Promoting directional axon growth from neural progenitors grafted into the injured spinal cord.
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.
Bonner
Joseph F
JF
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania.
Blesch
Armin
A
Neuhuber
Birgit
B
Fischer
Itzhak
I
D000375:Aging; D000818:Animals; D001369:Axons / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D049108:Cell Enlargement; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D009416:Nerve Regeneration / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology / Q000637:transplantation; D009474:Neurons / Q000166:cytology / Q000502:physiology* / Q000637:transplantation; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000503:physiopathology* / Q000601:surgery / Q000628:therapy; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid