Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations

Neuhuber, Birgit; Himes, B. Timothy; Shumsky, Jed S.; Gallo, Gianluca; Fischer, Itzhak

doi:10.1016/j.brainres.2004.11.055

Cited by 297 publications

(237 citation statements)

References 60 publications

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“…1 Somewhat surprisingly, MSCs have received considerable interest as possible donor cells in the development of cell transplantation therapies for spinal cord injury (SCI). [2][3][4][5][6][7] There are, however, a number of reasons for this. First and foremost, MSC transplantation has been demonstrated to enhance axonal regeneration and promote functional recovery in a variety of animal models of SCI.…”

Section: Introductionmentioning

confidence: 99%

“…First and foremost, MSC transplantation has been demonstrated to enhance axonal regeneration and promote functional recovery in a variety of animal models of SCI. [2][3][4][5][6][7] These studies have shown that transplanted MSCs integrate into host tissue following transplantation, supporting and remyelinating axons that traverse the injury site. MSCs also synthesize a number of growth factors that may contribute to tissue sparing and axonal regeneration, including nerve growth factor and brain-derived neurotrophic factor.…”

Section: Introductionmentioning

confidence: 99%

“…8 Importantly, though, MSCs represent an attractive donor source for various cell transplantation programmes, as they can be repeatedly isolated from bone marrow with relative ease, normally expanded into large numbers in vitro and reintroduced into patients as autografts, which prevents the need for immune rejection drugs in the clinical setting. 9 If donor cell number is a critical factor to the success of cell grafting for SCI treatment, as is likely to be the case, then it is important to note that the typical injury in rodent models of SCI is only a few millimetres in length, [2][3][4][5][6][7] whereas the length of lesions in humans can reach several centimetres. Recently, using an in vitro model, we have shown that human MSCs promote nerve growth over inhibitory molecules present at the lesion site in SCI; furthermore, the number of nerves that were subsequently able to grow over these molecules was related to the number of MSCs present.…”

Section: Introductionmentioning

confidence: 99%

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The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy

et al. 2008

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy

et al. 2008

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“…[54][55][56] Differentiation into defined cell types such as Schwann cells might further improve the outcome, 57 as might selection of MSCs from different donors because not all donors produce similarly effective cells, presumably because of the repertoire of cytokines and modulatory molecules that they produce. 58 An alternative source of adult transplantable cells with repair potential are olfactory ensheathing cells. 59 Two types of cells are generated from cultures of primary olfactory tissue: although both are essential for the reparative effect, the precise lineage relationship of the two cell types is not fully understood.…”

Section: Vertical Targetmentioning

confidence: 99%

International spinal research trust research strategy. III: A discussion document

Adams¹,

Carlstedt

Cavanagh³

et al. 2006

Spinal Cord

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Study design: Discussion document. Objectives/methods: To review the Research Strategy of the International Spinal Research Trust (ISRT), which identifies key areas of basic and clinical research that are likely to be beneficial in developing potential treatments for spinal cord injury for funding. This strategy is intended to both guide the programme of research towards areas of priority and stimulate discussion of the different avenues of research. This latest document has been developed to take into account the scientific progress in the 6 years since publication of the previous Research Strategy. Results/discussion: The latest scientific developments in research designed to repair the spinal cord and restore function following injury and how they might impact on spinal cord injury research are highlighted. Sponsored by: ISRT.

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“…The increased IL-6 may reflect a harmful process as an injurious mediator and a negative effect on neuroprotection. For example, IL-6 is a detrimental player contributing to the pathogenesis of many spinal cord diseases, for example, cervical spondylotic myelopathy and spinal cord injury (6)(7)(8). However, the increase of IL-6 may also represent a compensative mechanism for neural repair.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons

Chen

Sheng

et al. 2013

Acta Neuropsychiatr.

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ObjectiveInterleukin-6 (IL-6) is a pleiotropic proinflammatory cytokine that plays a key role in the injuries and diseases of the central nervous system (CNS). A voltage-gated Na+ channel (VGSC) is essential for the excitability and electrical properties of the neurons. However, there is still limited information on the role of IL-6 in voltage-gated sodium channels. Our study aimed to investigate the effects of IL-6 on Na+ currents in cultured spinal-cord neurons.MethodsVGSC currents were activated and recorded using whole-cell patch-clamp technique in the cultured rat spinal cord neurons. The effects of IL-6 concentration and exposure duration were examined. To determine whether any change in the number of channels in the plasma membrane can inhibit IL-6 on VGSC currents, we examined the expression of α1A (SCN1α) subunit mRNA level and protein level in the neurons before and after IL-6 induction using real-time polymerase chain reaction.ResultsWe verified that IL-6, through a receptor-mediated mechanism, suppressed Na+ currents in a time- and dose-dependent manner, but did not alter the voltage-dependent activation and inactivation. Gp130 was involved in this inhibition. Furthermore, the spike amplitude was also inhibited by IL-6 in the doses that decreased the Na+ currents.ConclusionVGSC currents are significantly inhibited by IL-6. Our findings reveal that the potential neuroprotection of IL-6 may result from the inhibitory effects on VGSC currents.

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Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations

Cited by 297 publications

References 60 publications

The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy

The cell culture expansion of bone marrow stromal cells from humans with spinal cord injury: implications for future cell transplantation therapy

International spinal research trust research strategy. III: A discussion document

Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons

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