Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation.,Stem Cell Reports

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Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation.
Stem Cell Reports ( IF 5.9 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.stemcr.2020.01.015
Charlene Smith-Geater ₁ , Sarah J Hernandez ₂ , Ryan G Lim ₃ , Miriam Adam ₄ , Jie Wu ₅ , Jennifer T Stocksdale ₂ , Brook T Wassie ₆ , Maxwell Philip Gold ₄ , Keona Q Wang ₂ , Ricardo Miramontes ₃ , Lexi Kopan ₂ , Iliana Orellana ₃ , Shona Joy ₇ , Paul J Kemp ₈ , Nicholas D Allen ₈ , Ernest Fraenkel ₄ , Leslie M Thompson ₉

Affiliation

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.
Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Department of Biological Chemistry, University of California Irvine, Irvine, CA 92617, USA.
LeadCrunch, San Diego, CA 92101, USA.
Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
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; Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Chemistry, University of California Irvine, Irvine, CA 92617, USA.

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.

中文翻译：

通过 WNT 信号调节纠正成人发病的亨廷顿病 iPSC 衍生的神经元培养物中的异常发育。

异常的神经元发育和有丝分裂细胞群的持续存在与多种神经系统疾病有关，包括亨廷顿病（HD）。然而，这种潜在病理学背后的机制仍不清楚。我们使用修改后的方案将来自 HD 患者和未受影响对照的诱导多能干细胞 (iPSC) 分化为富含中型多棘神经元的神经元培养物，中等棘神经元是 HD 中受影响最严重的细胞类型。我们进行了单细胞和批量转录组和表观基因组分析，并证明在分化过程中，在成体 HD iPSC 中选择性地观察到持续的细胞周期蛋白 D1 ⁺神经干细胞 (NSC) 群体。 WNT 抑制剂治疗可消除该 NSC 群，同时保留神经元。总而言之，我们的研究结果确定了一种可能促进成人 HD 纹状体神经元异常神经发育和成人神经发生的机制，并具有治疗补偿的潜力。

更新日期：2020-02-27

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