EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP.

Emanuela Nocita,Elena Romano,Antonella Ragnini-Wilson,Marcella Trombetta,Laura Boccuni,Alice Del Giovane,Alberto Rainer,Enrico Traversa,Marta Tiberi,Carola Sposato,Denise Fiorelli,Francesco Basoli

doi:10.3390/cells8080844

Abstract

Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by transcriptional and morphological changes. How this differentiation program is controlled remains unclear. We used two drugs that stimulate myelin basic protein (MBP) expression (Clobetasol and Gefitinib) alone or combined with epidermal growth factor receptor (EGFR) or Retinoid X Receptor gamma (RXRγ) gene silencing to decode the receptor signaling required for OPC differentiation in myelinating OLs. Electrospun polystyrene (PS) microfibers were used as synthetic axons to study drug efficacy on fiber engagement. We show that EGFR inhibition per se stimulates MBP expression and increases Clobetasol efficacy in OPC differentiation. Consistent with this, Clobetasol and Gefitinib co-treatment, by co-regulating RXRγ, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.

Highlights

The myelin sheath insulates axons of the central nervous system (CNS), allowing neural impulses to be transmitted rapidly along axons
Four main pharmacological classes have been identified in phenotypical screens for promyelinating agents based on myelin basic protein (MBP) upregulation: glucocorticoids, epidermal growth factor receptor (EGFR)/ErbB inhibitors, Benztropine/Bromocriptine and antifungal drugs such as Miconazole and Clotrimazole
The glucocorticoid receptor GR/NR3C1 was found at the node of the glucocorticoid group of compounds [8] and the EGFR/ErbB receptors at the node of Gefitinib and Erlotinib drug action

Summary

Introduction

The myelin sheath insulates axons of the central nervous system (CNS), allowing neural impulses to be transmitted rapidly along axons. Remyelination is the natural process that restores damaged myelin and thereby neuronal function in the adult brain. This ability declines as a consequence of aging or during the progressive phases of multiple sclerosis (MS) [1,2,3]. Pharmacologically-induced remyelination has been envisaged in co-therapies with disease modifying agents for relapsing remitting and secondary progressive MS (RRMS and SPMS, respectively), to restore neuronal function, and for its protective potential on neurodegeneration [1,2,3,4]. Cells 2019, 8, 844 promote myelin basic protein (MBP) expression in cell-based assays that employed either primary murine Oligodendrocyte Precursor Cells (OPCs) [5,6,7], mouse OPC cell lines such as Oli-neuM [8]. A rational use of such drugs in remyelination therapies awaits the clarification of their molecular targets [1,2,3,4,5,6,7,8,9,10]

Methods

Results

Conclusion