Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, Kentucky 40202, USA.
Stem Cells Transl Med. 2012 Jun;1(6):492-502. doi: 10.5966/sctm.2012-0012. Epub 2012 Jun 1.
Human adult olfactory epithelial-derived neural progenitors (hONPs) can differentiate along several neural lineages in response to morphogenic signals in vitro. A previous study optimized the transfection paradigm for the differentiation of hONPs to dopaminergic neurons. This study engrafted cells modified by the most efficient transfection paradigm for dopaminergic neural restriction and pretransfected controls into a unilateral neurotoxin, 6-hydroxydopamine-induced parkinsonian rat model. Approximately 35% of the animals engrafted with hONPs had improved behavioral recovery as demonstrated by the amphetamine-induced rotation test, as well as a corner preference and cylinder paw preference, over a period of 24 weeks. The pre- and post-transfected groups produced equivalent responses, indicating that the toxic host environment supported hONP dopaminergic differentiation in situ. Human fibroblasts used as a cellular control did not diminish the parkinsonian rotational deficits at any point during the study. Increased numbers of tyrosine hydroxylase (TH)-positive cells were detected in the engrafted brains compared with the fibroblast-implanted and medium-only controls. Engrafted TH-positive hONPs were detected for a minimum of 6 months in vivo; they were multipolar, had long processes, and migrated beyond their initial injection sites. Higher dopamine levels were detected in the striatum of behaviorally improved animals than in equivalent regions of their nonrecovered counterparts. Throughout these experiments, no evidence of tumorigenicity was observed. These results support our hypothesis that human adult olfactory epithelial-derived progenitors represent a unique autologous cell type with promising potential for future use in a cell-based therapy for patients with Parkinson's disease.
人成体嗅上皮来源的神经祖细胞（hONPs）在体外可响应形态发生信号沿多个神经谱系分化。先前的研究优化了 hONPs 向多巴胺能神经元分化的转染范例。本研究将通过最有效的转染范例修饰的细胞用于多巴胺能神经限制和预转染对照物植入单侧神经毒素，6-羟多巴胺诱导的帕金森大鼠模型。大约 35%的植入 hONPs 的动物表现出更好的行为恢复，如安非他命诱导的旋转测试所示，在 24 周的时间内，还表现出角偏好和圆柱爪偏好。预转染和后转染组产生了等效的反应，表明有毒的宿主环境支持 hONP 多巴胺能分化原位。作为细胞对照的人成纤维细胞在研究过程中的任何时间点都没有减轻帕金森旋转缺陷。与成纤维细胞植入和仅培养基对照相比，在植入的大脑中检测到更多的酪氨酸羟化酶（TH）阳性细胞。植入的 TH 阳性 hONPs 在体内至少持续 6 个月；它们是多极的，具有长过程，并迁移到其初始注射部位之外。行为改善动物的纹状体中检测到的多巴胺水平高于其未恢复对应物的等效区域。在整个这些实验中，没有观察到致瘤性的证据。这些结果支持我们的假设，即人成体嗅上皮来源的祖细胞代表一种独特的自体细胞类型，具有用于帕金森病患者细胞治疗的有前途的潜力。
