Myelination is essential to the normal physiology and function of the central nervous system (CNS). As an insulating layer that surrounds the axons of the central nervous system, myelin provides trophic support and allows the efficient conduction of electrophysiological signals through saltatory conduction. The importance of myelin becomes particularly evident in some pathological conditions. For example in multiple sclerosis (MS), the progressive loss of myelin is believed to contribute to axonal atrophy and dysfunction.
CNS myelin is formed by a population of specialized glial cells called oligodendrocytes, whereas PNS myelination is carried out by Schwann cells. Oligodendrocytes arise from restricted zones in the developing telencephalon and spinal cord. Under the influence of several transcription factors (e.g., the Olig1/2 and Sox family of proteins) and morphogens (e.g., Sonic hedgehog and BMPs), neural precursors specialize into oligodendrocyte precursor cells (OPCs) and migrate toward regions in the CNS. These proliferating OPCs express stage-specific proteins, such as PDGFαR and proteoglycan NG2, and remain responsive to mitogens (e.g., PDGF) during migration. Upon reaching their target, OPCs begin to differentiate into pre-myelinating oligodendrocytes and extend multiple processes to make contact with up to 50 axon segments. The establishment of this glialaxon interaction is a critical point in oligodendrocyte differentiation and mediates target-dependent oligodendrocyte survival. Ultimately, myelinating oligodendrocytes begin membrane expansion and synthesis of myelin components such as myelin basic protein (MBP), and will ensheath surrounding axons with myelin.
Multiple steps in oligodendroglial development have been shown to involve complex glial-matrix and glial-axon interactions. For instance, cell culture studies have shown that oligodendrocyte differentiation and membrane expansion are enhanced by the extracellular matrix protein laminin. In several genetic models, including invertebrates, glial cell function is influenced by neuronal contact. For example, in the C. elegans nervous system, although myelin is not formed, the glial ensheathment of neurons regulates synapse formation and function. In the drosophila CNS, the development of midline glia is tightly regulated by cell-cell contact with adjacent neurons. Also, in a study using rat-mouse cultures, mouse oligodendrocytes have enhanced proliferation and survival in the presence of rat dorsal root ganglia compared to when cultured alone. However, the factors and mechanisms that regulate axon-glial interactions during mammalian oligodendrocyte development and myelination in vivo remain largely uncharacterized. One group of molecules, however, that has been implicated in axon-glial interactions is the integrin family of receptors.
Oligodendrocyte Lineage Development
Despite the importance of myelin for the rapid transmission of action potentials, the molecular basis of oligodendrocyte differentiation and CNS myelination are still incompletely understood. Recently, neurons and glial cells have been successfully created from stem cells such as embryonic stem cells, mesenchymal stem cells, and neural stem cells. In order for stem-cell transplantation therapy to be effectively used in practice, however, two concerns must be addressed: to determine what kind of stem cells would be an ideal source for cellular grafts, and the mechanism by which transplantation of stem cells directs structural and functional recovery.
Stem cells are cells with the capability of continuous self-renewal and possess the pluripotent ability to differentiate into many diverse, specialized cell types. Two important types of mammalian pluripotent stem cells have been identified in the past which can give rise to various organs and tissues: embryonic stem cells (ESCs) derived from the inner cell mass of blastocysts and embryonic germ cells (EGCs) obtained from post-implantation embryos. More recently, there has been an exciting breakthrough in the generation of a new class of pluripotent stem cells, induced pluripotent cells (iPS cells), from adult somatic cells such as skin fibroblasts by induction of embryogenesis-related genes. This led to the isolation of tissue-specific stem cells from various tissues of more advanced developmental stages such as hematopoietic stem cells, bone marrow mesenchymal stem cells, adipose tissue-derived stem cells, and neural stem cells. Found in the developing or adult mammalian brain, these multipotent neural stem cells (NSCs) are capable of indefinite growth and the multipotent potential to differentiate into three major CNS cell types: neurons, astrocytes, and oligodendrocytes.
Figure 1 Human oligodendrocyte development. Oligodendrocyte lineage proceeds from first a neural stem cell, to an oligodendrocyte progenitor cell, then an immature oligodendrocyte, and finally a mature oligodendrocyte. The markers which signify each phase of development are listed. At certain stages the cells also have the potential to form astrocytes and immature neurons.
In humans, the existence of NSCs with multipotent differentiation capability has also been reported in the embryonic and adult human brain. These primary neural stem cells found in the ventricular zone of the human brain continue to divide asymmetrically and give rise to the intermediate progenitor cells in the sub ventricular zone. Developmentally, these cells are produced by sub ventricular cells in the brain and spinal cord that give rise to committed oligodendrocyte progenitor cells (OPCs) that divide and migrate throughout the CNS. These OPCs can then terminally differentiate into post-mitotic, pre-myelinating oligodendrocytes which, under appropriate environmental conditions, will further mature and myelinate nearby receptive axons. Oligodendrocyte progenitor cells have been defined as cells expressing NG2 and/or PDGFRA on their surface. These cells have been shown to respond to environmental factors to develop into oligodendrocytes capable of producing new myelin, and yet they also retain multi-lineage plasticity and can give rise to neurons and astrocytes when removed from the adult parenchymal environment. A substantial population of these OPCs remains in an undifferentiated state in the adult human brain as parenchymal glial progenitor cells and are recruited for repair of damaged CNS tissue. These adult OPCs can be potential targets for cell-based treatment of demyelinating diseases.