The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation

Abstract

Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA), generated by hyaluronidase activity, block OPC maturation and remyelination. Here, we aimed to identify which hyaluronidases are elevated in demyelinating lesions and to test if they influence OPC maturation and remyelination. We find that the Cell Migration Inducing and hyaluronan binding Protein (CEMIP) is elevated in demyelinating lesions in mice with experimental autoimmune encephalomyelitis during peak disease when neuroinflammatory mediators, including tumor necrosis factor-α (TNFα), are at high levels. CEMIP expression is also elevated in demyelinated MS patient lesions. CEMIP is expressed by OPCs, and TNFα induces increased CEMIP expression by OPCs. Both increased CEMIP expression and HA fragments generated by CEMIP block OPC maturation into OLs. CEMIP-derived HA fragments also prevent remyelination in vivo. These data indicate that CEMIP blocks remyelination by generating bioactive HA fragments that inhibit OPC maturation. CEMIP is therefore a potential target for therapies aimed at promoting remyelination.