The Interaction Between Mesenchymal Stem Cells, Neoangiogenesis And Functional Outcomes Of Processed Nerve Allografts In Peripheral Nerve Repair
Femke Mathot, MD1,2; Nadia Rbia, MD1,2; Mana Saffari, MD1,2; Allen T. Bishop, MD3; Alexander Y. Shin, MD4
1Mayo Clinic, Rochester, MN, 2Erasmus MC, Rotterdam, Netherlands, 3Microvascular Research Laboratory, Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, 4Department of Orthopedic Surgery, Microvascular Research Laboratory, Mayo Clinic, Rochester, MN
We hypothesized that the growth factors produced by undifferentiated MSCs (uMSCs) and MSCs differentiated into Schwann-like cells (dMSCs) seeded on a processed nerve allograft lead to enhanced angiogenesis which also provides extra neurotrophic growth factors to a regenerating nerve. Therefore, we expected this interaction to result in improved functional outcomes.
10mm Sciatic nerve grafts were obtained from Sprague-Dawley Rats, decellularized and transplanted back into Lewis rats. Before transplantation, 5 nerve allografts per group were seeded with either nothing (group II), 1 million uMSCs (group III) or 1 million MSCs differentiated into Schwann cell-like cells (group IV). These groups were compared with nerve autografts (group I). After 16 weeks, ITF, CMAP and tibial muscle mass were obtained. The vasculature of the nerve was preserved by aortic infusion of Microfil. The nerve grafts were dissected and with micro-CT and conventional photography, respectively the volume and the surface area of the vasculature were obtained. All outcomes were measured as a ratio of the untreated side and were analyzed blindly. The outcomes were compared using one way ANOVA analysis and multiple comparisons tests with Tukey-Kramer correction. The Pearson's correlation test was used to find correlations between the measurements.
The mean CMAP was the highest in group III, followed closely by group IV. The ITF results of group III and IV lagged the results of group I, but were better than those of group II. One way ANOVA showed no significant difference between groups for both outcome measures. In group IV, the highest vascular volume ratio and surface area ratio were found, followed by group I, group III and group II. One way ANOVA and multiple comparisons analysis showed significant differences between group IV and group II for the mean vascular surface area ratio (p<0.001). The vascular surface area measurements were significantly correlated to the vascular volume measurements (PC = 0.547; p=0.013) and the vascular surface area-measurements were significantly correlated to the ITF measurements (PC = 0.499; p=0.025).
MSC seeding seems to lead to better functional outcomes of processed nerve allografts, which is likely due to enhanced vascular ingrowth in the nerve allograft. This is supported by the significant correlation between the vascular surface area ratio and the ITF recovery. In our study, we successfully preserved the vasculature of nerves and objectively quantified the amount of neoangiogenesis. This study can function as a base for future research on the role of vascularity in nerve regeneration.
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