Promoting directional axon growth from neural progenitors grafted into the injured spinal cord

• Published in: Journal of neuroscience research Vol. 88; no. 6; pp. 1182 - 1192
• Main Authors: Bonner, Joseph F., Blesch, Armin, Neuhuber, Birgit, Fischer, Itzhak
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2010
• Subjects: Aging; Animals; Axons - physiology; brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Cell Enlargement; cell transplantation; dorsal columns; Female; gamma-Aminobutyric Acid - metabolism; Genetic Vectors - therapeutic use; Glutamic Acid - metabolism; Lentivirus; Lentivirus - genetics; Nerve Regeneration - physiology; neural stem cells; Neuroglia - physiology; Neuroglia - transplantation; Neurons - cytology; Neurons - physiology; Neurons - transplantation; neurotrophin gradients; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Spinal Cord Injuries - physiopathology; Spinal Cord Injuries - surgery; Spinal Cord Injuries - therapy; Stem Cell Transplantation; Stem Cells - cytology; Stem Cells - physiology
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22288

Spinal cord injury (SCI) is a devastating condition characterized by disruption of axonal connections, failure of axonal regeneration, and loss of motor and sensory function. The therapeutic promise of neural stem cells has been focused on cell replacement, but many obstacles remain in obtaining neuronal integration following transplantation into the injured CNS. This study investigated the neurotransmitter identity and axonal growth potential of neural progenitors following grafting into adult rats with a dorsal column lesion. We found that using a combination of neuronal and glial restricted progenitors (NRP and GRP) produced graft‐derived glutamatergic and GABAergic neurons within the injury site, with minimal axonal extension. Administration of brain‐derived neurotrophic factor (BDNF) with the graft promoted modest axonal growth from grafted cells. In contrast, injecting a lentiviral vector expressing BDNF rostral into the injured area generated a neurotrophin gradient and promoted directional growth of axons for up to 9 mm. Animals injected with BDNF lentivirus (at 2.5 and 5.0 mm) showed significantly more axons and significantly longer axons than control animals injected with GFP lentivirus. However, only the 5.0‐mm‐BDNF group showed a preference for extension in the rostral direction. We concluded that NRP/GRP grafts can be used to produce excitatory and inhibitory neurons, and neurotrophin gradients can guide axonal growth from graft‐derived neurons toward putative targets. Together they can serve as a building block for neuronal cell replacement of local circuits and formation of neuronal relays. © 2009 Wiley‐Liss, Inc.