@article{3c2fe9edb4b74f2285da13c683fe53d9,
title = "High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells",
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.",
keywords = "Cell biology, Neuroscience, Stem cells research",
author = "Weifeng Li and Cynthia Berlinicke and Yinyin Huang and Stefanie Giera and McGrath, {Anna G.} and Weixiang Fang and Chaoran Chen and Felipe Takaesu and Xiaoli Chang and Yukan Duan and Dinesh Kumar and Calvin Chang and Mao, {Hai Quan} and Guoqing Sheng and Dodge, {James C.} and Hongkai Ji and Stephen Madden and Zack, {Donald J.} and Xitiz Chamling",
note = "Funding Information: Funding: Grants from the Gilbert Family Foundation (DJZ, XC), National Institutes of Health grants P30 EY001765 (DJZ, Wilmer Eye Institute), Sanofi Inc. (XC, DJZ), National Institutes of Health grants K99 EY029011 and R00EY029011 (XC), Unrestricted funds from Research to Prevent Blindness (Wilmer Eye Institute), and Generous gifts from the Guerrieri Family Foundation (DJZ). Funding Information: Funding: Grants from the Gilbert Family Foundation (DJZ, XC), National Institutes of Health grants P30 EY001765 (DJZ, Wilmer Eye Institute), Sanofi Inc. (XC, DJZ), National Institutes of Health grants K99 EY029011 and R00EY029011 (XC), Unrestricted funds from Research to Prevent Blindness (Wilmer Eye Institute), and Generous gifts from the Guerrieri Family Foundation (DJZ). W.L. assisted with experimental designs, conducted experiments, conducted bioinformatic analysis, and edited the manuscript. C.B. assisted with experimental design and high-throughput screening assay and analysis. Y.H. G.S. S.M. and J.C.D. assisted with the screening and RNA work. F.T. X.C. and Y.D. assisted in generating the stem cell reporters and differentiation of hESC-derived OPCs. W.F. C.C. and H.J. assisted with bioinformatic analysis. D.J.Z. designed the study, edited the manuscript, and provided funding support. X.C. designed the study, performed experiments, wrote the manuscript, and provided funding support. D.J.Z. and X.C. are inventors on an intellectual property disclosure related to the technology described in the manuscript that has been filed with Johns Hopkins University, which seeks to license the technology. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = mar,
day = "17",
doi = "10.1016/j.isci.2023.106156",
language = "English (US)",
volume = "26",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "3",
}