Benefit of Adjuvant Mesenchymal Stem Cell Transplantation to Critical-Sized Peripheral Nerve Defect Repair: A Systematic Review and Meta-Analysis of Preclinical Studies

Abstract

Critically sized nerve defects cause devastating life-long disabilities and require interposition for reconstruction. Additional local application of mesenchymal stem cells (MSCs) is considered promising to enhance peripheral nerve regeneration. To better understand the role of MSCs in peripheral nerve reconstruction, we performed a systematic review and meta-analysis of the effects of MSCs on critically sized segment nerve defects in preclinical studies. 5146 articles were screened following PRISMA guidelines using PubMed and Web of Science. A total of 27 preclinical studies (n = 722 rats) were included in the meta-analysis. The mean difference or the standardized mean difference with 95% confidence intervals for motor function, conduction velocity, and histomorphological parameters of nerve regeneration, as well as the degree of muscle atrophy, was compared in rats with critically sized defects and autologous nerve reconstruction treated with or without MSCs. The co-transplantation of MSCs increased the sciatic functional index (3.93, 95% CI 2.62 to 5.24, p < 0.00001) and nerve conduction velocity recovery (1.49, 95% CI 1.13 to 1.84, p = 0.009), decreased the atrophy of targeted muscles (gastrocnemius: 0.63, 95% CI 0.29 to 0.97 p = 0.004; triceps surae: 0.08, 95% CI 0.06 to 0.10 p = 0.71), and promoted the regeneration of injured axons (axon number: 1.10, 95% CI 0.78 to 1.42, p < 0.00001; myelin sheath thickness: 0.15, 95% CI 0.12 to 0.17, p = 0.28). Reconstruction of critically sized peripheral nerve defects is often hindered by impaired postoperative regeneration, especially in defects that require an autologous nerve graft. This meta-analysis indicates that additional application of MSC can enhance postoperative peripheral nerve regeneration in rats. Based on the promising results in vivo experiments, further studies are needed to demonstrate potential clinical benefits.

Keywords: MSC; nerve injury; nerve reconstruction; peripheral nerve; stem cell; trauma.

Figure 1

The related studies were searched and included according to the PRISMA guidelines.

Figure 2

Characteristics of the included studies [5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Abbr: AT = adipose tissue, BM = bone marrow, PCL = poly(ε-caprolactone), PDMS = poly-dimethylsiloxane.

Figure 3

Results of the bias assessment using SYRCLE’s risk of bias tool [5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Abbr: L = low, U = unknown.

Figure 4

The forest plot shows the effect of MSCs on the sciatic functional index 2 weeks, 4 weeks, and 12 weeks after surgery [5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Plots on the right-hand side indicate favoring MSCs or MSCs-loaded scaffolds, while plots on the left side indicate favoring placebo-control treatment or blank scaffolds.

Figure 5

Meta-analysis of the effects of MSCs on nerve conduction velocity 8–12 weeks after implantation [5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Plots on the right-hand side indicate favoring MSCs or MSCs-loaded scaffolds, while plots on the left side indicate favoring placebo-control treatment or blank scaffolds.

Figure 6

Meta-analysis of the weight of gastrocnemius muscles 6 weeks and 12 weeks after surgery [5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Plots on the right-hand side indicate favoring MSCs or MSCs-loaded scaffolds, while plots on the left side indicate favoring placebo-control treatment or blank scaffolds.

Figure 7

Meta-analysis of the effects of MSCs on axon number (middle and distal parts of the nerve defects) 8–10 weeks and 12–16 weeks after implantation [5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Plots on the right-hand side indicate favoring MSCs or MSCs-loaded scaffolds, while plots on the left side indicate favoring placebo-control treatment or blank scaffolds.

Figure 8

The forest plot shows the effect of MSCs on myelin thickness (middle and distal parts of the nerve defects) 12 weeks after surgery [5,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Plots on the left-hand side indicate favoring MSCs or MSCs-loaded scaffolds, while plots on the right side indicate favoring placebo-control treatment or blank scaffolds.