Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas.
One of the impediments to the treatment of brain tumors (e.g., gliomas) has been the degree to which they expand, infiltrate surrounding tissue, and migrate widely into normal brain, usually rendering them "elusive" to effective resection, irradiation, chemotherapy, or gene therapy. We demonstrate that neural stem cells (NSCs), when implanted into experimental intracranial gliomas in vivo in adult rodents, distribute themselves quickly and extensively throughout the tumor bed and migrate uniquely in juxtaposition to widely expanding and aggressively advancing tumor cells, while continuing to stably express a foreign gene. The NSCs "surround" the invading tumor border while "chasing down" infiltrating tumor cells. When implanted intracranially at distant sites from the tumor (e.g., into normal tissue, into the contralateral hemisphere, or into the cerebral ventricles), the donor cells migrate through normal tissue targeting the tumor cells (including human glioblastomas). When implanted outside the CNS intravascularly, NSCs will target an intracranial tumor. NSCs can deliver a therapeutically relevant molecule-cytosine deaminase-such that quantifiable reduction in tumor burden results. These data suggest the adjunctive use of inherently migratory NSCs as a delivery vehicle for targeting therapeutic genes and vectors to refractory, migratory, invasive brain tumors. More broadly, they suggest that NSC migration can be extensive, even in the adult brain and along nonstereotypical routes, if pathology (as modeled here by tumor) is present.
Aboody
K S
KS
Departments of Neurology, Pediatrics, and Neurosurgery, Children's Hospital, Boston, MA, USA.
Brown
A
A
Rainov
N G
NG
Bower
K A
KA
Liu
S
S
Yang
W
W
Small
J E
JE
Herrlinger
U
U
Ourednik
V
V
Black
P M
PM
Breakefield
X O
XO
Snyder
E Y
EY
D000818:Animals; D001921:Brain / Q000473:pathology*; D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy; D002465:Cell Movement / Q000502:physiology; D043525:Cytosine Deaminase; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005909:Glioblastoma / Q000473:pathology* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009700:Nucleoside Deaminases / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D018523:Tropism
D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase