High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells

• Authors: Weifeng Li, Johns Hopkins School of Medicine; Cynthia Berlinicke, Wilmer Eye Institute; Yinyin Huang, Sanofi Inc.; Stefanie Giera, Sanofi Inc.; Anna G McGrath, Sanofi Inc.; Weixiang Fang, Johns Hopkins Bloomberg School of Public Health; Chaoran Chen, Johns Hopkins Bloomberg School of Public Health; Felipe Takaesu, Emory University School of Medicine; Xiaoli Chang, Wilmer Eye Institute; Yukan Duan, Wilmer Eye Institute; Dinesh Kumar, Sanofi Inc.; Calvin Chang, Johns Hopkins School of Medicine; Hai-Quan Mao, Johns Hopkins School of Medicine; Guoqing Sheng, Sanofi Inc.; James C Dodge, Sanofi Inc.; Hongkai Ji, Johns Hopkins Bloomberg School of Public Health; Stephen Madden, Sanofi Inc.; Donald J Zack, Johns Hopkins School of Medicine; Xitiz Chamling, Wilmer Eye Institute
• Journal Title: iScience
• Volume: Volume 26, Number 3
• Publisher: Elsevier Inc., | 2023-03-17, Pages 106156-106156
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.isci.2023.106156
• Subjects: Engineering, Biomedical
• Keywords: Cell biology; Neuroscience; Stem cells research

Abstract

Promoting myelination capacity of endogenous oligodendrocyte precursor cells (OPCs) is a promising therapeutic approach for CNS demyelinating disorders such as Multiple Sclerosis (MS). To aid in the discovery of myelination-promoting compounds, we generated a genome-engineered human pluripotent stem cell (hPSC) line that consists of three reporters: identification-and-purification tag, GFP, and secreted-NanoLuc, driven by the endogenous PDGFRA, PLP1, and MBP genes, respectively. Using this cell line, we established a high-throughput drug screening platform and performed a small-molecule screen, which identified at least two myelination-promoting small-molecule (Ro1138452 and SR2211) that target prostacyclin (IP) receptor and retinoic acid receptor-related orphan receptor γ (RORγ), respectively. Single-cell-transcriptomic analysis of differentiating OPCs treated with these molecules further confirmed that they promote oligodendrocyte differentiation and revealed several pathways that are potentially modulated by them. The molecules and their target pathways provide promising targets for the possible development of remyelination-based therapy for MS and other demyelinating disorders.