The synergistic regenerative and anti-inflammatory effects of Ponesimod and amniotic epithelial stem cells in the Cuprizone animal model of multiple sclerosis

Stem cells have shown potential in treating multiple sclerosis (MS) based on their capacity tonull inhibit pathogenic immune responses and release neuroprotective and oligodendrogenic molecules in favor of tissue repair. It has shown that human amniotic epithelial cells (hAECs) can release various neurotrophic, immunomodulatory, and anti-inflammatory factors; therefore, their potential as a cell therapy for MS is suggested. In this study, the synergistic therapeutic effect of hAECs and Ponesimod was investigated in the Cuprizone-induced animal model. Ponesimod is an FDA-approved drug for the treatment of MS with established immunomodulatory and neuroprotective effects. The effect of different treatment regimens was investigated, including Ponesimod, IV injection of hAECs, stereotaxic injection of hAECs, and concomitant administration of stereotaxic-injected hAECs and Ponesimod. Simultaneous administration of stereotaxic-injected hAECs and Ponesimod was the most potent in restoring Cuprizone-induced neurobehavioral deficit and brain atrophy. Immunostaining for oligodendrocytic, microglial, and astrocytic markers showed that cell and drug co-administration was superior to other treatments in rebuilding the oligodendrocyte cells in the CNS cell population and reversing Cuprizone-induced astrogliosis and microgliosis. Therefore, the combination therapy with hAECs and Ponesimod is promising in restoring the neurobehavioral deficit, pro-inflammatory glial response, and oligodendrocyte loss in the animal model, and is recommended as a candidate for treating MS.