Stem cell transplantation in traumatic spinal cord injury:a systematic review and meta-analysis of animal studies

Spinal cord injury (SCI) is a devastating condition that causes substantial morbidity and mortality and for which no treatments are available. Stem cells offer some promise in the restoration of neurological function. We used systematic review, meta-analysis, and meta-regression to study the impact of stem cell biology and experimental design on motor and sensory outcomes following stem cell treatments in animal models of SCI. One hundred and fifty-six publications using 45 different stem cell preparations met our prespecified inclusion criteria. Only one publication used autologous stem cells. Overall, allogeneic stem cell treatment appears to improve both motor (effect size, 27.2%; 95% Confidence Interval [CI], 25.0%-29.4%; 312 comparisons in 5,628 animals) and sensory (effect size, 26.3%; 95% CI, 7.9%-44.7%; 23 comparisons in 473 animals) outcome. For sensory outcome, most heterogeneity between experiments was accounted for by facets of stem cell biology. Differentiation before implantation and intravenous route of delivery favoured better outcome. Stem cell implantation did not appear to improve sensory outcome in female animals and appeared to be enhanced by isoflurane anaesthesia. Biological plausibility was supported by the presence of a dose-response relationship. For motor outcome, facets of stem cell biology had little detectable effect. Instead most heterogeneity could be explained by the experimental modelling and the outcome measure used. The location of injury, method of injury induction, and presence of immunosuppression all had an impact. Reporting of measures to reduce bias was higher than has been seen in other neuroscience domains but were still suboptimal. Motor outcomes studies that did not report the blinded assessment of outcome gave inflated estimates of efficacy. Extensive recent preclinical literature suggests that stem-cell-based therapies may offer promise, however the impact of compromised internal validity and publication bias mean that efficacy is likely to be somewhat lower than reported here

Human Ischaemic Cascade Studies Using SH-SY5Y Cells: a Systematic Review and Meta-Analysis

Low translational yield for stroke may reflect the focus of discovery science on rodents rather than humans. Just how little is known about human neuronal ischaemic responses is confirmed by systematic review and meta-analysis revealing that data for the most commonly used SH-SY5Y human cells comprises only 84 papers. Oxygen-glucose deprivation, H2O2, hypoxia, glucose-deprivation and glutamate excitotoxicity yielded − 58, − 61, − 29, − 45 and − 49% injury, respectively, with a dose-response relationship found only for H2O2 injury (R2 = 29.29%, p I2 = 99.36%, df = 132, p R2 = 44.77%, p R2 = 28.64%, p R2 = 4.13%, p p 2O2 injury reported only improvement. In studies using glucose deprivation, intervention generally worsened outcome. There was insufficient data to rank individual interventions, but of the studies reporting greatest improvement (> 90% effect size), 7/13 were of herbal medicine constituents (24.85% of the intervention dataset). We conclude that surprisingly little is known of the human neuronal response to ischaemic injury, and that the large impact of methodology on outcome indicates that further model validation is required. Lack of evidence for randomisation, blinding or power analysis suggests that the intervention data is at substantial risk of bias

Systematic review and meta-analysis of therapeutic hypothermia in animal models of spinal cord injury

Therapeutic hypothermia is a clinically useful neuroprotective therapy for cardiac arrest and neonatal hypoxic ischemic encephalopathy and may potentially be useful for the treatment of other neurological conditions including traumatic spinal cord injury (SCI). The pre-clinical studies evaluating the effectiveness of hypothermia in acute SCI broadly utilise either systemic hypothermia or cooling regional to the site of injury. The literature has not been uniformly positive with conflicting studies of varying quality, some performed decades previously.In this study, we systematically review and meta-analyse the literature to determine the efficacy of systemic and regional hypothermia in traumatic SCI, the experimental conditions influencing this efficacy, and the influence of study quality on outcome. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of the (i) reporting of efficacy of hypothermia on functional outcome (ii) number of animals and (iii) mean outcome and variance in each group.Systemic hypothermia improved behavioural outcomes by 24.5% (95% CI 10.2 to 38.8) and a similar magnitude of improvement was seen across a number of high quality studies. The overall behavioural improvement with regional hypothermia was 26.2%, but the variance was wide (95% CI -3.77 to 56.2). This result may reflect a preponderance of positive low quality data, although a preferential effect of hypothermia in ischaemic models of injury may explain some of the disparate data. Sufficient heterogeneity was present between studies of regional hypothermia to reveal a number of factors potentially influencing efficacy, including depth and duration of hypothermia, animal species, and neurobehavioural assessment. However, these factors could reflect the influence of earlier lower quality literature.Systemic hypothermia appears to be a promising potential method of treating acute SCI on the basis of meta-analysis of the pre-clinical literature and the results of high quality animal studies

Meta-analysis of pre-clinical studies of early decompression in acute spinal cord injury:a battle of time and pressure

