Cellular repair strategies need a helping hand

The use of cellular grafts or transplants to aid recovery of function after SCI is attractive for a number of reasons. They can potentially replace lost cells, act as cellular factories producing biological molecules to stimulate and support axonal growth or they could potentially repair the spinal circuitry that’s become disrupted by the loss of the insulating myelin sheath. All these strategies are being investigated by researchers around the world.

One particular cell type – the Schwann cell – is normally found in the peripheral nervous system (PNS) where it wraps the axons of neurons in a blanket of insulating myelin. The PNS is far better than the central nervous system (CNS) at repairing itself after injury and Schwann cells may be partly responsible for that. Schwann cells are also fairly easy to “harvest” from the body and grow in sufficient numbers for transplantations making them a clinically viable cell type. For these reasons Schwann cells have been investigated as potential therapeutic grafts. Indeed, grafting Schwann cells into SCI results in robust axon regeneration into the graft and remyelination. So far so good, but their contribution to repair is somewhat restricted by a failure of these same regenerating axons that enter the graft to re-exit; they find it very comfortable there.

One strategy being looked at to overcome this has been to introduce the equivalent of cellular candy. Neurotrophins stimulate growth and axons like it. So injecting some neurotrophins just outside the graft may entice the axons to come of the graft and form a connection with spinal cord below. Direct delivery of neurotrophins has caused (sensory) axons to leave the confines of the graft, but muscle control is provided by axons coming down from the brain in long tracts and little investigation of the graft/neurotrophin approach on descending axons has been carried out.

Oudega presented a poster at the meeting investigating this very thing. Schwann cells were grafted into the injury site and below the injury they injected a viral vector modified to carry the gene for D15A [a protein with 2 neurotrophin activities; NT-3 and BDNF]. The gene enters the cell carried by the viral vector and begins to produce the neurotrophins. Oudega and co-workers found some functional improvement in treated animals but when they looked surprisingly there was still no evidence of axons leaving the graft. So what’s the mechanism? It’s unclear to them and they continue to work on this problem.