Robust Growth of Chronically Injured Spinal Cord Axons Induced by Grafts of Genetically Modified NGF-Secreting Cells

• Published in: Experimental neurology Vol. 148; no. 2; pp. 444 - 452
• Main Authors: Grill, R.J., Blesch, A., Tuszynski, M.H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.12.1997; Elsevier
• Subjects: Animals; Axonal Transport; Axons - physiology; Axons - ultrastructure; Axotomy; Biological and medical sciences; Cell Division; chronic spinal cord injury; Female; Fibroblasts - transplantation; gene therapy; Gene Transfer Techniques; Genetic Therapy - methods; genetically modified fibroblasts; graft; Graft Survival - physiology; Injuries of the nervous system and the skull. Diseases due to physical agents; Medical sciences; Nerve Fibers - physiology; Nerve Fibers - ultrastructure; nerve growth factor; Nerve Growth Factors - biosynthesis; Nerve Growth Factors - physiology; Nerve Regeneration; Rats; Rats, Inbred F344; regeneration; Serotonin - analysis; Spinal Cord Injuries - pathology; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - therapy; supraspinal; Transplantation, Isogeneic - methods; Transplantation, Isogeneic - physiology; Traumas. Diseases due to physical agents; trophic factors; trophic factors; supraspinal; graft; nerve growth factor; regeneration; genetically modified fibroblasts; chronic spinal cord injury; gene therapy; Neurotrophin; Nervous system diseases; Spinal cord; Pathophysiology; Rat; Cytokine; Rodentia; Axon; Nerve growth factor; Trauma; Regeneration; Vertebrata; Mammalia; Polypeptide; Animal; Central nervous system disease; Genetic engineering; Spinal cord disease; Growth factor
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1006/exnr.1997.6704

Little spontaneous regeneration of axons occurs after acute and chronic injury to the CNS. Previously we have shown that the continuous local delivery of neurotrophic factors to the acutely injured spinal cord induces robust growth of spinal and supraspinal axons. In the present study we examined whetherchronicallyinjured axons also demonstrate significant neurotrophin responsiveness. Adult rats underwent bilateral dorsal hemisection lesions that axotomize descending supraspinal pathways, including the corticospinal, rubrospinal, and cerulospinal tracts, and ascending dorsal spinal sensory projections. One to three months later, injured rats received grafts of syngenic fibroblasts genetically modified to produce nerve growth factor (NGF). Control subjects received unmodified cell grafts or cells transduced to express the reporter gene β-galactosidase. Three to five months after grafting, animals that received NGF-secreting grafts showed dense growth of putative cerulospinal axons and primary sensory axons of the dorsolateral fasciculus into the grafted lesion site. Growth from corticospinal, raphaespinal, and local motor axons was not detected. Thus, robust growth of defined populations of supraspinal and spinal axons can be elicited in chronic stages after spinal cord injury by localized, continuous transgenic delivery of neurotrophic factors.