, without significant anatomical or histological differences among the groups. All groups also showed similar patterns of functional deficits and recovery in the 12 weeks after injury and in the 8 weeks after transplantation using the Basso, Beattie, and Bresnahan rating score, the grid test, and the Von Frey test for mechanical allodynia. A notable exception was group 4 (NPC together with chondroitinase and neurotrophins), which showed a significant improvement in bladder function. This study underscores the therapeutic challenges facing transplantation strategies in a chronic SCI in which even the inclusion of treatments designed to reduce scarring and increase neurotrophic support produce only modest functional improvements. Further studies will have to identify the combination of acute and chronic interventions that will augment the survival and efficacy of neural cell transplants.
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Affiliation(s)
- Y Jin
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States.
| | - J Bouyer
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States
| | - J S Shumsky
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States
| | - C Haas
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States
| | - I Fischer
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia PA 19129, United States.
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Ghosh M, Xu Y, Pearse DD. Cyclic AMP is a key regulator of M1 to M2a phenotypic conversion of microglia in the presence of Th2 cytokines. J Neuroinflammation 2016; 13:9. [PMID: 26757726 PMCID: PMC4711034 DOI: 10.1186/s12974-015-0463-9] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 12/17/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Microglia and macrophages play a central role in neuroinflammation. Pro-inflammatory cytokines trigger their conversion to a classically activated (M1) phenotype, sustaining inflammation and producing a cytotoxic environment. Conversely, anti-inflammatory cytokines polarize the cells towards an alternatively activated (M2), tissue reparative phenotype. Elucidation of the signal transduction pathways involved in M1 to M2 phenotypic conversion may provide insight into how the innate immune response can be harnessed during distinct phases of disease or injury to mediate neuroprotection and neurorepair. METHODS Microglial cells (cell line and primary) were subjected to combined cyclic adenosine monophosphate (cyclic AMP) and IL-4, or either alone, in the presence of pro-inflammatory mediators, lipopolysaccharide (LPS), or tumor necrosis factor-α (TNF-α). Their effects on the expression of characteristic markers for M1 and M2 microglia were assessed. Similarly, the M1 and M2 phenotypes of microglia and macrophages within the lesion site were then evaluated following a contusive spinal cord injury (SCI) to the thoracic (T8) spinal cord of rats and mice when the agents were administered systemically. RESULTS It was demonstrated that cyclic AMP functions synergistically with IL-4 to promote M1 to M2 conversion of microglia in culture. The combination of cyclic AMP and IL-4, but neither alone, induced an Arg-1(+)/iNOS(-)cell phenotype with concomitant expression of other M2-specific markers including TG2 and RELM-α. M2-converted microglia showed ameliorated production of pro-inflammatory cytokines (TNF-α and IP-10) and reactive oxygen species, with no alteration in phagocytic properties. M2a conversion required protein kinase A (PKA), but not the exchange protein directly activated by cyclic AMP (EPAC). Systemic delivery of cyclic AMP and IL-4 after experimental SCI also promoted a significant M1 to M2a phenotypic change in microglia and macrophage population dynamics in the lesion. CONCLUSIONS Using primary microglia, microglial cell lines, and experimental models of CNS injury, we demonstrate that cyclic AMP levels are a critical determinant in M1-M2 polarization. High levels of cyclic AMP promoted an Arg-1(+) M2a phenotype when microglia were activated with pro-inflammatory stimuli and Th2 cytokines. Th2 cytokines or cyclic AMP independently did not promote these changes. Phenotypic conversion of microglia provides a powerful new therapeutic approach for altering the balance of cytotoxic to reparative microglia in a diversity of neurological diseases and injury.
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Affiliation(s)
- Mousumi Ghosh
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. .,Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| | - Yong Xu
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| | - Damien D Pearse
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. .,Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. .,The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. .,The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
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Acute Putrescine Supplementation with Schwann Cell Implantation Improves Sensory and Serotonergic Axon Growth and Functional Recovery in Spinal Cord Injured Rats. Neural Plast 2015; 2015:186385. [PMID: 26550496 PMCID: PMC4621347 DOI: 10.1155/2015/186385] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 06/25/2015] [Accepted: 07/02/2015] [Indexed: 01/29/2023] Open
Abstract
Schwann cell (SC) transplantation exhibits significant potential for spinal cord injury (SCI) repair and its use as a therapeutic modality has now progressed to clinical trials for subacute and chronic human SCI. Although SC implants provide a receptive environment for axonal regrowth and support functional recovery in a number of experimental SCI models, axonal regeneration is largely limited to local systems and the behavioral improvements are modest without additional combinatory approaches. In the current study we investigated whether the concurrent delivery of the polyamine putrescine, started either 30 min or 1 week after SCI, could enhance the efficacy of SCs when implanted subacutely (1 week after injury) into the contused rat spinal cord. Polyamines are ubiquitous organic cations that play an important role in the regulation of the cell cycle, cell division, cytoskeletal organization, and cell differentiation. We show that the combination of putrescine with SCs provides a significant increase in implant size, an enhancement in axonal (sensory and serotonergic) sparing and/or growth, and improved open field locomotion after SCI, as compared to SC implantation alone. These findings demonstrate that polyamine supplementation can augment the effectiveness of SCs when used as a therapeutic approach for subacute SCI repair.
