Skin derived precursor Schwann cells improve behavioral recovery for acute and delayed nerve repair.
Previous work has shown that infusion of skin-derived precursors pre-differentiated into Schwann cells (SKP-SCs) can remyelinate injured and regenerating axons, and improve indices of axonal regeneration and electrophysiological parameters in rodents. We hypothesized that SKP-SC therapy would improve behavioral outcomes following nerve injury repair and tested this in a pre-clinical trial in 90 rats. A model of sciatic nerve injury and acellular graft repair was used to compare injected SKP-SCs to nerve-derived Schwann cells or media, and each was compared to the gold standard nerve isograft repair. In a second experiment, rats underwent right tibial nerve transection and received either acute or delayed direct nerve repair, with injections of either 1) SKP-SCs distal to the repair site, 2) carrier medium alone, or 3) dead SKP-SCs, and were followed for 4, 8 or 17weeks. For delayed repairs, both transected nerve ends were capped and repaired 11weeks later, along with injections of cells or media as above, and followed for 9 additional weeks (total of 20weeks). Rats were serially tested for skilled locomotion and a slip ratio was calculated for the horizontal ladder-rung and tapered beam tasks. Immediately after nerve injury and with chronic denervation, slip ratios were dramatically elevated. In the GRAFT repair study, the SKP-SC treated rats showed statistically significant improvement in ladder rung as compared to all other groups, and exhibited the greatest similarity to the sham controls on the tapered beam by study termination. In the ACUTE repair arm, the SKP-SC group showed marked improvement in ladder rung slip ratio as early as 5weeks after surgery, which was sustained for the duration of the experiment. Groups that received media and dead SKP-SCs improved with significantly slower progression. In the DELAYED repair arm, the SKP-SC group became significantly better than other groups 7weeks after the repair, while the media and the dead SKP-SCs showed no significant improvement in slip ratios. On histomorphometrical analysis, SKP-SC group showed significantly increased mean axon counts while the percent myelin debris was significantly lower at both 4 and 8weeks, suggesting that a less inhibitory micro-environment may have contributed to accelerated axonal regeneration. For delayed repair, mean axon counts were significantly higher in the SKP-SC group. Compound action potential amplitudes and muscle weights were also improved by cell therapy. In conclusion, SKP-SC therapy improves behavioral recovery after acute, chronic and nerve graft repair beyond the current standard of microsurgical nerve repair.
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada; Service de Neurochirurgie, Département des Sciences Neurologiques, CHU-de Québec (Hôpital de l'Enfant-Jésus), Centre de Recherché du CHU-de Québec, Canada; Division de Neurochirurgie, Département de Chirurgie, Université Laval, 1401, 18e rue, Québec, Québec G1J 1Z4, Canada.
Helene T
HT
Khuong
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Ranjan
R
Kumar
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Ferry
F
Senjaya
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Joey
J
Grochmal
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Aleksandra
A
Ivanovic
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Antos
A
Shakhbazau
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Joanne
J
Forden
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Aubrey
A
Webb
Alberta Children's Hospital Research Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada.
Jeffrey
J
Biernaskie
Hotchkiss Brain Institute and Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N4N1, Canada. Electronic address: rajmidha@ucalgary.ca.
Rajiv
R
Midha
D000208:Acute Disease; D053687:Adult Stem Cells / Q000166:cytology / Q000637:transplantation*; D000818:Animals; D000831:Animals, Newborn; D020405:Dermis / Q000166:cytology* / Q000294:innervation; D005260:Female; D008297:Male; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000294:innervation; D009416:Nerve Regeneration / Q000502:physiology*; D059348:Peripheral Nerve Injuries / Q000473:pathology / Q000628:therapy*; D061251:Primary Cell Culture; D051381:Rats; D011917:Rats, Inbred Lew; D012583:Schwann Cells / Q000166:cytology / Q000637:transplantation*; D012584:Sciatic Nerve / Q000166:cytology; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors
Behavior; Cell therapy; Locomotion; Nerve graft; Nerve regeneration