TrkC overexpression enhances survival and migration of neural stem cell transplants in the rat spinal cord.
Although CNS axons have the capacity to regenerate after spinal cord injury when provided with a permissive substrate, the lack of appropriate synaptic target sites for regenerating fibers may limit restoration of spinal circuitry. Studies in our laboratory are focused on utilizing neural stem cells to provide new synaptic target sites for regenerating spinal axons following injury. As an initial step, rat neural precursor cells genetically engineered to overexpress the tyrosine kinase C (trkC) neurotrophin receptor were transplanted into the intact rat spinal cord to evaluate their survival and differentiation. Cells were either pretreated in vitro prior to transplantation with trkC ligand neurotrophin-3 (NT-3) to initiate differentiation or exposed to NT-3 in vivo following transplantation via gelfoam or Oxycel. Both treatments enhanced survival of trkC-overexpressing stem cells to nearly 100%, in comparison with approximately 30-50% when either NT-3 or trkC was omitted. In addition, increased migration of trkC-overexpressing cells throughout the spinal gray matter was noted, particularly following in vivo NT-3 exposure. The combined trkC expression and NT-3 treatment appeared to reduce astrocytic differentiation of transplanted neural precursors. Decreased cavitation and increased beta-tubulin fibers were noted in the vicinity of transplanted cells, although the majority of transplanted cells appeared to remain in an undifferentiated state. These findings suggest that genetically engineered neural stem cells in combination with neurotrophin treatment may be a useful addition to strategies for repair of spinal neurocircuitry following injury.
Castellanos
Daniel A
DA
The Miami Project to Cure Paralysis, University of Miami School of Medicine, FL 33136, USA.
Tsoulfas
Pantelis
P
Frydel
Beata R
BR
Gajavelli
Shyam
S
Bes
Jean-Claude
JC
Sagen
Jacqueline
J
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D048429:Cell Size; D002470:Cell Survival; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D005260:Female; D007150:Immunohistochemistry; D009416:Nerve Regeneration / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D020933:Neurotrophin 3 / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000601:surgery*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D020933:Neurotrophin 3; D020812:Receptor, trkC