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Vadivelu S, Stewart TJ, Qu Y, Horn K, Liu S, Li Q, Silver J, McDonald JW. NG2+ progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury. Stem Cells Transl Med 2015; 4:401-11. [PMID: 25713464 DOI: 10.5966/sctm.2014-0107] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The glial scar resulting from spinal cord injury is rich in chondroitin sulfate proteoglycan (CSPG), a formidable barrier to axonal regeneration. We explored the possibility of breaching that barrier by first examining the scar in a functional in vitro model. We found that embryonic stem cell-derived neural lineage cells (ESNLCs) with prominent expression of nerve glial antigen 2 (NG2) survived, passed through an increasingly inhibitory gradient of CSPG, and expressed matrix metalloproteinase 9 (MMP-9) at the appropriate stage of their development. Outgrowth of axons from ESNLCs followed because the migrating cells sculpted pathways in which CSPG was degraded. The degradative mechanism involved MMP-9 but not MMP-2. To confirm these results in vivo, we transplanted ESNLCs directly into the cavity of a contused spinal cord 9 days after injury. A week later, ESNLCs survived and were expressing both NG2 and MMP-9. Their axons had grown through long distances (>10 mm), although they preferred to traverse white rather than gray matter. These data are consistent with the concept that expression of inhibitory CSPG within the injury scar is an important impediment to regeneration but that NG2+ progenitors derived from ESNLCs can modify the microenvironment to allow axons to grow through the barrier. This beneficial action may be partly due to developmental expression of MMP-9. We conclude that it might eventually be possible to encourage axonal regeneration in the human spinal cord by transplanting ESNLCs or other cells that express NG2.
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Affiliation(s)
- Sudhakar Vadivelu
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Todd J Stewart
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yun Qu
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Kevin Horn
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Su Liu
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Qun Li
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jerry Silver
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - John W McDonald
- The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Yılmaz T, Kaptanoğlu E. Current and future medical therapeutic strategies for the functional repair of spinal cord injury. World J Orthop 2015; 6:42-55. [PMID: 25621210 PMCID: PMC4303789 DOI: 10.5312/wjo.v6.i1.42] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Spinal cord injury (SCI) leads to social and psychological problems in patients and requires costly treatment and care. In recent years, various pharmacological agents have been tested for acute SCI. Large scale, prospective, randomized, controlled clinical trials have failed to demonstrate marked neurological benefit in contrast to their success in the laboratory. Today, the most important problem is ineffectiveness of nonsurgical treatment choices in human SCI that showed neuroprotective effects in animal studies. Recently, attempted cellular therapy and transplantations are promising. A better understanding of the pathophysiology of SCI started in the early 1980s. Research had been looking at neuroprotection in the 1980s and the first half of 1990s and regeneration studies started in the second half of the 1990s. A number of studies on surgical timing suggest that early surgical intervention is safe and feasible, can improve clinical and neurological outcomes and reduce health care costs, and minimize the secondary damage caused by compression of the spinal cord after trauma. This article reviews current evidence for early surgical decompression and nonsurgical treatment options, including pharmacological and cellular therapy, as the treatment choices for SCI.
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Abstract
Three theories of regeneration dominate neuroscience today, all purporting to explain why the adult central nervous system (CNS) cannot regenerate. One theory proposes that Nogo, a molecule expressed by myelin, prevents axonal growth. The second theory emphasizes the role of glial scars. The third theory proposes that chondroitin sulfate proteoglycans (CSPGs) prevent axon growth. Blockade of Nogo, CSPG, and their receptors indeed can stop axon growth in vitro and improve functional recovery in animal spinal cord injury (SCI) models. These therapies also increase sprouting of surviving axons and plasticity. However, many investigators have reported regenerating spinal tracts without eliminating Nogo, glial scar, or CSPG. For example, many motor and sensory axons grow spontaneously in contused spinal cords, crossing gliotic tissue and white matter surrounding the injury site. Sensory axons grow long distances in injured dorsal columns after peripheral nerve lesions. Cell transplants and treatments that increase cAMP and neurotrophins stimulate motor and sensory axons to cross glial scars and to grow long distances in white matter. Genetic studies deleting all members of the Nogo family and even the Nogo receptor do not always improve regeneration in mice. A recent study reported that suppressing the phosphatase and tensin homolog (PTEN) gene promotes prolific corticospinal tract regeneration. These findings cannot be explained by the current theories proposing that Nogo and glial scars prevent regeneration. Spinal axons clearly can and will grow through glial scars and Nogo-expressing tissue under some circumstances. The observation that deleting PTEN allows corticospinal tract regeneration indicates that the PTEN/AKT/mTOR pathway regulates axonal growth. Finally, many other factors stimulate spinal axonal growth, including conditioning lesions, cAMP, glycogen synthetase kinase inhibition, and neurotrophins. To explain these disparate regenerative phenomena, I propose that the spinal cord has evolved regenerative mechanisms that are normally suppressed by multiple extrinsic and intrinsic factors but can be activated by injury, mediated by the PTEN/AKT/mTOR, cAMP, and GSK3b pathways, to stimulate neural growth and proliferation.
