Division of Molecular Endocrinology, Medical Clinic III, Carl Gustav Carus University Clinic, Technische Universität Dresden, Dresden, Germany.
Departments of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
Mol Psychiatry. 2015 Aug;20(8):941-50. doi: 10.1038/mp.2015.3. Epub 2015 Feb 24.
The antiepileptic drug valproic acid (VPA) has been shown to influence the neural differentiation and neurite outgrowth of neural stem cells. Sympathoadrenal progenitor cells share properties with neural stem cells and are considered a potential cell source in the treatment of neurodegenerative diseases. The present study therefore aims at modulating the neural differentiation potential of these cells by treatment with the histone deacetylase inhibitor VPA. We studied the epigenetic effects of VPA in two culture conditions: suspension conditions aimed to expand adrenomedullary sympathoadrenal progenitors within free-floating chromospheres and adherent cell cultures optimized to derive neurons. Treatment of chromospheres with VPA may launch neuronal differentiation mechanisms and improve their neurogenic potential upon transplantation. However, also transplantation of differentiated functional neurons could be beneficial. Treating chromospheres for 7 days with clinically relevant concentrations of VPA (2 mm) revealed a decrease of neural progenitor markers Nestin, Notch2 and Sox10. Furthermore, VPA initiated catecholaminergic neuronal differentiation indicated by upregulation of the neuronal marker β-III-tubulin, the dopaminergic transcription factor Pitx3 and the catecholaminergic enzymes TH and GTPCH. In adherent neural differentiation conditions, VPA treatment improved the differentiation of sympathoadrenal progenitor cells into catecholaminergic neurons with significantly elevated levels of nor- and epinephrine. In conclusion, similar to neural stem cells, VPA launches differentiation mechanisms in sympathoadrenal progenitor cells that result in increased generation of functional neurons. Thus, data from this study will be relevant to the potential use of chromaffin progenitors in transplantation therapies of neurodegenerative diseases.
抗癫痫药物丙戊酸（VPA）已被证明能影响神经干细胞的神经分化和突生长。交感肾上腺祖细胞具有与神经干细胞相似的特性，被认为是治疗神经退行性疾病的潜在细胞来源。因此，本研究旨在通过用组蛋白去乙酰化酶抑制剂 VPA 处理来调节这些细胞的神经分化潜能。我们在两种培养条件下研究了 VPA 的表观遗传效应：悬浮条件旨在在游离的嗜铬球体中扩增肾上腺髓质交感肾上腺祖细胞，贴壁细胞培养条件优化用于衍生神经元。用 VPA 处理球体可能会启动神经元分化机制，并提高其移植后的神经发生潜能。然而，分化的功能性神经元的移植也可能是有益的。用临床相关浓度的 VPA（2mM）处理球体 7 天，显示神经祖细胞标记物巢蛋白、Notch2 和 Sox10 减少。此外，VPA 启动了儿茶酚胺能神经元分化，表现为神经元标记物 β-III-微管蛋白、多巴胺能转录因子 Pitx3 和儿茶酚胺酶 TH 和 GTPCH 的上调。在贴壁神经分化条件下，VPA 处理改善了交感肾上腺祖细胞向儿茶酚胺能神经元的分化，导致去甲肾上腺素和肾上腺素的水平显著升高。总之，与神经干细胞类似，VPA 启动了交感肾上腺祖细胞的分化机制，导致功能性神经元的生成增加。因此，本研究的数据将与嗜铬祖细胞在神经退行性疾病移植治疗中的潜在用途相关。
