Improved motor function of denervated rat hindlimb muscles induced by embryonic spinal cord grafts

Loss of motoneurons results in a decrease in force production by skeletal muscles and paralysis. Although it has been shown that missing motoneurons of rats can be replaced by embryonic homotopic neurons, attempts to guide their axons to their target muscles that have lost their innervation have been unsuccessful. In this study attempts were made to guide axons from grafted embryonic motoneurons to their target via a reimplanted ventral root. Adult hosts that received an embryonic graft prelabelled with 5-bromo-2'-deoxyuridine had their L4 ventral root avulsed and reimplanted into the spinal cord. Three to six months later, neurons that had their axons in the L4 ventral ramus were retrogradely labelled with fast blue and diamidino yellow. In five animals that had received an embryonic graft 116 +/- 16 cells were retrogradely labelled, and of these at least 15% were of graft origin, since they were positive for 5-bromo-2'-deoxyuridine. In five animals that had their L4 ventral root reimplanted but did not receive a graft, only 12 +/- 1.3 cells were retrogradely labelled. However, meaningful functional recovery could be achieved only if the regenerating axons of embryonic motoneurons found in the L4 ventral ramus were able to reverse the loss of force of muscles that had lost their innervation. This study shows that axons of embryonic motoneurons grafted into an adult rat spinal cord, as well as some axons of host origin, can be guided to denervated hindlimb muscles via reimplanted lumbar ventral roots. In normal rats approximately 30 motor axons innervated the extensor digitorum longus and 60 innervated the tibialis anterior via the L4 ventral root. In rats that did not receive a graft only 3.7 +/- 1.2 axons reached the extensor digitorum longus and 3.5 +/- 0.4 reached the tibialis anterior muscle via the implanted L4 ventral root. In animals that had an embryonic graft, 7.6 +/- 0.5 axons innervated the extensor digitorum longus and 8.5 +/- 0.5 reached the tibialis anterior muscle via the implanted root. In rats without a transplant the maximum tetanic tension elicited by stimulating the implanted L4 root was 16 +/- 7 g for the extensor digitorum longus and 53 +/- 36 g for the tibialis anterior muscle, whereas the corresponding muscles in animals that had an embryonic graft developed 82 +/- 16 and 281 +/- 95 g respectively. Thus it appears that the grafted motoneurons contributed to the innervation and functional recovery of the denervated muscles.