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Affiliation(s)
- Wise Young
- W. M. Keck Center for Collaborative Neuroscience, Rutgers, State University of New Jersey, Piscataway, NJ, USA
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Kanno H, Pearse DD, Ozawa H, Itoi E, Bunge MB. Schwann cell transplantation for spinal cord injury repair: its significant therapeutic potential and prospectus. Rev Neurosci 2015; 26:121-8. [DOI: 10.1515/revneuro-2014-0068] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 10/16/2014] [Indexed: 11/15/2022]
Abstract
AbstractTransplantation of Schwann cells (SCs) is a promising therapeutic strategy for spinal cord repair. The introduction of SCs into the injured spinal cord has been shown to reduce tissue loss, promote axonal regeneration, and facilitate myelination of axons for improved sensorimotor function. The pathology of spinal cord injury (SCI) comprises multiple processes characterized by extensive cell death, development of a milieu inhibitory to growth, and glial scar formation, which together limits axonal regeneration. Many studies have suggested that significant functional recovery following SCI will not be possible with a single therapeutic strategy. The use of additional approaches with SC transplantation may be needed for successful axonal regeneration and sufficient functional recovery after SCI. An example of such a combination strategy with SC transplantation has been the complementary administration of neuroprotective agents/growth factors, which improves the effect of SCs after SCI. Suspension of SCs in bioactive matrices can also enhance transplanted SC survival and increase their capacity for supporting axonal regeneration in the injured spinal cord. Inhibition of glial scar formation produces a more permissive interface between the SC transplant and host spinal cord for axonal growth. Co-transplantation of SCs and other types of cells such as olfactory ensheathing cells, bone marrow mesenchymal stromal cells, and neural stem cells can be a more effective therapy than transplantation of SCs alone following SCI. This article reviews some of the evidence supporting the combination of SC transplantation with additional strategies for SCI repair and presents a prospectus for achieving better outcomes for persons with SCI.
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Gladwin K, Choi D. Olfactory Ensheathing Cells: Part I—Current Concepts and Experimental Laboratory Models. World Neurosurg 2015; 83:114-9. [DOI: 10.1016/j.wneu.2013.03.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Revised: 01/22/2013] [Accepted: 03/08/2013] [Indexed: 10/27/2022]
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Walker CL, Wang X, Bullis C, Liu NK, Lu Q, Fry C, Deng L, Xu XM. Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury. Exp Neurol 2014; 264:163-72. [PMID: 25510318 DOI: 10.1016/j.expneurol.2014.12.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Revised: 11/30/2014] [Accepted: 12/03/2014] [Indexed: 11/20/2022]
Abstract
Schwann cells (SCs) hold promise for spinal cord injury (SCI) repair; however, there are limitations for its use as a lone treatment. We showed that acute inhibition of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) by bisperoxovanadium (bpV) was neuroprotective and enhanced function following cervical hemicontusion SCI. We hypothesized that combining acute bpV therapy and delayed SC engraftment would further improve neuroprotection and recovery after cervical SCI. Adult female Sprague-Dawley (SD) rats were randomly sorted into 5 groups: sham, vehicle, bpV, SC transplantation, and bpV+SC transplantation. SCs were isolated from adult green fluorescent protein (GFP)-expressing SD rats (GFP-SCs). 200 μg/kg bpV(pic) was administered intraperitoneally (IP) twice daily for 7 days post-SCI in bpV-treated groups. GFP-SCs (1×10(6) in 5 μl medium) were transplanted into the lesion epicenter at the 8th day post-SCI. Forelimb function was tested for 10 weeks and histology was assessed. bpV alone significantly reduced lesion (by 40%, p<0.05) and cavitation (by 65%, p<0.05) and improved functional recovery (p<0.05) compared to injury alone. The combination promoted similar neuroprotection (p<0.01 vs. injury); however, GFP-SCs alone did not. Both SC-transplanted groups exhibited remarkable long-term SC survival, SMI-31(+) axon ingrowth and RECA-1(+) vasculature presence in the SC graft; however, bpV+SCs promoted an 89% greater axon-to-lesion ratio than SCs only. We concluded that bpV likely contributed largely to the neuroprotective and functional benefits while SCs facilitated considerable host-tissue interaction and modification. The combination of the two shows promise as an attractive strategy to enhance recovery after SCI.
