Grafts of BDNF-producing fibroblasts rescue axotomized rubrospinal neurons and prevent their atrophy

We have reported that intraspinal transplants of fibroblasts genetically modified to express brain-derived neurotrophic factor (BDNF) promote rubrospinal axon regeneration and functional recovery following subtotal cervical hemisection that completely ablated the rubrospinal tract. In the present study we examined whether these transplants could prevent cell loss and/or atrophy of axotomized Red nucleus neurons. Adult rats received a subtotal spinal cord cervical hemisection followed by a graft of unmodified fibroblasts or fibroblasts producing BDNF into the lesion cavity. One or 2 months later, fluorogold was injected several segments caudal to the lesion-transplant site to retrogradely label those Red nucleus neurons whose axons have regenerated. Unmodified fibroblasts failed to protect against either cell loss or atrophy. Neuron counts and soma-size measurements in Nissl-stained preparations showed a 45% loss of recognizable neurons and 40% atrophy of the surviving neurons in the injured Red nucleus. Grafts of BDNF-producing fibroblasts reduced neuron loss to less than 15% and surviving neurons showed only a 20% decrease in mean soma size. Soma size analysis of fluorogold-labeled Red nucleus neurons indicated that the Red nucleus neurons whose axons regenerated caudal to the graft did not atrophy. We conclude that fibroblasts engineered ex vivo to secrete BDNF and grafted into a partial cervical hemisection promote axon regeneration while reducing cell loss and atrophy of neurons in the Red nucleus. These results suggest that transplants of genetically engineered cells could be an important tool for delivery of therapeutic factors that contribute to the repair of spinal cord injury.