Spinal cord grafts : Interaction with cografts and effects of trophic factors

ÑSpinal cord injury is common in the modern society, often afflictsyoung individuals, and often has devastating consequences. The present workstudies possibilities to obtain better conditions for regeneration of the transectedspinal cord in rats, conditions under which spinal cord grafts are able toestablish structural and functional connections with "natural" targets, andeffects of a series of neurotrophic factors on spinal cord graft survival andgrowth. Recognizing that the spinal cord is normally under tension, leading toseparation of the stumps after transection, stump approximation through verte-bral shortening was studied. While complicated by the need for better vertebralcolumn stabilization measures, and while regeneration of descending 5HT fiberswas not improved in comparison to spinal cord transection alone, animals inwhich the spinal cord transection was combined with vertebral shorteningshowed modest, but significantly improved, hindlimb motor function comparedto spinal cord transection only. To further elucidate establishment of spinal cordconnectivity, grafts of spinal cord tissue to the anterior chamber of the eye werecombined with either cortex cerebri or another spinal cord graft. Both cortexcerebri and spinal cord were able to establish functional excitatory inputs to themature spinal cord graft, suggesting that fetal cerebral cortex or spinal cord tis-sue grafted to the adult injured spinal cord might establish similar connections.Graft growth was not influenced in these double-graft situations, suggestingthat the spinal cord did not exert any major trophic effects on itself or on cortexcerebri. When instead fetal spinal cord and fetal skeletal muscle were combinedin the eye chamber, the two tissues exerted reciprocal trophic effects upon eachother, and stimulation of the spinal cord graft elicited specific muscle contrac-tions. Spinal cord grafts were also able to exert a trophic, neuron-rescuing effecton fetal cografts of dorsal root ganglia.To elucidate trophic effects exerted by skeletal muscle on spinal cord grafts,single spinal cord grafts to the eye chamber were treated with two trophic fac-tors abundantly present in skeletal muscle, namely GDNF and NT4. Effects ofthese factors were compared to the possible effects of NGF, BDNF, NT3 andCNTF. GDNF exerted marked trophic effects on survival and growth of spinalcord grafts both in terms of graft volume and graft morphology, manifest as sur-vival of a larger number of neurons and a less pronounced gliosis. Remarkably,GDNF exerted strong effects also on postnatal grafts obtained from 1-, 8- or 14-day-old donors. All neurotrophins except NGF stimulated spinal cord grafts.BDNF was able to stimulate prenatal grafts while NT4, assumed to act uponthe same set of receptors as BDNF, exerted strong stimulatory effects on post-natal grafts only. CNTF also stimulated postnatal grafts.Taken together, the data demonstrate that several known neurotrophic factorsexert potent stimulatory effects of spinal cord grafts. The use of neurotrophicfactors extends the time window within which spinal cord tissue can be graftedwell into the second postnatal week. It is predicted that treatments with neuro-trophic factors or, particularly combinations of neurotrophic factors such asGDNF and NT4, should also enhance survival of immature spinal cord tissuegrafted to the adult injured spinal cord. It is further predicted that treatmentwith combinations of neurotrophic factors might have neuroprotective effectsand/or enhance regeneration in the adult injured spinal cord.KeywordsÑSpinal cord injury, spinal cord transplants, regeneration, GDNF,neurotrophins, CNTF, 5HT, immunohistochemistryKatarzyna Trok, 1996ISBN 91-628-2062-