A (heat) shock to the system promotes peripheral nerve regeneration

So, how can we solve the problem of chronic denervation and lack of regeneration after proximal nerve lesions? There are two ways. 

One is to figure out how to keep the Schwann cells and muscle cells in a “reactive” state, so that Schwann cells can support regeneration as the axons slowly regenerate and muscle cells can accept reinnervation and formation of functional neuromuscular junctions. 

Another way to solve this problem would be to accelerate the rate at which axons regenerate, so that chronic denervation changes in the pathway (i.e., in Schwann cells) and target (i.e., the denervated muscle) do not occur. 

For this strategy to succeed with brachial plexus injuries, the rate of axonal regeneration needs to be increased to at least 2- to 3-fold faster than the natural rate of 1 inch per month.

We know that the rate of axonal regeneration can be accelerated, although previous attempts have resulted only in relatively modest increases. A classic example of an increase in the rate of regeneration has been achieved through conditioning lesion (19). 

That is, the rate of nerve regeneration is accelerated if a peripheral nerve is injured by crushing the nerve a week before a second more severe injury such as nerve transection. 

This effect depends on changes in gene expression in the dorsal root ganglia, and one of the primary transcription factors that is upregulated after peripheral axon injury is activating transcription factor 3 (ATF3) (20). 

Overexpression of ATF3 in dorsal root ganglion sensory neurons resulted in accelerated regeneration of sensory axons (21), but the effect was very modest, and the results await confirmation in a large animal model of long-distance regeneration after nerve repair.

In this issue of the JCI, Ma and colleagues used an unbiased bioinformatics approach to identify genes that play a key role in the regenerative response to nerve transection or crush injury in mouse dorsal root ganglion neurons and identified Hsp27 as a potential candidate to enhance the intrinsic state of neurons for regeneration (8). 

Using transgenic mice that overexpressed human Hsp27, the authors demonstrated that the rate of axonal regeneration was enhanced in both motor and sensory axons at a rate similar to that observed with ATF3 overexpression (Figure 2). 

What is interesting in this study is that the authors found that wild-type littermates of the human Hsp27–overexpressing transgenic mice never regained full function of toe spreading after axotomy, even after 8 weeks, but that the transgenic mice exhibited proper reinnervation of the neuromuscular junctions and partial recovery of toe spread. 

The authors concluded that if the distal foot muscles are not reinnervated within 5 to 6 weeks, the neuromuscular junctions become difficult to reinnervate and thus there is a critical period in which reinnervation of the distal muscles has to take place. 

However, I believe that this conclusion is premature, as they used only one functional index, toe spread, instead of multiple outcome measures. 

As noted by others (reviewed in ref. 22), toe spread alone is not a reliable measure of full functional recovery after sciatic nerve transection and repair. 

Ma and colleagues also noted that 8 weeks after nerve transection and repair, neuromuscular junctions were not fully reinnervated in wild-type littermates but had fully recovered to control levels in the human Hsp27–overexpressing transgenic mice. 

The way the neuromuscular junctions were quantified needs verification, as only 80% of neuromuscular junctions were innervated in controls, which would be unusual and indicate a problem of neuromuscular innervation in this mouse background.

https://www.jci.org/articles/view/59320