High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells
Weifeng Li,
Cynthia Berlinicke,
Yinyin Huang,
Stefanie Giera,
Anna G. McGrath,
Weixiang Fang,
Chaoran Chen,
Felipe Takaesu,
Xiaoli Chang,
Yukan Duan,
Dinesh Kumar,
Calvin Chang,
Hai-Quan Mao,
Guoqing Sheng,
James C. Dodge,
Hongkai Ji,
Stephen Madden,
Donald J. Zack,
Xitiz Chamling
Affiliations
Weifeng Li
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Cynthia Berlinicke
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Yinyin Huang
Sanofi Inc., Translational Science, 350 Water Street, Cambridge, MA, 02141, USA
Stefanie Giera
Sanofi Inc., Rare and Neurologic Diseases Therapeutic Area, 350 Water Street, Cambridge, MA, 02141, USA
Anna G. McGrath
Sanofi Inc., Rare and Neurologic Diseases Therapeutic Area, 350 Water Street, Cambridge, MA, 02141, USA
Weixiang Fang
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Chaoran Chen
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Felipe Takaesu
Wallace H. Coulter Department of Biomedical Engineering, Emory University School of Medicine & Georgia Institute of Technology, Atlanta, GA, USA
Xiaoli Chang
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Yukan Duan
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Dinesh Kumar
Sanofi Inc., Translational Science, 350 Water Street, Cambridge, MA, 02141, USA
Calvin Chang
Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
Hai-Quan Mao
Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; Institute for NanoBioTechnology, Johns Hopkins University, Whiting School of Engineering Baltimore, MD 21218, USA
Guoqing Sheng
Sanofi Inc., Rare and Neurologic Diseases Therapeutic Area, 350 Water Street, Cambridge, MA, 02141, USA
James C. Dodge
Sanofi Inc., Rare and Neurologic Diseases Therapeutic Area, 350 Water Street, Cambridge, MA, 02141, USA
Hongkai Ji
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Stephen Madden
Sanofi Inc., Translational Science, 350 Water Street, Cambridge, MA, 02141, USA
Donald J. Zack
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Xitiz Chamling
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Corresponding author
Summary: 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.
