Priming the stump in peripheral nerve injury (Commentary on Zhang et al. (2017))

Nerve transfers have made the transition into clinical use (Rinker, 2015). These procedures transfer a nerve to a denervated recipient nerve stump in order to mitigate an important functional loss with one less critical. Classical examples like the Oberlin transfer, where portions of the ulnar nerve are donated to the biceps muscle, have proven to be very effective, whereas other transfers are not as reliable (Giuffre et al., 2015). The critical focus of nerve transfer surgery is the optimisation of the number of neurons available for growth into the recipient stump with the promise of possible sensory reinnervation possibly outweighing the costs of more difficult motor re-education as compared with classical tendon transfers.

In this issue of The European Journal of Neuroscience, Zhang et al. implant stem cells from the spinal cord into a peripheral nerve injury gap months before a nerve transfer. They show that the implanted cells differentiate into motor neurons in a model which mimics a real-life clinical scenario.

All too often animal surgery is optimised with injury and treatment occurring at the same time. This is because recovery surgery in animals can involve death and sometimes requires the use of more animals to overcome attritional losses. Unfortunately, such interventions in models of nerve transfer deviate significantly from the clinical scenario, where a gap in a nerve often exists for months of waiting for definitive diagnosis of the gap or grafting. In the work by Zhang et al., the authors use a clinically relevant model to demonstrate the role of stem-cell intervention.

Every rat in their paper undergoes three surgeries. The first is to induce an injury gap where no possibility of regeneration remains. The injury is a ligation and severing of the tibial branch of the sciatic nerve. This causes a clinically-relevant denervation injury in a subset of muscles in the leg. Then, the animals undergo a second surgery where nothing is repaired but the distal stump of the nerve is treated with embryonic spinal cord stem cells. These are allowed to integrate into the distal stump for three months before a third surgery where a nerve transfer is performed. This nerve transfer moves the proximal end of the hitherto uninjured peroneal branch of the sciatic nerve to the severed distal stump of the tibial nerve. The experiment is designed to see whether or not the implanted cells make a difference in growth of the peroneal nerve axons into the tibial nerve stump. The answer is that they do indeed make a positive difference: about 25% more neurons grow down into the tibial nerve stump than in control samples where animals receive an injection of control medium without stem cells. The authors adequately prove that the cells implanted are capable of increasing the number of axons which regrow into the stump months after an injury in rats.

The field of nerve transfer surgery currently focuses on optimising the number of neurons transferred. Such optimisation has gone so far as to ‘charge’ transfers with end-to-side anastomoses of nerves to bolster regeneration of axons through an injury site (Tung & Mackinnon, 2010; Barbour et al., 2012; Isaacs, 2013). There is heated debate as to the mechanics and precise optimisation required to make nerve transfers work.

The idea that the cells implanted are a place holder for the regrowing axons, which will eventually be provided after nerve transfer, is not standard in peripheral nerve surgery. It could be that these cells are providing cellular support factors through the presence of differentiated Schwann cells or that these differentiated neurons are actually providing paracrine support of the nerve stump in a novel way. The work provides a new focus for nerve surgeons on the effect of implanting cells as a way to provide regrowth support weeks after an injury for a reconstructive surgery which will not be performed until months later. The issue here is ‘priming’ of the distal stump with cells. Priming the stump may be clinically relevant in the common setting of a severe injury where nerve regrowth and nerve transfer outcomes are tenuous. This is especially true where the intervention is clinically applicable and minimally invasive using modern image-guided injection techniques.

This paper has the key ingredients of some really interesting peripheral nerve science. It has an injury that is clinically relevant and is hard to treat. It has an effect size which would be relevant in humans. This is not just baby-sitting a nerve stump, it is priming the stump to promote late regeneration after nerve transfer.