Grafts of Fibroblasts Genetically Modified to Secrete Ngf, Bdnf, Nt-3, or Basic Fgf Elicit Differential Responses in the Adult Spinal Cord

Abstract

Neuronal and axonal responses to neurotrophic factors in the developing spinal cord have been relatively well characterized, but little is known about adult spinal responses to neurotrophic factors. We genetically modified primary rat fibroblasts to produce either nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or basic fibroblast growth factor (bFGF), then grafted these neurotrophic factor-secreting cells into the central gray matter of the spinal cord in adult rats. Spinal cord lesions were not made prior to grafting. From 2 wk to 6 mo later, sensory neurites of dorsal root origin extensively penetrated NGF-, NT-3-, and bFGF-producing grafts, whereas BDNF-secreting grafts elicited no growth responses. Putative noradrenergic neurites also penetrated NGF-secreting cell grafts. Local motor and corticospinal motor axons did not penetrate any of the neurotrophic factor-secreting grafts. These results indicate that unlesioned or minimally lesioned adult spinal cord sensory and putative noradrenergic populations retain significant neurotrophic factor responsiveness, whereas motor neurites are comparatively resistant even to those neurotrophic factors to which they exhibit survival dependence during development. Grafts of genetically modified cells can be a useful tool for characterizing neurotrophic factor responsiveness in the adult spinal cord and designing strategies to promote axonal regeneration after injury.