Local Environment Induces Differential Gene Expression in Regenerating Nerves

Approximately 80% of amputations are complicated by neuromas. Methods for neuroma management include nerve translocation into bone and implantation into skeletal muscle grafts, which have also facilitated the development of regenerative neural interfaces to enable fixation of prosthetics with motor and sensory feedback. However, molecular-level differences between nerves in these environments have not been investigated. This study aimed to elucidate the physiology of regenerating nerves in different settings by assessing gene expression.New Zealand white rabbits underwent transfemoral amputation with sciatic nerve transposition into the femur or tacked to skeletal muscle. At 5 wk, ribonucleic acid (RNA) sequencing of samples of distal nerve terminating in bone or muscle and nerve of the contralateral limb (control) identified differentially expressed genes (DEGs) and biochemical pathways (α = 0.05).Three samples of nerve housed in bone, four of nerve tacked to muscle, and seven naïve controls were analyzed. Relative to controls, nerve housed in bone had little within-group variation and 13,028 DEGs, and nerve tacked to muscle had dramatic within-group variation and 12,811 DEGs. These samples upregulated the following pathways: lysosome, phagosome, antigen processing/presentation, and cell adhesion molecule. Relative to nerve housed in bone, nerve tacked to muscle had 12,526 DEGs, demonstrating upregulation of pathways of B-cell receptor signaling, focal adhesion, natural killer-cell mediated cytotoxicity, leukocyte transendothelial migration, and extracellular matrix-receptor interactions.Nerve housed in bone has a more predictable molecular profile than does nerve tacked to muscle. Thus, the intramedullary canal may provide a more reliable setting for neuroma prevention and neural interfacing.