Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation

Charlene Smith-Geater; Sarah J Hernandez; Ryan G Lim; Miriam Adam; Jie Wu; Jennifer T Stocksdale; Brook T Wassie; Maxwell Philip Gold; Keona Q Wang; Ricardo Miramontes; Lexi Kopan; Iliana Orellana; Shona Joy; Paul J Kemp; Nicholas D Allen; Ernest Fraenkel; Leslie M Thompson

doi:10.1016/j.stemcr.2020.01.015

Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation

Stem Cell Reports. 2020 Mar 10;14(3):406-419. doi: 10.1016/j.stemcr.2020.01.015. Epub 2020 Feb 27.

Authors

Charlene Smith-Geater¹, Sarah J Hernandez², Ryan G Lim³, Miriam Adam⁴, Jie Wu⁵, Jennifer T Stocksdale², Brook T Wassie⁶, Maxwell Philip Gold⁴, Keona Q Wang², Ricardo Miramontes³, Lexi Kopan², Iliana Orellana³, Shona Joy⁷, Paul J Kemp⁸, Nicholas D Allen⁸, Ernest Fraenkel⁴, Leslie M Thompson⁹

Affiliations

¹ Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92697, USA.
² Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 96267, USA.
³ Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
⁴ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
⁵ Department of Biological Chemistry, University of California Irvine, Irvine, CA 92617, USA.
⁶ LeadCrunch, San Diego, CA 92101, USA.
⁷ Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
⁸ School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
⁹ 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. Electronic address: [email protected].

Abstract

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.

Keywords: Huntington's disease; WNT signaling; adult-onset HD; cell cycle; development; induced pluripotent stem cells; medium spiny neurons; neural stem cells; single-cell RNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Age of Onset
Cell Cycle / genetics
Cell Differentiation / genetics
Cells, Cultured
Epigenesis, Genetic
Humans
Huntington Disease / genetics
Huntington Disease / pathology*
Induced Pluripotent Stem Cells / pathology*
Mitosis
Neostriatum / pathology
Neural Stem Cells / metabolism
Neurons / pathology*
Transcription Factors / metabolism
Transcriptome / genetics
Up-Regulation / genetics
Wnt Signaling Pathway*

Substances

Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding