title: Experimental traumatic brain injury modulates the survival, migration, and terminal phenotype of transplanted epidermal growth factor receptor-activated neural stem cells.
abstract: OBJECTIVE
  We have previously shown that constitutively active epidermal growth factor receptor signaling enhances the survival and motility of engrafted neural stem cells (NSCs) when transplanted into normal adult brain. In the present study, using the C17.2 NSC line stably transfected with the constitutively active epidermal growth factor receptor vIII, we sought to evaluate the phenotype of NSCs after engraftment into the milieu of traumatic head injury.
  
  
  METHODS
  We performed intracerebral NSC transplantation with C17.2 NSCs overexpressing the active epidermal growth factor receptor vIII receptor into the ipsilateral (n=17) or contralateral (n=19) corpus callosum at 48 hours after severe experimental traumatic brain injury (TBI) or after sham injury (n=12) in rats.
  
  
  RESULTS
  All sham-injured animals (100%) showed NSC graft survival, compared with 65% of brain-injured animals receiving ipsilateral NSC transplants, and only 10% of brain-injured animals had surviving transplants after engraftment into the contralateral uninjured corpus callosum. A marked elevation of nerve growth factor (pg/mg protein) was observed at 72 hours after injury in the injured hemisphere (x=80 +/- 10 pg/mg) compared with the contralateral uninjured hemisphere (35 +/- 0 pg/mg) (P <0.05), and this elevation of nerve growth factor may have contributed to enhanced survival of engrafted NSCs. In uninjured control animals, NSC transplants proliferated actively, as evidenced by incorporation of bromodeoxyuridine. After TBI, however, transplanted NSCs failed to proliferate, regardless of the site of implantation. Morphologically, NSCs transplanted into the injured brain showed extensive process formation suggestive of a more differentiated phenotype, in contrast to NSCs engrafted into uninjured brain that appear undifferentiated, with round soma and no processes. NSCs transplanted into the corpus callosum of brain-injured animals also expressed NG2, a pro-oligodendrocyte marker that was not seen in cells transplanted into uninjured brain. Although migration of NSCs was much more pronounced in the uninjured brain, 2 weeks after TBI, NSCs transplanted into the ipsilateral corpus callosum were found to have migrated to the injury cavity. Moreover, NSCs transplanted into the corpus callosum contralateral to the site of injury were observed crossing the corpus callosum by 2 weeks after transplantation.
  
  
  CONCLUSIONS
  Our results suggest that the environment associated with acute experimental TBI can significantly modulate the phenotype and migratory patterns of the engrafted NSC. These findings have particularly important implications for transplantation of NSCs into the traumatically injured nervous system.
authors.affiliation: Department of Neurosurgery, Weill Cornell Medical College, New York, New York 10021, USA. jab2029@med.cornell.edu
authors.forename: John A
authors.initials: JA
authors.lastname: Boockvar
authors.forename: Joost
authors.initials: J
authors.lastname: Schouten
authors.forename: Nicolas
authors.initials: N
authors.lastname: Royo
authors.forename: Marie
authors.initials: M
authors.lastname: Millard
authors.forename: Zak
authors.initials: Z
authors.lastname: Spangler
authors.forename: Debbie
authors.initials: D
authors.lastname: Castelbuono
authors.forename: Evan
authors.initials: E
authors.lastname: Snyder
authors.forename: Donald
authors.initials: D
authors.lastname: O'Rourke
authors.forename: Tracy
authors.initials: T
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology* / Q000502:physiology; D001930:Brain Injuries / Q000601:surgery*; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D066246:ErbB Receptors / Q000502:physiology*; D008297:Male; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation
chemical_list: C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors