GRAFTS OF GENETICALLY-MODIFIED SCHWANN-CELLS TO THE SPINAL-CORD - SURVIVAL, AXON GROWTH, AND MYELINATION

Schwann cells naturally support axonal regeneration after injury in th e peripheral nervous system, and have also shown a significant, albeit limited, ability to support axonal growth and remyelination after gra fting to the central nervous system (CNS), It is possible that Schwann cell-induced axonal growth in the CNS could be substantially increase d by genetic manipulation to secrete augmented amounts of neurotrophic factors, To test this hypothesis, cultured primary adult rat Schwann cells were genetically modified using retroviral vectors to produce an d secrete high levels of human ner ie growth factor (NGF). These cells were then grafted to the midthoracic spinal cords of adult rats, Find ings were compared to animals that received grafts of nontransduced Sc hwann cells, Spinal cord lesions were not placed prior to grafting bec ause the primary aim of this study was to examine features of grafted Schwann cell survival, growth, and effects on host axons, In vitro pri or to grafting, Schwann cells secreted 1.5 +/- 0.1 ng human NGF/ml/10( 6) cells/day, Schwann cell transplants readily survived for 2 wk to 1 yr after in vivo placement, Some NGF-transduced grafts slowly increase d in size over time compared to nontransduced grafts; the latter remai ned stable in size, NGF-transduced transplants were densely penetrated by primary sensory nociceptive axons originating from the dorsolatera l fasciculus of the spinal cord, whereas control grafts showed signifi cantly fewer penetrating sensory axons. Over time, Schwann cell grafts also became penetrated by TH- and DBH-labeled axons of putative coeru lospinal origin, unlike control cell grafts, Ultrastructurally, axons in both graft types were extensively myelinated by Schwann cells, Graf ted animals showed no changes in gross locomotor function, In vivo exp ression of the human NGF transgene mas demonstrated for periods of at least 6 m, These findings demonstrate that primary adult Schwann cells 1) can be transduced to secrete augmented levels of neurotrophic fact ors, 2) survive grafting to the CNS for prolonged time periods, 3) eli cit robust growth of host neurotrophin-responsive axons, 4) myelinate CNS axons, and 5) express the transgene for prolonged time periods in vivo, Some grafts slowly enlarge over time, a feature that may be attr ibutable to the propensity of Schwann cells to immortalize after multi ple passages, Transduced Schwann cells merit further study as tools fo r promoting CNS regeneration, (C) 1998 Elsevier Science Inc.