Retinal pigment epithelial cell transplantation could provide trophic support in Parkinson's disease: results from an in vitro model system.
Transplantation of retinal pigment epithelial (RPE) cells in the basal ganglia could provide a novel cell-based therapy for Parkinson's disease by providing a constant source of dopamine replacement via the melanin synthetic pathway enzyme tyrosinase. We now demonstrate that human RPE cells also produce a neurotrophic effect on primary cultures of rat striatal (enkephalinergic) and mesencephalic (dopaminergic) neurons. Differentiation of RPE cells to a pigmented monolayer using a Ca(++)-switch protocol increased the potency of the neurotrophic effect on dopaminergic neurons. Conditioned medium derived from differentiated RPE cells increased neurite outgrowth in dopaminergic neurons by 125% compared to 25% for undifferentiated RPE cells. The neurotrophic effect was not due to tyrosinase activity. Differentiation of RPE cells doubled the production of pigment-derived epithelial factor (PEDF). However, PEDF accounted for only a portion of the neurotrophic effect as determined by depletion experiments and dose-response comparisons with purified PEDF, indicating that differentiation increased the production of other trophic factors as well. Conditioned medium from differentiated RPE cells also provided a neurotrophic effect on a subset of enkephalinergic striatal neurons increasing neurite outgrowth by 78%. Survival of enkephalinergic neurons in vitro was increased by RPE conditioned medium. In untreated cultures the number of enkephalinergic neurons declined 62% over a 2-week period compared to a 29% decline in RPE-treated cultures. These results indicate that transplantation RPE cells could potentially provide a dual benefit in Parkinson's disease producing both dopamine and neurotrophic support of the basal ganglia.
McKay
Brian S
BS
Department of Ophthalmology and Vision Science, Cell Biology and Anatomy, The University of Arizona, Tucson, AZ, USA.
Goodman
Brooke
B
Falk
Torsten
T
Sherman
Scott J
SJ
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D017690:Cell Transplantation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins / Q000302:isolation & purification / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects; D009414:Nerve Growth Factors / Q000302:isolation & purification / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000601:surgery*; D010857:Pigment Epithelium of Eye / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000302:isolation & purification / Q000494:pharmacology; D000099174:Pigment Epithelium-Derived Factor
D017077:Culture Media, Conditioned; D004298:Dopamine; D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor