Stem Cell Transplantation in Traumatic Spinal Cord Injury: A Systematic Review and Meta-Analysis of Animal Studies

Abstract

A systematic analysis of the literature shows that stem cell implantation can improve function in animal models of spinal cord injury, depending on the methods used.

Abstract

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.

Author Summary

Spinal cord injury is an important cause of disability in young adults, and stem cells have been proposed as a possible treatment. Here we systematically assess the evidence in the scientific literature for the effectiveness of stem-cell–based therapies in animal models of spinal cord injury. More studies reported effects on the ability to move (“motor outcomes”) than on sensation (“sensory outcomes”). Overall, treatment improves both sensory and motor outcomes, and for sensory outcome there was a dose–response effect (which suggests an underlying biological basis). Although more measures were taken to reduce the risk of bias than in other areas of translational neuroscience, unblinded studies tended to overstate the effectiveness of the treatment. The variability observed between the studies is not explained by differences in the stem cells used, but does seem to depend on the different injury models used to emulate human spinal cord injury. This suggests that the mechanism of injury should be an important consideration in the design of future clinical trials. Furthermore, open questions arise about the use of immunosuppressive drugs, and efficacy in female animals; these should be addressed before proceeding to clinical trial.