Carvey P M, Ling Z D, Sortwell C E, Pitzer M R, McGuire S O, Storch A, Collier T J
Department of Pharmacology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois, USA.
Exp Neurol. 2001 Sep;171(1):98-108. doi: 10.1006/exnr.2001.7735.
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.
如果能够确定控制神经祖细胞转化为多巴胺（DA）神经元所需的信号，那么神经祖细胞就有可能为帕金森病（PD）患者提供无限的、按需的移植细胞来源。我们最近发现，在造血系统中指导细胞分裂和分化的细胞因子可能在中枢神经系统中发挥类似的功能。我们已经表明，有丝分裂祖细胞可以从胚胎大鼠中脑分离出来，并且这些细胞对白细胞介素-1、白细胞介素-11、白血病抑制因子和胶质细胞系源性神经营养因子的组合有反应，在总细胞的20%至25%中产生酪氨酸羟化酶免疫反应性（THir）表型。在本研究中，检测了来自中脑增殖球单细胞的24个克隆细胞系对细胞因子混合物的反应。选择产生THir神经元百分比最高（98%）的克隆进行进一步研究。该克隆表达了DA神经元的几个表型特征以及Nurr1的表达。对细胞因子的反应在传代几次以及冷冻保存几个月后都是稳定的。当移植到DA耗尽大鼠的纹状体中时，这些细胞减轻旋转不对称的程度与新鲜收获的胚胎DA神经元相同。这些数据表明，中脑祖细胞可以在培养中进行克隆扩增，并在造血细胞因子存在下分化，以产生富集的DA神经元群体。移植后，这些细胞在PD大鼠模型中提供了显著的功能益处。
