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Preparation of Rat Oligodendrocyte Progenitor Cultures and Quantification of Oligodendrogenesis Using Dual-infrared Fluorescence Scanning
Published on: February 17, 2016
Pharmacological modulation of inflammatory oligodendrocyte progenitor cells using three multiple sclerosis disease
Larissa Jank1, Riley B Catenacci2, Veronica Minney1
1Department of Neurology, Johns Hopkins University School of Medicine, United States.
Abstract:
Preclinical studies of pro-remyelinating therapies for multiple sclerosis tend to neglect the effect of the disease-relevant inflammatory milieu. Interferon-gamma (IFN-γ) is known to suppress oligodendrocyte progenitor cell (OPC) differentiation and induce a recently described immune OPC (iOPC) phenotype characterized by expression of major histocompatibility complex (MHC) molecules. We tested the effects of cladribine (CDB), dimethylfumarate (DMF), and interferon-beta (IFN-β), existing anti-inflammatory therapies for MS, on the IFN-γ-induced iOPC formation and OPC differentiation block. In line with previous reports, we demonstrate that IFN-β and DMF inhibit OPC proliferation, while CDB had no effect. None of the drugs exhibited cytotoxic effects at the physiological concentrations tested in vitro. In a differentiation assay, none of the drugs were able to promote differentiation, under inflammatory or basal conditions. To study drug effects on iOPCs, we monitored MHC expression in vitro with live cell imaging using cells isolated from MHC reporter mice. IFN-β suppressed induction of MHC class II, and DMF led to suppression of both class I and II. CDB had no effect on MHC induction. We conclude that promoting proliferation and differentiation and suppressing iOPC induction under inflammatory conditions may require separate therapeutic strategies and must be balanced for maximal repair. Our in vitro MHC screening assay can be leveraged across cell types to test the effects of drug candidates and disease-related stimuli.
Insights
Existing multiple sclerosis therapies like cladribine, dimethylfumarate, and interferon-beta do not promote oligodendrocyte progenitor cell differentiation or block immune cell formation. Separate strategies are needed for maximal repair in multiple sclerosis.
Area of Science:
- Neuroimmunology
- Regenerative Medicine
- Pharmacology
Background:
- Multiple sclerosis (MS) preclinical studies often overlook inflammatory effects on remyelination.
- Interferon-gamma (IFN-γ) inhibits oligodendrocyte progenitor cell (OPC) differentiation and promotes an immune OPC (iOPC) phenotype.
- iOPCs express major histocompatibility complex (MHC) molecules, contributing to the inflammatory milieu.
Purpose of the Study:
- To evaluate the impact of cladribine (CDB), dimethylfumarate (DMF), and interferon-beta (IFN-β) on IFN-γ-induced iOPC formation.
- To assess the effects of these MS therapies on OPC differentiation block.
- To investigate the modulation of MHC expression on iOPCs by these drugs.
Main Methods:
- In vitro testing of CDB, DMF, and IFN-β on OPC proliferation and differentiation.
- Assessment of drug cytotoxicity at physiological concentrations.
- Live cell imaging of MHC expression in iOPCs derived from MHC reporter mice.
Main Results:
- IFN-β and DMF inhibited OPC proliferation; CDB had no effect.
- No tested drug promoted OPC differentiation under basal or inflammatory conditions.
- IFN-β suppressed MHC class II induction, DMF suppressed both class I and II, and CDB had no effect on MHC expression.
Conclusions:
- Promoting OPC proliferation, differentiation, and suppressing iOPC induction may necessitate distinct therapeutic approaches for effective MS repair.
- Current MS therapies have varied effects on the immune response within the central nervous system.
- An in vitro MHC screening assay can be utilized to evaluate drug candidates and disease-related stimuli across various cell types.
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