Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

Abstract

Background: No treatment is available to reverse injury associated with traumatic brain injury (TBI). Progenitor cell therapies show promise in both preclinical and clinical studies. We conducted a meta-analysis of preclinical studies using progenitor cells to treat TBI.

Methods: EMBASE, MEDLINE, Cochrane Review, Biosis, and Google Scholar were searched for articles using prespecified search strategies. Studies meeting inclusion criteria underwent data extraction. Analysis was performed using Review Manager 5.3 according to a fixed-effects model, and all studies underwent quality scoring.

Results: Of 430 abstracts identified, 38 met inclusion criteria and underwent analysis. Average quality score was 4.32 of 8 possible points. No study achieved a perfect score. Lesion volume (LV) and neurologic severity score (NSS) outcomes favored cell treatment with standard mean difference (SMD) of 0.86 (95% CI: 0.64-1.09) and 1.36 (95% CI: 1.11-1.60), respectively. Rotarod and Morris water maze outcomes also favored treatment with improvements in SMD of 0.34 (95% CI: 0.02-0.65) and 0.46 (95% CI: 0.17-74), respectively. Although LV and NSS were robust to publication bias assessments, rotarod and Morris water maze tests were not. Heterogeneity (I²) ranged from 74%-85% among the analyses, indicating a high amount of heterogeneity among studies. Precision as a function of quality score showed a statistically significant increase in the size of the confidence interval as quality improved.

Conclusions: Our meta-analysis study reveals an overall positive effect of progenitor cell therapies on LV and NSS with a trend toward improved motor function and spatial learning in different TBI animal models.

Keywords: Animal TBI model; Meta-analysis; Preclinical studies; Progenitor cells; Traumatic brain injury.

Figure 1:

Flow diagram of the studies evaluated.

Figure 2:

Forest plot of LV results. The fixed-effects pooled SMD for LV outcomes was −0.86 (95%CI −1.09, −0.64), which signifies a large treatment effect. A negative effect in this instance indicates a reduction in the size of the lesion volume and improvement after treatment. Heterogeneity was 85%, and p-value for the model was < 0.001.

Figure 3:

Forest plot of NSS results. The fixed-effects pooled SMD for NSS outcomes was −1.36 (95%CI −1.60, −1.11), which signifies a large treatment effect. A negative result indicates a lower degree of injury in those subjects treated with progenitor cell therapy. Heterogeneity was 80%, and p-value for the model was < 0.001.

Figure 4:

Forest plot of RR results. The fixed-effects pooled SMD for RR outcomes was 0.34 (95%CI 0.02, 0.65) which signifies a small to moderate treatment effect. A positive result indicates a better score on the RR test and overall improved outcome after treatment. Heterogeneity was 74%, and p-value for the model was 0.04.

Figure 5:

Forest plot of MWM results. The fixed-effects pooled SMD for MWM outcomes was −0.46 (95%CI −0.74, −0.17), which signifies a moderate treatment effect. A negative result indicates that the treated animals had a lower latency, or time to reach the platform in the MWM, and overall better outcomes. Heterogeneity was 84%, and p-value for the model was 0.002.

Figure 6:

Funnel plots depicting publication bias. Funnel plots show the reverse standard error on the Y-axis and the SMD on the X-axis. The vertical dotted line shows the pooled treatment effect, and diagonal lines show the 95% confidence interval if there is no heterogeneity or publication bias present. Publication bias can be seen by an absence of studies to the LEFT of the treatment effect in (A) the RR plot, and to the RIGHT of the treatment effect in (B) LV, (C) NSS, and (D) MWM. All outcomes evaluated were susceptible to varying degrees of publication bias. Trim-and-fill test indicated that (A) RR and (D) MWM lost their statistically significant treatment effect when adjusted, though (B) LV and (C) NSS retained their statistical significance.