MAPC® cells provide benefit in multiple models of multiple sclerosis and promote differentiation of oligodendrocytes Rochelle Cutrone1, Sarah A. Busch1, Jason A. Hamilton1, Bradley T. Lang1, Robert H. Miller2, and Robert W. Mays1 1Athersys, Inc., Cleveland, OH; 2School of Medicine and Health Sciences; George Washington University, Washington, DC
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Considerable research has implicated the hyperactive immune system as a primary driver of the disease. While current standard of care can curtail disease progression and lessen symptoms in some patients, it is ineffective in promoting repair to the damaged nervous system. Comprehensive treatment must include both safely diminishing the inflammatory response as well as promoting remyelination to improve quality of life. Multipotent adult progenitor cells (MAPC®) are a well characterized population of bone marrow-derived cells that exhibit immunomodulatory effects in central nervous system injury models such traumatic brain injury, stroke, and spinal cord injury. Here we show that MAPC cell therapy reduces deficits in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental allergic encephalomyelitis (EAE). MAPC cells administered at the time of symptom onset, or two weeks following symptom onset, resulted in statistically significant behavioral improvement compared to vehicle treatment. Luxol fast blue (LFB) staining demonstrated decreased lesion burden within the spinal cord, and a shift from complete to partial lesions, in MAPC cell-treated animals compared to controls and electron microscopic analysis provided evidence of remyelination. Additionally, direct injection of MAPC cells into lysolecithin-induced spinal cord lesions resulted in an increased white matter density, suggesting a reduction in demyelination and/or a promotion of remyelination. As the immunomodulatory ability of MAPC cell therapy is well characterized, we next investigated the capacity for MAPC cells and MAPC cell-secreted factors to promote the differentiation of mouse oligodendrocytes. In vitro, we observed a significant increase in the number of MBP and O1 positive oligodendrocytes in the presence of MAPC cells or MAPC cell-conditioned media when compared to control. Depletion of extracellular vesicles from MAPC cell-conditioned media diminished the increase of MBP and O1 positive cells. Our results suggest that MAPC cell-secreted soluble factor(s) and/or extracellular vesicles are capable of promoting oligodendrocyte differentiation. We are currently investigating the role of MAPC cell therapy in the regulation of human oligodendrocyte maturation as a possible therapy for treatment of primary and secondary progressive MS.
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