Abstract
Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8–29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3–5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI.
Highlights
Cellular transplantation strategies applying different cellular sources have been tested in experimental spinal cord injury (SCI) models as a possible treatment to propagate functional recovery [1,2,3]
Given the conflicting results of these experiments, we investigate the in vivo evidence for the efficacy of Olfactory ensheathing cell (OEC) transplantation after traumatic experimental SCI, applying a systematic review and meta-analysis with the DerSimonian and Laird random effects model
Nine studies were excluded because they reported combined interventions (“cocktails”), three studies did not measure behavioral outcome, five studies had an inappropriate outcome scale, one study was a duplicate, one study was a review, one study did not transplant OECs, a further one did not include a control group, and six studies could not be taken into account due to statistical inconsistencies
Summary
Cellular transplantation strategies applying different cellular sources have been tested in experimental spinal cord injury (SCI) models as a possible treatment to propagate functional recovery [1,2,3]. Restoration of function after SCI remains one of the most formidable challenges in regenerative medicine, and the development of effective treatments is an unmet medical need. Pioneering studies by Ramón-Cueto and Nieto-Sampedro [4] reported the purification of olfactory ensheathing cells (OECs) to study regenerative paradigms and were followed by seminal work from the Raisman group, who showed that OEC transplants were populated by host axonal fibers after SCI, associated with neurological recovery [5]. OEC transplantation restored salutatory nerve conduction of sensory axons [10] and fostered the recovery of locomotion after SCI [11,12,13]. OEC transplantation can be classified as a bridging, non-relay approach [14]
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