Activated Integrins Boost Sensory Nerve Regeneration

Posted by Sam Maddox in Research News on September 01, 2016

A recent paper from the James Fawcett group at the University of Cambridge, U.K. reports that spinal cord sensory nerves can regenerate with the help of some precise biochemical manipulation.

The paper, Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord, appeared in the Journal of Neuroscience several weeks ago. Fawcett, as regular readers know, is a member of the Reeve Foundation’s International Research Consortium on Spinal Cord Injury, an elite collaborative of seven labs in Europe and the U.S. This study was funded in part by Reeve.

Before getting to Fawcett’s activated integrin paper, let’s recap this segment of spinal cord research, which we might call glial inhibition.

One of Fawcett’s areas of study has been the area around a spinal cord lesion that prevents nerve axons from passing through. This is the so-called glial scar – it’s not usually thought to be a good thing, but then recent studies have shown that it’s not necessarily a bad thing either. Getting rid of the glial scar altogether does not result in robust nerve growth or recovery. Parts of the scar are bad, especially an aggregate of proteins called proteoglycans. We’ve followed closely a number of studies of one of these inhibitors, chondroitin sulfate; it can be dissolved using a molecule with the nickname chase, for chrondroitinase ABC. Here are some past reports, from 2011, 2013, 2014, and 2015.

Chase remains a potential therapy for spinal cord injury; the trick is delivering the molecule, which is in fact a temperature-sensitive bacterial toxin, to the right place at the right time. Acorda Therapeutics, a biotech in New York, long ago obtained patent rights to develop chase; after early reports of effect in animal models, the company later removed chase from its development pipeline.

The field hasn’t given up. The best bet for bringing chase forward is Chase-It, a collaboration between four lab groups, led by Elizabeth Bradbury (King’s College London); Elizabeth Muir (University of Cambridge); Joost Verhaagen (Netherlands Institute for Neuroscience); and Rafael Yáñez-Muñoz (Royal Holloway, University of London).

Chase-It is supported by the UK-based Spinal Research charity. The group is also putting funds toward a trial at Iowa State using chase for chronic paralysis in dogs, which, alas, is fairly common.

Back to the new Fawcett paper, which indeed is centered on glial inhibition. The researchers found a way to turn up integrins – these are receptors on the surface of cells, important for signaling and directing growth mechanisms. Turns out integrins are inhibited by chondroitin sulfate proteoglycans, the stuff chase goes after. There’s no way to avoid getting into the complexities of the biology, but here’s the gist of this: The Fawcett study, also led by Melissa R. Andrews of University of St. Andrew, reports that adding alpha 9 integrin, mutes a normally formidable growth blocker called Tenascin C. Further, adding a chemical activator of integrin, kindling-1, shuts down the blocking effect of CSPGs.

The study used a viral vector method to deliver the molecules to the dorsal root entry zone, the area of transition between central and peripheral nerves. The combination overcame inhibition and allowed regeneration of axons.

From the paper:

We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery.

Does this have any clinical significance for people with spinal cord injury paralysis? Probably, say the authors, but keep in mind the effect is not on motor function, only sensory. The α9 integrin and kindlin-1 combo promotes axon regeneration over what the authors call “remarkably long distances, 25 mm or seven spinal levels and more, all the way up to the medulla.” The regenerating axons appear to move along normal nerve pathways, re-form nerve-to-nerve connections (synapses) in the correct places of the dorsal horn. They re-establish sensory and sensory–motor behaviors: thermal pain sensation, pressure sensation and ladder walking proprioception.

What about using this method for axons in the spinal cord? Not so easy: integrins are not found on mature cortical axons.

From the published report:

The prolific regeneration that we have seen in sensory axons forced to express α9 integrin and kindlin-1 begs the question of whether this strategy could be used to promote regeneration of CNS axons. However, there are problems with this approach ... trafficking of integrins in cortical neuron axons is very different. During developmental growth, cortical neurons transport integrins, but with neuronal maturity integrins become restricted to the somatodendritic domain and are excluded from the axons, hence contributing to the developmental loss of regenerative ability in CNS axons. Extension of the α9 integrin–kindlin-1 approach to CNS axons will require a solution to this issue.

Motor recovery is often the primary goal of SCI research, but sensory recovery shouldn’t be considered some kind of second prize; the authors are aware of the clinical potential:

... it is now reasonable to ask whether it would be possible to restore useful sensation to patients with spinal injuries. Restoration of sensation would enable patients to avoid burns, pressure sores, and other damage and to improve manipulative ability. In addition, restoration of genital sensation is a desired outcome for many patients.