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Affiliation(s)
- Chandler L Walker
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Xiaofei Wang
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Carli Bullis
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Nai-Kui Liu
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Qingbo Lu
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Colin Fry
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Lingxiao Deng
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Xiao-Ming Xu
- Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Goodman Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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White Matter Repair: Skin-Derived Precursors as a Source of Myelinating Cells. Can J Neurol Sci 2014; 37 Suppl 2:S34-41. [DOI: 10.1017/s0317167100022411] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
ABSTRACT:Stem cell based therapies hold great promise for repair and functional restoration following neurological injury and disease. Skin-derived precursors (or “SKPs”) are a novel, multipotent somatic stem cell that resides within the mammalian dermis. SKPs persist within the skin throughout adulthood and yet intriguingly, exhibit many similarities to embryonic neural crest stem cells (NCSCs). For example, SKPs give rise to both neural and mesodermal cell types, and the former appear biased to peripheral nervous system fates. As such, SKPs are capable of generating Schwann cells, the myelinating glial cell of the peripheral nervous system. Here we discuss our current understanding of the biological origin of SKPs and specifically the potential therapeutic utility of SKPs as a highly accessible and autologous source of Schwann cells for remyelination and repair of the injured or diseased nervous system.
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Leng Z, He X, Li H, Wang D, Cao K. Olfactory ensheathing cell transplantation for spinal cord injury: An 18-year bibliometric analysis based on the Web of Science. Neural Regen Res 2014; 8:1286-96. [PMID: 25206423 PMCID: PMC4107648 DOI: 10.3969/j.issn.1673-5374.2013.14.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2012] [Accepted: 02/22/2013] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Olfactory ensheathing cell (OEC) transplantation is a promising new approach for the treatment of spinal cord injury (SCI), and an increasing number of scientific publications are devoted to this treatment strategy. This bibliometric analysis was conducted to assess global research trends in OEC transplantation for SCI. DATA SOURCE All of the data in this study originate from the Web of Science maintained by the Institute for Scientific Information, USA, and includes SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, CCR-EXPANDED and IC. The Institute for Scientific Information's Web of Science was searched using the keywords "olfactory ensheathing cells" or "OECs" or "olfactory ensheathing glia" or "OEG" or "olfactory ensheathing glial cells" or "OEGs" and "spinal cord injury" or "SCI" or "spinal injury" or "spinal transection" for literature published from January 1898 to May 2012. DATA SELECTION Original articles, reviews, proceedings papers and meeting abstracts, book chapters and editorial materials on OEC transplantation for SCI were included. Simultaneously, unpublished literature and literature for which manual information retrieval was required were excluded. MAIN OUTCOME MEASURES ALL SELECTED LITERATURES ADDRESSING OEC TRANSPLANTATION FOR SCI WERE EVALUATED IN THE FOLLOWING ASPECTS: publication year, document type, language, author, institution, times cited, Web of Science category, core source title, countries/territories and funding agency. RESULTS In the Web of Science published by the Institute for Scientific Information, the earliest literature record was in April, 1995. Four hundred and fourteen publications addressing OEC transplantation for SCI were added to the data library in the past 18 years, with an annually increasing trend. Of 415 records, 405 publications were in English. Two hundred and fifty-nine articles ranked first in the distribution of document type, followed by 141 reviews. Thirty articles and 20 reviews, cited more than 55 times by the date the publication data were downloaded by us, can be regarded as the most classical references. The journal Experimental Neurology published the most literature (32 records), followed by Glia. The United States had the most literature, followed by China. In addition, Yale University was the most productive institution in the world, while The Second Military Medical University contributed the most in China. The journal Experimental Neurology published the most OEC transplantation literature in the United States, while Neural Regeneration Research published the most in China. CONCLUSION This analysis provides insight into the current state and trends in OEC transplantation for SCI research. Furthermore, we anticipate that this analysis will help encourage international cooperation and teamwork on OEC transplantation for SCI to facilitate the development of more effective treatments for SCI.
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Affiliation(s)
- Zikuan Leng
- Department of Orthopedics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Xijing He
- Department of Orthopedics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Haopeng Li
- Department of Orthopedics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Dong Wang
- Department of Orthopedics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
| | - Kai Cao
- Department of Orthopedics, the Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China
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