Adipose Stem Cells Enhance Nerve Regeneration and Muscle Function In A Peroneal Nerve Ablation Model.

Severe peripheral nerve injuries have devastating consequences on quality of life in affected patients, and represent a significant unmet medical need. Destruction of nerve fibers results in denervation of targeted muscles, which subsequently undergo progressive atrophy and loss of function. Timely restoration of neural innervation to muscle fibers is crucial to preservation of muscle homeostasis and function. The goal of this study was to evaluate the impact of addition of adipose stem cells (ASCs) to polycaprolactone (PCL) nerve conduit guides on peripheral nerve repair and functional muscle recovery in the setting of a critical size nerve defect. To this end, peripheral nerve injury was created by surgically ablating 6 mm of the common peroneal nerve in a rat model. A PCL nerve guide, filled with ASCs and/or Poloxamer hydrogel, was sutured to the nerve ends. Negative and positive controls included nerve ablation only (no repair), and reversed polarity autograft nerve implant, respectively. Tibialis anterior muscle (TA) function was assessed at 4, 8 and 12 weeks post-injury, and nerve and muscle tissue was retrieved at the 12 week terminal time point. Inclusion of ASCs in the PCL nerve guide elicited statistically significant time-dependent increases in functional recovery (contraction) after denervation; ~25% higher than observed in acellular (poloxamer-filled) implants and indistinguishable from autograft implants, respectively, at 12 weeks post-injury (p<0.05, n=7-8 in each group). Analysis of single muscle fiber cross-sectional area (CSA) revealed that ASC-based treatment of nerve injury provided a better recapitulation of the overall distribution of muscle fiber CSAs observed in the contralateral TA muscle of uninjured limbs. In addition, the presence of ASCs was associated with improved features of re-innervation distal to the defect, with respect to neurofilament and S100 (Schwann cell marker) expression. In conclusion, these initial studies indicate significant benefits of inclusion of ASCs to the rate and magnitude of both peripheral nerve regeneration and functional recovery of muscle contraction-to levels equivalent to autograft. These findings have important implications to improved nerve repair, and provide input for future work directed to restoration of nerve and muscle function following polytraumatic injury.