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

Abstract

Demyelination contributes to the loss of function consequent to central nervous system (CNS) injury. Enhanced remyelination through transplantation of myelin-producing cells may offer a pragmatic approach to restoring meaningful neurological function. An unlimited source of cells suitable for such transplantation 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-induced ES cells and that these oligodendrocytes can myelinate axons in vitro. Methods were further developed for generating highly enriched cultures of oligodendrocytes through an additional culturing step, producing an intermediate ''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 adult rat spinal cord 3 days after chemical demyelination. In the demyelination site, large numbers of ES cells survived and differentiated primarily into mature oligodendrocytes that were capable of myelinating axons. Furthermore, when oligosphere cells were transplanted into the spinal cords of myelindeficient shiverer (shi/shi) mutant mice, the ES cell-derived oligodendrocytes migrated into the host tissue, produced myelin and myelinated host axons. These studies demonstrate the ability of ES cell-derived oligodendrocytes 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 treatment of primary and secondary demyelinating diseases in the adult CNS. R ecovery in central nervous system (CNS) disorders is hindered by the limited ability of the vertebrate CNS to regenerate lost cells, replace damaged myelin, and re-establish functional neural connections. In many CNS disorders, including multiple sclerosis, stroke, spinal cord injury, and other trauma, demyelination of intact axons (1-4) is an important factor contributing to loss of function. Previous studies suggest that substantial recovery of function might be achieved through remyelination of otherwise intact axons (5). As a therapeutic modality, functional recovery through remyelination may prove to be a pragmatic approach to regeneration.Ethical considerations and a lack of a reliable source for undifferentiated pluripotent cells have limited the application of neural transplantation studies in humans. Embryonic stem cells (ES cells) provide a partial solution to these problems because they are genetically normal, pluripotent, capable of indefinite replication (6), and have been derived from several vertebrate species including mice (7,8) The purpose of the present studies was threefold: (i) to develop methods for producing enriched cultures of ES cell-derived oligodendrocytes, (ii) to determine whether these cells could myelinate axons in vitro, and (iii) to determine whether ES cells would survive transplantati...

Cell Therapy for Multiple Sclerosis

“…Embryonic stem (ES) cells are derived from the inner cell mass of blastocyst-stage embryos, and are pluripotent cells that are able to generate the entire repertoire of cell types in the body. Glial precursors with myelinogenic properties were derived from mouse ES cells [196][197][198]. Human ES cells [199,200] can be directed into neural fate [201,202].…”

Neuropathology: the foundation for new treatments in spinal cord injury

“…They also have the advantage of being able to migrate into the surrounding tissues. [61][62][63][64] ESC have also been shown to have the ability to differentiate into oligodendrocytes and myelinate naked axons in culture. The outcome in animal models of SCI is improved by the use of suitable polymer scaffolds within the lesion site designed to provide a framework for the regenerating axons.…”

Complex Treatment of Multiple Sclerosis Patients by Use of Fetal Stem Cells

“…ESCs express distinct surface markers, such as Oct-4, Sox-2 and SSEA-1/2/3/4. Several studies identified an ability of such cells to differentiate into myelin-producing cells (oligodendrocytes) [25][26][27][28][29][30][31][32][33] and neurons [34][35][36] therefore, became suitable candidates for neuro-regeneration and remyelination in diseases such as MS. In a recent study it was established that neurospheres derived from ESCs being obtained from ILRIL6 chimeras (soluble IL-6 receptor fused to IL-6) and could exhibit higher differentiation into oligodendrocytes with more branches and peripheral accumulation of myelin-basic protein on myelin membranes [36].…”