A therapy that combines differentiated stem cells with myelin inhibitors and a motor axon tropic factor helped paralyzed rats restore functional motor units and gain some physical recovery.

" This is the first report, to our knowledge, of the anatomical and functional replacement of a motor neuron circuit within the adult, mammalian host," the authors report.

Researchers' ability to differentiate stem cells toward specific mature cell lineages is assisting in the study of diseases and the development of new treatments. Embryonic stem cells can be induced to create normal pathways for the generation of spinal motor neurons, and this activity can be encouraged by certain pharmacologic agents. The results could help victims of paralysis regain motor function.

Based on this hypothesis, researchers led by Douglas Kerr, of Johns Hopkins University School of Medicine explored different strategies to restore motor function in paralyzed rats. They used agents to inhibit myelin-mediated axon repulsion and others to provide attractive cues within peripheral nerves. They hoped to stimulate the formation of functional muscular units.

They began by inducing embryonic stem cells from rats to differentiate into motor neurons. They then injected the neurons near the spinal cords of rats that had been paralyzed by a virus. To explore treatment strategies, they divided the rats into 8 groups. Some received neurons that had been treated to potentially increase their survival and their ability to extend axons. Some groups received injections of Rolipram and dibutyrl cAMP to potentially neutralize the inhibitory effects of myelin on axon outgrowth. And some groups received a motor axon tropic factor, GDNF, to potentially attract transplanted axons toward skeletal muscle targets. They then examined innervation of host skeletal muscle, electrophysiologic evidence of functioning motor units and signs of recovery from hind limb paralysis.

Their results suggest that GDNF acts as a focal attractive cue for embryonic stem cell-derived motor axons. When co-administered with bcAMP and Rolipram, it seemed to facilitate the establishment of neuromuscular junctions between transplant and host, resulting in noticeable recovery.

" Animals transplanted with inhibitors of myelin and GDNF within the peripheral nervous system formed approximately 125 new connections with host skeletal muscle, 50 of which were electrically active in the distal hind limb," the authors report. "We also provide several lines of evidence that strongly suggest that this functional innervation was required for the behavioral recovery observed."

They concluded that functional restoration of motor units with embryonic stem cell-derived motor neurons is possible in adult paralyzed rats and the technique, " represents a potential therapeutic intervention for humans with paralysis."

Source: Annals of Neurology, 2006


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