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      Chronic spinal cord injury treated with transplanted autologous bone marrow-derived mesenchymal stem cells tracked by magnetic resonance imaging: a case report

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          Abstract

          Introduction

          Intrathecal transplantation is a minimally invasive method for the delivery of stem cells, however, whether the cells migrate from the lumbar to the injured cervical spinal cord has not been proved in humans. We describe an attempt to track bone marrow-derived mesenchymal stem cells in a patient with a chronic cervical spinal cord injury.

          Case presentation

          A 33-year-old Thai man who sustained an incomplete spinal cord injury from the atlanto-axial subluxation was enrolled into a pilot study aiming to track bone marrow-derived mesenchymal stem cells, labeled with superparamagnetic iron oxide nanoparticles, from intrathecal transplantation in chronic cervical spinal cord injury. He had been dependent on respiratory support since 2005. There had been no improvement in his neurological function for the past 54 months. Bone marrow-derived mesenchymal stem cells were retrieved from his iliac crest and repopulated to the target number. One half of the total cells were labeled with superparamagnetic iron oxide nanoparticles before transplantation to the intrathecal space between L4 and L5. Magnetic resonance imaging studies were performed immediately after the transplantation and at 48 hours, two weeks, one month and seven months after the transplantation. His magnetic resonance imaging scan performed immediately after the transplantation showed hyposignal intensity of paramagnetic substance tagged stem cells in the subarachnoid space at the lumbar spine area. This phenomenon was observed at the surface around his cervical spinal cord at 48 hours. A focal hyposignal intensity of tagged bone marrow-derived stem cells was detected at his cervical spinal cord with magnetic resonance imaging at 48 hours, which faded after two weeks, and then disappeared after one month. No clinical improvement of the neurological function had occurred at the end of this study. However, at 48 hours after the transplantation, he presented with a fever, headache, myalgia and worsening of his motor function (by one grade of all key muscles by the American Spinal Injury Association impairment scale), which lasted for 48 hours.

          Conclusion

          Intrathecal injection of bone marrow-derived stem cells at the lumbar spine level could deliver the cells to the injured cervical spinal cord. Transient complications should be observed closely in the first 48 hours after transplantation. Further study should be carried out to evaluate the result of the treatment.

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          Most cited references26

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          Adult rat and human bone marrow stromal cells differentiate into neurons.

          Bone marrow stromal cells exhibit multiple traits of a stem cell population. They can be greatly expanded in vitro and induced to differentiate into multiple mesenchymal cell types. However, differentiation to non-mesenchymal fates has not been demonstrated. Here, adult rat stromal cells were expanded as undifferentiated cells in culture for more than 20 passages, indicating their proliferative capacity. A simple treatment protocol induced the stromal cells to exhibit a neuronal phenotype, expressing neuron-specific enolase, NeuN, neurofilament-M, and tau. With an optimal differentiation protocol, almost 80% of the cells expressed NSE and NF-M. The refractile cell bodies extended long processes terminating in typical growth cones and filopodia. The differentiating cells expressed nestin, characteristic of neuronal precursor stem cells, at 5 hr, but the trait was undetectable at 6 days. In contrast, expression of trkA, the nerve growth factor receptor, persisted from 5 hr through 6 days. Clonal cell lines, established from single cells, proliferated, yielding both undifferentiated and neuronal cells. Human marrow stromal cells subjected to this protocol also differentiated into neurons. Consequently, adult marrow stromal cells can be induced to overcome their mesenchymal commitment and may constitute an abundant and accessible cellular reservoir for the treatment of a variety of neurologic diseases. Copyright 2000 Wiley-Liss, Inc.
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            Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis.

            To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). A phase 1/2 open-safety clinical trial. Patients  Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention  After culture, a mean (SD) of 63.2 × 10(6) (2.5 × 10(6)) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex). The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation. Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4(+)CD25(+) regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40(+), CD83(+), CD86(+), and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation. Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects. Trial Registration  clinicaltrials.gov Identifier: NCT00781872.
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              Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome.

              Several studies have reported functional improvement after transplantation of neural stem cells into injured spinal cord. We now provide evidence that grafting of adult neural stem cells into a rat thoracic spinal cord weight-drop injury improves motor recovery but also causes aberrant axonal sprouting associated with allodynia-like hypersensitivity of forepaws. Transduction of neural stem cells with neurogenin-2 before transplantation suppressed astrocytic differentiation of engrafted cells and prevented graft-induced sprouting and allodynia. Transduction with neurogenin-2 also improved the positive effects of engrafted stem cells, including increased amounts of myelin in the injured area, recovery of hindlimb locomotor function and hindlimb sensory responses, as determined by functional magnetic resonance imaging. These findings show that stem cell transplantation into injured spinal cord can cause severe side effects and call for caution in the consideration of clinical trials.
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                Author and article information

                Contributors
                areesak.cho@mahidol.ac.th
                monchai.ortho@gmail.com
                pipat8999@yahoo.com
                adisak.won@mahidol.ac.th
                kittipong.suj@mahidol.ac.th
                Journal
                J Med Case Rep
                J Med Case Rep
                Journal of Medical Case Reports
                BioMed Central (London )
                1752-1947
                9 April 2015
                9 April 2015
                2015
                : 9
                : 79
                Affiliations
                [ ]Department of Orthopaedic Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Rd, Bangkoknoi, Bangkok 10700 Thailand
                [ ]Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Rd, Bangkoknoi, Bangkok 10700 Thailand
                [ ]Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Rd, Bangkoknoi, Bangkok 10700 Thailand
                [ ]Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Rd, Bangkoknoi, Bangkok 10700 Thailand
                Article
                535
                10.1186/s13256-015-0535-6
                4414006
                25885347
                32f3e8a5-988e-4d6c-891b-51cc61e972f4
                © Chotivichit et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 18 September 2014
                : 28 January 2015
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2015

                Medicine
                spinal cord injury,mesenchymal stem cells,superparamagnetic iron oxide,magnetic resonance imaging,tracking

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