Challenging Dogma: Non-uniformity in regenerative potentials of nerves
Jenna-Lynn B Senger, MD, PhD1, Terence Kwan-Wong, MD, FRCSC2, Susanne Lingrell1, Ming Chan, MD3 and Christine A Webber, PhD1, (1)University of Alberta, Edmonton, AB, Canada, (2)Hospital for Sick Children, Toronto, ON, Canada, (3)Department of Plastic and Reconstructive Surgery, University of Alberta, Edmonton, AB, Canada
Background: Peripheral nerves are generally assumed to have a regeneration rate of approximately 1 mm per day, and prognostication of recovery is often hinged on this dogma. However, clinical observations suggest that certain nerves may have a higher likelihood of spontaneous or enhanced recovery following injury. To resolve this discrepancy, we compared the innate regenerative rates and mechanisms of eight nerves in the upper and lower extremities following nerve injury.
Methods: The regenerative potential of the Sprague-Dawley rat tibial, common fibular, sural, musculocutaneous, medial pectoral, median, ulnar, and radial nerves were measured. In the first cohort, tissue samples from naïve nerves, and three days following a nerve transection were collected and qRT-PCR analysis was performed to identify differences in gene expression. In the second cohort, the eight nerves were collected seven days following a cut and computation, and the length of axon regeneration was quantified immunohistochemically using NF200.
Results: Among the eight nerves studied, regeneration associated genes including GAP-43, ATF-3, GFAP, CNTF, and CREB3 were differentially expressed in the individual naïve nerves and three days following nerve transection (p<0.05). Expression of polysialytransferase (PST) and sialytransferase-X (STX), enzymes that contribute to polysialylated neuronal cell adhesion molecule (PSA-NCAM), suggest that these nerves have different specificity in preferential motor reinnervation (p<0.05). A direct comparison identified alterations in the lipid metabolism of sensory and motor nerves, as evidenced by significant differences in expression of sterol regulatory element-binding protein 1 (Srebp1c) and fatty acid synthase (fasn) (p<0.05). Similar to transcriptional changes, one week following nerve transection and repair, the length of axons extension of the sural and radial nerve was significantly longer than other nerves of the hindpaw and forepaw (p<0.05).
Conclusions: Our findings demonstrate that distinct nerves have different expressions of genes responsible for lipid metabolism, nerve regeneration, and axon guidance. Similarly, the rate of axon extension differs between nerves in the upper and lower extremity, and those of pure sensory, or mixed constituents. These results may have significant implications for prognosticating patients with peripheral nerve injury and identifying strategies for surgical interventions.
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