Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92697, USA.
Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 96267, USA.
Stem Cell Reports. 2020 Mar 10;14(3):406-419. doi: 10.1016/j.stemcr.2020.01.015. Epub 2020 Feb 27.
Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD. We performed single-cell and bulk transcriptomic and epigenomic analyses and demonstrated that a persistent cyclin D1 neural stem cell (NSC) population is observed selectively in adult-onset HD iPSCs during differentiation. Treatment with a WNT inhibitor abrogates this NSC population while preserving neurons. Taken together, our findings identify a mechanism that may promote aberrant neurodevelopment and adult neurogenesis in adult-onset HD striatal neurons with the potential for therapeutic compensation.
异常的神经元发育和有丝分裂细胞群体的持续存在与多种神经疾病有关，包括亨廷顿病（HD）。然而，这种潜在病理学的机制尚不清楚。我们使用改良的方案将来自 HD 患者和未受影响的对照者的诱导多能干细胞（iPSC）分化为富含中型棘突神经元的神经元培养物，这是 HD 中受影响最大的细胞类型。我们进行了单细胞和批量转录组和表观基因组分析，结果表明，在分化过程中，选择性地在成年发病的 HD iPSC 中观察到持续存在的细胞周期蛋白 D1 神经干细胞（NSC）群体。用 WNT 抑制剂处理可消除该 NSC 群体，同时保留神经元。总之，我们的研究结果确定了一种可能促进成年发病的 HD 纹状体神经元异常神经发育和成年神经发生的机制，具有潜在的治疗补偿作用。
