Introduction: Unlike visceral organ transplants, vascular composite allotransplantation such as limb and face require successful nerve regeneration and reinnervation of graft motor and sensory targets for optimal functional recovery. We investigated whether administration of mesenchymal stem cells (MSCs) and novel biologic factors can improve functional recovery in a nerve transection repair model. Methods: Under general anesthesia the right hind limb (femoral region) of the Lewis rat was exposed, the sciatic nerve branches (tibial, peroneal and sural) were identified and transected. The transected nerves were left for an hour without any manipulation; then the epineurium of the proximal and distal ends of respective transected nerves were approximated using 10-O sutures. Autologous bone marrow derived MSCs (5 x10⁶; passage ≤6), G-CSF (50 ¯o;g/kg), Dihexa (2 mg/kg) or Vehicle were administered locally at the nerve repair sites and intravenously. The motor (walking track analysis) and sensory (cutaneous reaction test) functions were assessed at 1-2 week intervals following nerve repair. Results: MSCs expanded ex vivo were positive (CD29, CD90, MHC Class I, CD45^low) and negative (CD34, CD31, Class II) for MSC specific cell surface markers. MSCs were pluripotent as determined by ex vivo differentiation in to adipocytes, osteocytes and chondrocytes. At two weeks post nerve repair, total sensory nerve function (peroneal, tibial and sural) in all groups was ∼1.5 on a scale of Grade 0-3 (0=No function; 3= Normal function). However, at two weeks the tibial nerve function in all groups ranged from 0.12 to 0.75; by 4 weeks it was 1.5±1.0 , 2.0±0.9, 1.4±0.8, and 1.1±0.6 in MSC, Dihexa, G-CSF and Vehicle treated groups, respectively. At 8 weeks, sensory function was ≥2.5 in all treatment and nerve repair groups (n≥6/group). The peroneal nerve sensory function recovery was as early as one week (≥2) but not tibial or sural nerve function (∼0.5). At five weeks post nerve repair, the sciatic nerve function index (SFI) a measure of motor function (0=normal function; -100=nonfunctional) was ∼ -50 in G-CSF, and ∼ -80 in MSC, Dihexa, and Vehicle treated groups. By 12 weeks, SFI in G-CSF group was -25 and in all other groups it ranged from -60 to -70. Gastrocnemius muscle atrophy was 75, 73, and 70% in Vehicle, G-CSF, and Dihexa groups, respectively. Conclusions: MSC and novel biologic therapies studied appear to promote sensory and motor nerve functional recovery.

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