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 o f cells for grafting into patients with Parkinson's disease (PD) if the sig nals needed to control their conversion into dopamine (DA) neurons could be identified. We have recently shown that cytokines which instruct cell divi sion and differentiation within the hematopoeitic system may provide simila r functions in the central nervous system. We have shown that mitotic proge nitor 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 ne urons (98%) was selected for further study. This clone expressed several ph enotypic characteristics of DA neurons and expression of Nurrl. The respons e to cytokines was stable for several passages and after cryopreservation f or several months. When grafted into the striatum of DA-depleted rats, thes e cells attenuated rotational asymmetry to the same extent as freshly harve sted embryonic DA neurons. These data demonstrate that mesencephalic progen itor cells can be clonally expanded in culture and differentiated in the pr esence of hematopoietic cytokines to yield enriched populations of DA neuro ns. When transplanted, these cells provide significant functional benefit i n the rat model of PD. (C) 2001 Academic Press.