Retinal pigment epithelial cells secrete neurotrophic factors and synthesize dopamine: possible contribution to therapeutic effects of RPE cell transplantation in Parkinson's disease.
BACKGROUND
New strategies for the treatment of Parkinson's disease (PD) are shifted from dopamine (DA) replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE) cells as substitution for degenerated dopaminergic (DAergic) neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA.


METHODS
We evaluated the protective effects of conditioned medium (CM) from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA)- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR).


RESULTS
We report here: (1) CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2) cultured RPE cells express L-dopa decarboxylase (DDC) and synthesize DA; (3) RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4) GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues.


CONCLUSIONS
These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.
Ming
Ming
M
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China. mming@sibs.ac.cn
Li
Xuping
X
Fan
Xiaolan
X
Yang
Dehua
D
Li
Liang
L
Chen
Sheng
S
Gu
Qing
Q
Le
Weidong
W
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis*; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D009414:Nerve Growth Factors / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000628:therapy*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000637:transplantation*; D012402:Rotenone / Q000633:toxicity
D018663:Adrenergic Agents; D019208:Brain-Derived Neurotrophic Factor; D017077:Culture Media, Conditioned; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009498:Neurotoxins; D012402:Rotenone; D016627:Oxidopamine; D004298:Dopamine