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

doi:10.1016/j.isci.2023.106156

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	106156
Journal	iScience
Volume	26
Issue number	3
DOIs	https://doi.org/10.1016/j.isci.2023.106156
State	Published - Mar 17 2023

Keywords

Cell biology
Neuroscience
Stem cells research

ASJC Scopus subject areas

General

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10.1016/j.isci.2023.106156

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Li, W., Berlinicke, C., Huang, Y., Giera, S., McGrath, A. G., Fang, W., Chen, C., Takaesu, F., Chang, X., Duan, Y., Kumar, D., Chang, C., Mao, H. Q., Sheng, G., Dodge, J. C., Ji, H., Madden, S., Zack, D. J., & Chamling, X. (2023). High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells. iScience, 26(3), Article 106156. https://doi.org/10.1016/j.isci.2023.106156

Li, W, Berlinicke, C, Huang, Y, Giera, S, McGrath, AG, Fang, W, Chen, C, Takaesu, F, Chang, X, Duan, Y, Kumar, D, Chang, C, Mao, HQ, Sheng, G, Dodge, JC, Ji, H, Madden, S, Zack, DJ & Chamling, X 2023, 'High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells', iScience, vol. 26, no. 3, 106156. https://doi.org/10.1016/j.isci.2023.106156

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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",

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AU - Li, Weifeng

AU - Berlinicke, Cynthia

AU - Huang, Yinyin

AU - Giera, Stefanie

AU - McGrath, Anna G.

AU - Fang, Weixiang

AU - Chen, Chaoran

AU - Takaesu, Felipe

AU - Chang, Xiaoli

AU - Duan, Yukan

AU - Kumar, Dinesh

AU - Chang, Calvin

AU - Mao, Hai Quan

AU - Sheng, Guoqing

AU - Dodge, James C.

AU - Ji, Hongkai

AU - Madden, Stephen

AU - Zack, Donald J.

AU - Chamling, Xitiz

PY - 2023/3/17

Y1 - 2023/3/17

N2 - 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.

AB - 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.

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KW - Neuroscience

KW - Stem cells research

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

Abstract

Keywords

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