Oligodendrocyte Progenitor Cells Differentiation Induction with MAPK/ERK Inhibitor Fails to Support Repair Processes in the Chronically Demyelinated CNS
Omri Zveik1, Tal Ganz1, Nina Fainstein1, Marva Lachish1, Ariel Rechtman1, Lihi Sofer1, Tamir Ben-Hur1, Adi Vaknin-Dembinsky1
1The Department of Neurology and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center
Objective:
We aimed to examine the effect of PD0325901 treatment on the chronically-inflamed CNS, and to further characterize its immunosuppressive properties on different cell populations.
Background:
Remyelination failure is considered a major obstacle in treating chronic-progressive Multiple Sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need of a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models.
Design/Methods:
We examined the pathological and clinical effect of PD0325901 in Biozzi mouse EAE model in vivo, as well as its effect on OPCs differentiation and immune function in vitro.
Results:
Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive EAE with PD0325901 showed no clinical improvement in comparison to control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC.
Conclusions:
Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.