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Skin Derived Precursor Schwann Cells Improve Behavioral Recovery for Acute and Delayed Nerve Repair
Helene T. Khuong1, Ferry Senjaya1, Ranjan Kumar1, Aleksandra Ivanovic1, Joanne Forden1, Jeff Biernaskie2 and Rajiv Midha, MD, MSc, FRCS(C)1
1Department of Clinical Neuroscience and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada,2 Department of Comparative Biology and Experimental Medicine, University of Calgary, Calgary, AB, Canada
Background and hypothesis: Previous work has shown that infusion of skin-derived precursors pre-differentiated into Schwann cell (SKP-SCs) can improve indices of axonal regeneration and electrophysiological parameters. We hypothesized that SKP-SCs therapy would improve behavioural outcomes for nerve injury repair.
Methods: 61 adult male Lewis rats were trained prior to surgery to perform a validated skilled locomotion task (horizontal ladder-rung). The animals underwent a right tibial nerve transection and were allocated to different groups within 2 arms - acute and delayed direct repair. In the acute repair arm, one group (n=10) received an injection of SKP-SCs distal to the repair site, another group (n=10) carrier medium and a third group (n=5) dead SKP-SCs. Animals were followed for 8 or 17 weeks. Additional animals (n=12 nerves) were included for histomorphometrical analysis at 4 weeks. In the delayed repair arm, both nerve ends were capped after transection to allow chronic denervation. Eleven weeks later, the nerve was directly repaired. Groups (n=8, each) received an injection of SKP-SCs, carrier medium or dead SKP-SCs. All animals were followed for 9 more weeks (total 20 weeks). Common control groups (n=6, each) underwent sham surgery or transection without repair. At defined time-points, a slip ratio was calculated as the number of slips by the injured limb over the total number of steps for the horizontal ladder-rung.
Results: Baseline slip ratios were similar across all groups, at 2-5%. Immediately after nerve injury and with chronic denervation, slip ratios were approximately 50%. In the ACUTE repair arm, the group with SKP-SCs showed marked improvement in slip ratio 5 weeks after surgery. The groups that received media and dead SKP-SCs both evolved with a much slower progression. In the DELAYED repair arm, the SKP-SCs group becoming significantly better than other groups 7 weeks after the repair, while the media and the dead SKP-SCs showed no significant improvement in slip ratios. On histomorphometrical analysis at 4 weeks, the group with SKP-SCs showed a significantly increased mean axon count while the percent myelin debris was significantly lower at both 4 and 8 weeks. For delayed repair, mean axon counts were significantly higher in the SKP-SCs group.
Conclusions: SKP-SCs therapy improves behavioural recovery in acute and chronic nerve repair beyond the current standard of microsurgical nerve repair. It does so by augmenting endogenous SC and enhancing myelin clearance, thereby making the nerve more hospitable to accelerated axonal regeneration in the denervated nerve microenvironment.
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