Aponso P M, Faull R L M, Connor B
Department of Anatomy with Radiology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Neuroscience. 2008 Feb 19;151(4):1142-53. doi: 10.1016/j.neuroscience.2007.11.036. Epub 2007 Dec 4.
The existence of endogenous progenitor cells in the adult mammalian brain presents an exciting and attractive alternative to existing therapeutic options for treating neurodegenerative diseases such as Parkinson's disease (PD). However, prior to designing endogenous cell therapies, the effect of PD neuropathology on endogenous progenitor cell proliferation and their neurogenic potential must be investigated. This study examined the effect of dopaminergic cell loss on the proliferation and differentiation of subventricular zone- (SVZ) and midbrain-derived progenitor cells in the adult rodent brain, using the partial progressive 6-hydroxydopamine (6-OHDA) lesion model of PD. Cell proliferation and differentiation were assessed with 5-bromo-2'-deoxyuridine (BrdU) labeling and immunohistochemistry for cell type-specific markers. Tyrosine hydroxylase immunohistochemistry demonstrated a complete loss of nigrostriatal projections in the striatum and a subsequent progressive loss of dopamine (DA) cells in the SN. Quantification indicated that 6-OHDA lesion-induced cell degeneration produced a significant increase in BrdU immunoreactivity in the SVZ, ipsilateral to the lesioned hemisphere from 3 to 21 days post-lesion, compared with sham-lesioned animals. Similarly, in the striatum we observed a significant increase in the total number of BrdU positive cells in 6-OHDA-lesioned animals at all time points examined. More importantly, a significant increase in midbrain-derived BrdU positive cells was demonstrated in 6-OHDA-lesioned animals 28 days post-lesion. While we did not detect neurogenesis, BrdU labeled cells co-expressing the astrocytic marker glial fibrillary acidic protein (GFAP) were widely distributed throughout the 6-OHDA-lesioned striatum at all time points. In contrast, BrdU-labeled cells in the SN of 6-OHDA-lesioned animals did not co-express neural markers. These results demonstrate that DA-ergic neurodegeneration in the partial progressive 6-OHDA-lesioned rat brain increases SVZ- and midbrain-derived progenitor cell proliferation. While, newborn striatal progenitors undergo robust astrogenesis, newborn midbrain-derived progenitors remain in an undifferentiated state suggesting local environments differentially regulate endogenous progenitor cell populations in PD.
成年哺乳动物大脑中内源性祖细胞的存在，为治疗帕金森病（PD）等神经退行性疾病的现有治疗方案提供了一种令人兴奋且颇具吸引力的替代方案。然而，在设计内源性细胞疗法之前，必须研究PD神经病理学对内源性祖细胞增殖及其神经发生潜能的影响。本研究使用PD的部分渐进性6-羟基多巴胺（6-OHDA）损伤模型，检测了多巴胺能细胞缺失对成年啮齿动物脑室下区（SVZ）和中脑来源的祖细胞增殖及分化的影响。通过5-溴-2'-脱氧尿苷（BrdU）标记和针对细胞类型特异性标志物的免疫组织化学来评估细胞增殖和分化。酪氨酸羟化酶免疫组织化学显示，纹状体中黑质纹状体投射完全丧失，随后黑质中多巴胺（DA）细胞逐渐减少。定量分析表明，与假手术动物相比，6-OHDA损伤诱导的细胞变性在损伤后3至21天使损伤半球同侧SVZ中的BrdU免疫反应性显著增加。同样，在纹状体中，我们在所有检测时间点均观察到6-OHDA损伤动物中BrdU阳性细胞总数显著增加。更重要的是，在损伤后28天的6-OHDA损伤动物中，中脑来源的BrdU阳性细胞显著增加。虽然我们未检测到神经发生，但在所有时间点，共表达星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）的BrdU标记细胞广泛分布于6-OHDA损伤的纹状体中。相比之下，6-OHDA损伤动物黑质中的BrdU标记细胞不共表达神经标志物。这些结果表明，部分渐进性6-OHDA损伤大鼠脑中的多巴胺能神经变性增加了SVZ和中脑来源的祖细胞增殖。虽然新生纹状体祖细胞经历了强大的星形胶质细胞生成，但新生中脑来源的祖细胞仍处于未分化状态，这表明局部环境对PD中的内源性祖细胞群体有不同的调节作用。
