Human Huntington's Disease iPSC-Derived Cortical Neurons Display Altered Transcriptomics, Morphology, and Maturation

Shagun R Mehta; Colton M Tom; Yizhou Wang; Catherine Bresee; David Rushton; Pranav P Mathkar; Jie Tang; Virginia B Mattis

doi:10.1016/j.celrep.2018.09.076

Human Huntington's Disease iPSC-Derived Cortical Neurons Display Altered Transcriptomics, Morphology, and Maturation

Cell Rep. 2018 Oct 23;25(4):1081-1096.e6. doi: 10.1016/j.celrep.2018.09.076.

Authors

Shagun R Mehta¹, Colton M Tom¹, Yizhou Wang², Catherine Bresee³, David Rushton¹, Pranav P Mathkar¹, Jie Tang², Virginia B Mattis⁴

Affiliations

¹ The Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Genomics Core Facility, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Biostatistics & Bioinformatics Research Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴ The Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: virginiamattis@gmail.com.

PMID: 30355486
DOI: 10.1016/j.celrep.2018.09.076

Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat in the Huntingtin (HTT) gene. Induced pluripotent stem cell (iPSC) models of HD provide an opportunity to study the mechanisms underlying disease pathology in disease-relevant patient tissues. Murine studies have demonstrated that HTT is intricately involved in corticogenesis. However, the effect of mutant Hungtintin (mtHTT) in human corticogenesis has not yet been thoroughly explored. This examination is critical, due to inherent differences in cortical development and timing between humans and mice. We therefore differentiated HD and non-diseased iPSCs into functional cortical neurons. While HD patient iPSCs can successfully differentiate toward a cortical fate in culture, the resulting neurons display altered transcriptomics, morphological and functional phenotypes indicative of altered corticogenesis in HD.

Keywords: Huntingtin; Huntington’s disease; cerebral cortex; corticogenesis; differentiation; iPSC.

Publication types

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

MeSH terms

Cell Differentiation / genetics*
Cell Shape / genetics*
Cells, Cultured
Cerebral Cortex / pathology*
Gene Regulatory Networks
Humans
Huntington Disease / pathology*
Induced Pluripotent Stem Cells / pathology*
Neurites / metabolism
Neurons / metabolism
Neurons / pathology*
Phenotype
Transcriptome / genetics*