Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation

Demyelination contributes to the loss of function consequent to central ner vous system (CNS) injury. Enhanced remyelination through transplantation of myelin-producing cells may offer a pragmatic approach to restoring meaning ful neurological function. An unlimited source of cells suitable for such t ransplantation therapy can be derived from embryonic stem (ES) cells, which are both pluripotent and genetically flexible. In this paper we show that oligodendrocyte cultures can be reliably produced from retinoic acid-induce d ES cells and that these oligodendrocytes can myelinate axons in vitro. Me thods were further developed for generating highly enriched cultures of oli godendrocytes through an additional culturing step, producing an intermedia te "oligosphere" stage. To test whether ES cells can survive, migrate, and differentiate into mature myelin-producing cells in areas of demyelination in the adult CNS, ES cells were transplanted into the dorsal columns of adu lt rat spinal cord 3 days after chemical demyelination, In the demyelinatio n site, large numbers of ES cells survived and differentiated primarily int o mature oligodendrocytes that were capable of myelinating axons, Furthermo re, when oligosphere cells were transplanted into the spinal cords of myeli n-deficient shiverer (shi/shi) mutant mice, the ES cell-derived oligodendro cytes migrated into the host tissue, produced myelin and myelinated host ax ons. These studies demonstrate the ability of ES cell-derived oligodendrocy tes to myelinate axons in culture and to replace lost myelin in the injured adult CNS, Transplantation of ES cells may be a practical approach to trea tment of primary and secondary demyelinating diseases in the adult CNS.