A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson's disease.
Neural progenitor cells potentially provide a limitless, on-demand source of cells for grafting into patients with Parkinson's disease (PD) if the signals needed to control their conversion into dopamine (DA) neurons could be identified. We have recently shown that cytokines which instruct cell division and differentiation within the hematopoeitic system may provide similar functions in the central nervous system. We have shown that mitotic progenitor cells can be isolated from embryonic rat mesencephalon and that these cells respond to a combination of interleukin-1, interleukin-11, leukemia inhibitory factor, and glial cell line-derived neurotrophic factor yielding a tyrosine hydroxylase-immunoreactive (THir) phenotype in 20-25% of total cells. In the present study, 24 clonal cell lines derived from single cells of mesencephalic proliferation spheres were examined for their response to the cytokine mixture. The clone yielding the highest percentage of THir neurons (98%) was selected for further study. This clone expressed several phenotypic characteristics of DA neurons and expression of Nurr1. The response to cytokines was stable for several passages and after cryopreservation for several months. When grafted into the striatum of DA-depleted rats, these cells attenuated rotational asymmetry to the same extent as freshly harvested embryonic DA neurons. These data demonstrate that mesencephalic progenitor cells can be clonally expanded in culture and differentiated in the presence of hematopoietic cytokines to yield enriched populations of DA neurons. When transplanted, these cells provide significant functional benefit in the rat model of PD.
Carvey
P M
PM
Department of Pharmacology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois, USA.
Ling
Z D
ZD
Sortwell
C E
CE
Pitzer
M R
MR
McGuire
S O
SO
Storch
A
A
Collier
T J
TJ
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D015925:Cryopreservation; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006085:Graft Survival / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D017370:Interleukin-11 / Q000494:pharmacology; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000166:cytology* / Q000196:embryology; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D014157:Transcription Factors / Q000096:biosynthesis; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006131:Growth Inhibitors; D007375:Interleukin-1; D017370:Interleukin-11; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine