Intrastriatal implants of polymer encapsulated cells genetically modified to secrete human nerve growth factor: trophic effects upon cholinergic and noncholinergic striatal neurons.
Nerve growth factor selectively prevents the degeneration of cholinergic neurons following intrastriatal infusion but rescues both cholinergic and noncholinergic striatal neurons if the nerve growth factor is secreted from grafts of genetically modified fibroblasts. The present study evaluated whether grafted fibroblasts genetically modified to secrete human nerve growth factor could provide trophic influences upon intact cholinergic and noncholinergic striatal neurons. Unilateral striatal grafts of polymer-encapsulated cells genetically modified to secrete human nerve growth factor induced hypertrophy and significantly increased the optical density of choline acetyltransferase-immunoreactive striatal neurons one, two, and four weeks post-transplantation relative to rats receiving identical grafts missing only the human nerve growth factor construct. Nerve growth factor secreting grafts also induced a hypertrophy of noncholinergic neuropeptide Y-immunoreactive striatal neurons one, two, and four weeks post-transplantation. Glutamic acid decarboxylase-immunoreactive neurons were unaffected by the human nerve growth factors secreting grafts. The effects upon choline acetyltransferase-immunoreactive and neuropeptide Y-immunoreactive striatal neurons dissipated following retrieval of the implants. Immunocytochemistry for nerve growth factor revealed intense graft-derived immunoreactivity for up to 1000 microns from the capsule extending along the dorsoventral axis of the striatum. Nerve growth factor-immunoreactivity was also observed within a subpopulation of striatal neurons and may represent nerve growth factor consumer neurons which retrogradely transported graft-derived nerve growth factor. When explanted, grafts produced 2-4 ng human nerve growth factor/24 h over the time course of this study indicating that this level of continuous human nerve growth factor secretion was sufficient to mediate the effects presently observed.
Kordower
J H
JH
Department of Neurological Sciences, Rush Presbyterian Medical Center, Chicago, IL 60612, USA.
Chen
E Y
EY
Mufson
E J
EJ
Winn
S R
SR
Emerich
D F
DF
D000818:Animals; D002460:Cell Line; D017690:Cell Transplantation / Q000379:methods*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D009478:Neuropeptide Y / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure
D009414:Nerve Growth Factors; D009478:Neuropeptide Y; D011108:Polymers; D002795:Choline O-Acetyltransferase