Transplantation of bone marrow stem cells into spinal cord lesions enhances axonal regeneration and promotes functional recovery in animal studies. There are two types of adult bone marrow stem cell; hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). The mechanisms by which HSCs and MSCs might promote spinal cord repair following transplantation have been extensively investigated. The objective of this review is to discuss these mechanisms; we briefly consider the controversial topic of HSC and MSC transdifferentiation into central nervous system cells but focus on the neurotrophic, tissue sparing, and reparative action of MSC grafts in the context of the spinal cord injury (SCI) milieu. We then discuss some of the specific issues related to the translation of HSC and MSC therapies for patients with SCI and present a comprehensive critique of the current bone marrow cell clinical trials for the treatment of SCI to date. Stem Cells 2011;29:169–178
Study design:This is a mixed-method consensus development project.Objectives:The objective of this study was to identify a top ten list of priorities for future research into spinal cord injury (SCI).Setting:The British Spinal Cord Injury Priority Setting Partnership was established in 2013 and completed in 2014. Stakeholders included consumer organisations, healthcare professional societies and caregivers.Methods:This partnership involved the following four key stages: (i) gathering of research questions, (ii) checking of existing research evidence, (iii) interim prioritisation and (iv) a final consensus meeting to reach agreement on the top ten research priorities. Adult individuals with spinal cord dysfunction because of trauma or non-traumatic causes, including transverse myelitis, and individuals with a cauda equina syndrome (henceforth grouped and referred to as SCI) were invited to participate in this priority setting partnership.Results:We collected 784 questions from 403 survey respondents (290 individuals with SCI), which, after merging duplicate questions and checking systematic reviews for evidence, were reduced to 109 unique unanswered research questions. A total of 293 people (211 individuals with SCI) participated in the interim prioritisation process, leading to the identification of 25 priorities. At a final consensus meeting, a representative group of individuals with SCI, caregivers and health professionals agreed on their top ten research priorities.Conclusion:Following a comprehensive, rigorous and inclusive process, with participation from individuals with SCI, caregivers and health professionals, the SCI research agenda has been defined by people to whom it matters most and should inform the scope and future activities of funders and researchers for the years to come.Sponsorship:The NIHR Oxford Biomedical Research Centre provided core funding for this project.
Study design: Previous studies have shown that transplantation of bone marrow stromal cells (MSCs) in animal models of spinal cord injury (SCI) encourages functional recovery. Here, we have examined the growth in cell culture of MSCs isolated from individuals with SCI, compared with non-SCI donors. Setting: Centre for Spinal Studies, Midland Centre for Spinal Injuries, RJAH Orthopaedic Hospital, Oswestry, UK. Methods: Bone marrow was harvested from the iliac crest of donors with long-term SCI (43 months, n ¼ 9) or from non-SCI donors (n ¼ 7). Mononuclear cells were plated out into tissue culture flasks and the adherent MSC population subsequently expanded in monolayer culture. MSC were passaged by trypsinization at 70% confluence and routinely seeded into new flasks at a density of 5 Â 10 3 cells per cm 2 . Expanded cell cultures were phenotypically characterized by CD-immunoprofiling and by their differentiation potential along chondrocyte, osteoblast and adipocyte lineages. The influence of cellseeding density on the rate of cell culture expansion and degree of cell senescence was examined in separate experiments. Results: In SCI, but not in non-SCI donors the number of adherent cells harvested at passage I was age-related. The proliferation rate (culture doubling times) between passages I and II was significantly greater in cultures from SCI donors with cervical lesions than in those with thoracic lesions. There was no significant difference, however, in either the overall cell harvests at passages I or II or in the culture doubling times between SCI and non-SCI donors. At passage II, more than 95% of cells were CD34Àve, CD45Àve and CD105 þ ve, which is characteristic of human MSC cultures. Furthermore, passage II cells differentiated along all three mesenchymal lineages tested. Seeding passage I-III cells at cell densities lower than 5 Â 10 3 cells per cm 2 significantly reduced culture doubling times and significantly increased overall cell harvests while having no effect on cell senescence. Conclusion: MSCs from individuals with SCI can be successfully isolated and expanded in culture; this is encouraging for the future development of MSC transplantation therapies to treat SCI. Age, level of spinal injury and cell-seeding density were all found to relate to the growth kinetics of MSC cultures in vitro, albeit in a small sample group. Therefore, these factors should be considered if either the overall number or the timing of MSC transplantations post-injury is found to relate to functional recovery.
For research purposes on the integrity of the spinal sympathetic pathways, a battery of test approach is probably needed, using a combination of stimuli above and below the lesion, evaluating both cardiovascular and sudomotor pathways.
The management of the traumatic spinal cord injury remains controversial. Guttmann demonstrated that with simultaneous attention to all medical and non-medical effects of the spinal cord injury, a significant number of patients recovered motor and sensory functions to ambulate and the majority were pain-free following conservative management. Active physiological conservative management of the spinal injury requires simultaneous scrupulous care of the injured spine together with; the multisystem neurogenic effects of the spinal cord injury on the respiratory, cardiovascular, urinary, gastrointestinal, dermatological, sexual and reproductive functions; the management of the associated psychological effects of paralysis from the early hours or days of injury as well as; the physical rehabilitation and modification of the environment. To date, there is no evidence to suggest that the surgical decompression and/or stabilisation of the neurologically impaired spinal cord injury patient is advantageous. This article considers the debates and evidence of surgical management including the effects of timing of the surgical decompression. Also addressed are the factors influencing decisions on management, prognostic indicators of recovery and natural history of complete and incomplete cord injuries. Traumatic biomechanical instability of the spine, physiological instability of the spinal cord, traumatic spinal canal encroachment and traumatic cord compression are also discussed. Early mobilisation, indications for surgery at the RJAH and economic considerations of spinal cord injuries are presented. The ultimate goals of the active physiological conservative management are to ensure maximum neurological recovery and independence, a painfree and flexible spine, safe and convenient functioning of the various systems of the body with minimal inconvenience to patients and the prevention of complications.
BACKGROUND CONTEXT: Transplantation of bone marrow cells into spinal cord lesions promotes functional recovery in animal models and recent clinical trials suggest possible recovery also in humans. The mechanisms responsible for these improvements are still unclear. PURPOSE: To characterise spinal cord motor neurite interactions with human bone marrow stromal cells (MSC) in an in vitro model of spinal cord injury (SCI). STUDY DESIGN/SETTING: Previously we have reported that human MSC promote the growth of extending sensory neurites from dorsal root ganglia (DRG), in the presence of some of the molecules present in the glial scar which are attributed with inhibiting axonal regeneration following SCI. We have adapted and optimized this system replacing the DRG with a spinal cord culture to produce a central nervous system (CNS) model which is more relevant to the SCI situation. METHODS: We have developed and characterised a novel spinal cord culture system. Human MSC were co-cultured with spinal motor neurites in substrate choice assays containing glial scar associated inhibitors of nerve growth. In separate experiments MSC conditioned media was analysed and added to spinal motor neurites in substrate choice assays. RESULTS: As has been reported previously with DRG, substrate-bound neurocan and Nogo-A repelled spinal neuronal body adhesion and neurite outgrowth, but these inhibitory effects were abrogated in MSC/ spinal cord co-cultures. However, unlike DRG, spinal neuronal bodies and neurites showed no inhibition to substrates of myelin associated glycoprotein. In addition, the MSC secretome contained numerous neurotrophic factors which stimulated spinal neurite outgrowth, but these were not sufficient stimuli to promote spinal neurite extension over inhibitory concentrations of neurocan or Nogo-A. CONCLUSIONS: These findings provide novel insight into how MSC transplantation may promote regeneration and functional recovery in animal models of SCI and in the clinic, especially in the chronic situation where glial scars (and associated neural inhibitors) are well established. In addition, we have confirmed that this CNS model predominantly comprises of motor neurons via immunocytochemical characterisation. We hope that this model may be used in future research to test various other potential interventions for spinal injury or disease states.
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