The use of early decompression in the management of acute spinal cord injury (SCI) remains contentious despite many pre-clinical studies demonstrating benefits and a small number of supportive clinical studies. Although the pre-clinical literature favours the concept of early decompression, translation is hindered by uncertainties regarding overall treatment efficacy and timing of decompression.We performed meta-analysis to examine the pre-clinical literature on acute decompression of the injured spinal cord. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of (i) the reporting of efficacy of decompression at various time intervals (ii) number of animals and (iii) the mean outcome and variance in each group. Random effects meta-analysis was used and the impact of study design characteristics assessed with meta-regression.Overall, decompression improved behavioural outcome by 35.1% (95%CI 27.4-42.8; I(2)=94%, p<0.001). Measures to minimise bias were not routinely reported with blinding associated with a smaller but still significant benefit. Publication bias likely also contributed to an overestimation of efficacy. Meta-regression demonstrated a number of factors affecting outcome, notably compressive pressure and duration (adjusted r(2)=0.204, p<0.002), with increased pressure and longer durations of compression associated with smaller treatment effects. Plotting the compressive pressure against the duration of compression resulting in paraplegia in individual studies revealed a power law relationship; high compressive forces quickly resulted in paraplegia, while low compressive forces accompanying canal narrowing resulted in paresis over many hours.These data suggest early decompression improves neurobehavioural deficits in animal models of SCI. Although much of the literature had limited internal validity, benefit was maintained across high quality studies. The close relationship of compressive pressure to the rate of development of severe neurological injury suggests that pressure local to the site of injury might be a useful parameter determining the urgency of decompression

Therapeutic potential of neuroepithelial cells on the injured rat spinal cord

© 2014 Dr. Taryn Elizabeth WillsHuman spinal cord injury is a devastating condition severely impacting the health and quality of life of affected individuals and their families. It is a neurological condition that results in the loss of both sensory and motor function within the central nervous system (CNS) as damaged cells (neurons) within the spinal cord are unable to regrow (regenerate). Recent research suggests that, in the rat, early embryonic spinal cord cells known as neuroepithelial cells (NE) may have the potential to form a supportive bridge across the wound site, stimulating damaged corticospinal tract (CST) axons and encouraging growth in the adult spinal cord after injury. The aims of this thesis were to (i) identify the in vitro characteristics of rat NE cells, (ii) examine regenerative potential of the embryonic rat spinal cord in utero, and (iii) examine the growth promoting potential of NE cells on CST axons after implantation into an adult rat spinal cord injury via histological and microarray techniques. Methods: Neuroepithelial cells were isolated from age specific rat embryos (embryonic day (E) 10.5 and E11.5) and characterised using histological techniques. Optimal age specific E11.5 NE cells (0hrs and 48hrs), as determined in vitro, were implanted into an adult rat spinal cord injury to examine the growth potential of these cells. RNA was also extracted from the age specific NE cells and the differences in gene expression examined via microarray analysis. Using precise surgical techniques, spinal cord regrowth potential after spinal cord injury was examined in embryonic rats. Results: Neuroepithelial cells less than 7 days old were characterised as cuboidal, undifferentiated ‘stem cell like’ cells with the potential to become CNS neurons and glia beyond one week of age. Neuroepithelial cells implanted into the adult injured spinal cord generate both scarring and neural cell pockets within the implant site. Significantly increased CST sprouting was observed within 0hr NE cell implants compared to 48hr NE cells and controls with sprouting axons associated with the presence of mature neurons, as opposed to the presence of both microglia/macrophages and blood vessels. A significant improvement in motor outcome was also observed. Microarray analysis identified a significant difference in selected neuronal gene expression between the two NE cell implantation time points, suggesting cellular age may be important in successful NE cell therapy. Due to a lack of tissue preservation, no regeneration was observed in embryonic rats after spinal cord injury at gestation E17-E20. Surgical limitations prevented surgery being performed at younger gestational stages. Conclusions: Young NE cells grown in culture display stem cell like qualities. Implanted NE cells demonstrate axonal regrowth potential with CST axons growing significantly further into the implant. However while neuronal rich regions vigorously stimulate growth, areas of scar tissue appear to form barriers preventing the passage of axons. Thus reducing the degree of scar formation may increase axonal growth within NE cell implants after rat spinal cord injury suggesting therapeutic benefit for the future

Treatment specific parameters of regional hypothermia experiments.

<p>Effect of (<b>A</b>) temperature range of hypothermia induction, (<b>B</b>) time of hypothermia administration, (<b>C</b>) duration of hypothermia and, (<b>D</b>) experimental cotreatment on the effect size reported within experiments employing regional hypothermia. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The width of each bar reflects the log of the number of animals contributing to that comparison. Each stratification accounts for a significant proportion of the heterogeneity observed between studies.</p

Model specific parameters of regional hypothermia experiments.

<p>Effect of (<b>A</b>) animal species, (<b>B</b>) anaesthetic, and (<b>C</b>) induction of injury used, on the effect size observed within experiments utilising regional hypothermia. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The width of each bar reflects the log of the number of animals contributing to that comparison. Each stratification accounts for a significant proportion of the heterogeneity observed between studies.</p

Publication bias.

<p>(<b>A</b>) Eggar regression showing publication bias within the included studies. (<b>B</b>) Funnel plot showing the regional data in black and the systemic data in grey. No additional studies were suggested by trim and fill analysis.</p

Heterogeneity within systemic hypothermia experiments.

<p>Effect of neurobehavioural scale used on effect size reported for experiments employing systemic hypothermia. The shaded gray bar represents the 95% confidence limits of the global estimate. The vertical error bars represent the 95% confidence intervals for the individual estimates. The width of each bar reflects the log of the number of animals contributing to that comparison. Each stratification accounts for a significant proportion of the heterogeneity observed between studies.</p