High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte
Weifeng Li1, Cynthia Berlinicke2, Yinyin Huang3
1Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Iscience
|February 28, 2023
Summary
This study developed a novel human stem cell line to screen for drugs that promote myelination. Two compounds targeting IP receptor and RORγ were identified, offering potential for treating demyelinating disorders like Multiple Sclerosis.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Pharmacology
Background:
- Central nervous system (CNS) demyelinating disorders, such as Multiple Sclerosis (MS), are characterized by damage to myelin.
- Enhancing the myelination capacity of endogenous oligodendrocyte precursor cells (OPCs) is a key therapeutic strategy.
- Developing effective remyelination therapies requires robust methods for identifying pro-myelinating compounds.
Purpose of the Study:
- To create a genome-engineered human pluripotent stem cell (hPSC) line for high-throughput screening of myelination-promoting compounds.
- To identify novel small molecules that enhance OPC differentiation and promote myelination.
- To explore the molecular pathways modulated by identified pro-myelinating compounds.
Main Methods:
- Generation of a reporter hPSC line engineered to track OPC differentiation via PDGFRA, PLP1, and MBP gene expression.
- Establishment of a high-throughput drug screening platform using the engineered hPSC line.
- Small-molecule screening, followed by single-cell transcriptomic analysis of drug-treated OPCs.
Main Results:
- Identification of two small molecules, Ro1138452 and SR2211, that promote myelination.
- Ro1138452 targets the prostacyclin (IP) receptor, while SR2211 targets the retinoic acid receptor-related orphan receptor γ (RORγ).
- Transcriptomic analysis confirmed enhanced oligodendrocyte differentiation and revealed modulated cellular pathways.
Conclusions:
- The developed hPSC-based screening platform is effective for discovering myelination-promoting compounds.
- The identified small molecules and their targeted pathways represent promising candidates for remyelination therapies.
- This approach holds potential for developing new treatments for MS and other demyelinating CNS disorders.
