Astronauts who spend significant time in space may experience intracranial hypertension (pressure inside the skull), which often does not normalize upon return to Earth. This type of intracranial pressure can cause vision problems, headaches, glaucoma, and other serious health problems, making it a significant obstacle to long-duration space exploration missions. NASA is hoping that a better understanding of how central nervous system stem cells divide in microgravity will help lead to ways to protect astronauts from problems with intracranial pressure and to design adequate preventive measures. These studies examine cell growth and division of neural stem cells that experienced microgravity on the International Space Station and were returned to normal gravity prior to live-cell imaging studies to determine cell changes.

Glial progenitor cells (GPCs) comprise the most abundant population of progenitor cells in the adult human brain. They are responsible for central nervous system (CNS) remyelination, and likely contribute to the astrogliotic response to brain injury and degeneration as well. Adult human GPCs are biased to differentiate as oligodendrocytes and elaborate new myelin, and yet they retain multilineage plasticity, and can give rise to neurons as well as astrocytes and oligodendrocytes once removed from the adult parenchymal environment. GPCs retain strong mechanisms for cell-autonomous self-renewal, and yet both their phenotype and fate may be dictated by their microenvironment. Using the transcriptional profiles of acutely isolated GPCs, we have begun to understand the operative ligand–receptor interactions involved in these processes, and have identified several key signaling pathways by which adult human GPCs may be reliably instructed to either oligodendrocytic or astrocytic fate. In addition, we have noted significant differences between the expressed genes and dominant signaling pathways of fetal and adult human GPCs, as well as between rodent and human GPCs. The latter data in particular call into question therapeutic strategies predicated solely upon data obtained using rodents, while perhaps highlighting the extent to which evolution has been attended by the phylogenetic modification of glial phenotype and function.

Glutamate is the principal excitatory neurotransmitter in the CNS, but it is also a potent neurotoxin that can kill nerve cells. Glutamate damages oligodendrocytes, like neurons, by excitotoxicity which is caused by sustained activation of AMPA, kainate and NMDA receptors. Glutamate excitotoxicity depends entirely on Ca2+ overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death which is prevented by glutamate receptor antagonists. In turn, activated, but not resting microglia, can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity, which is attenuated either by AMPA/kainate antagonists or by the blockade of the system xc_ antiporter present in microglia. By contrast, non-lethal, brief, activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack. Intriguingly, these effects are exclusively mediated by kainate receptors which induce Ca2+ overload of the cytosol and the generation of reactive oxygen species. In conjunction, these observations reveal novel mechanisms by which neuroinflammation alters glutamate homeostasis and triggers oligodendrocyte death. Conversely, they also show how glutamate signaling in oligodendrocytes might induce immune attack. In both instances direct activation of glutamate receptors present in oligodendrocytes plays a pivotal role in either initiating or executing death signals, which might be relevant to the pathogenesis of white matter disorders.

Of the axonal signals influencing myelination, adhesion molecules expressed at the axonal surface are strong candidates to mediate interactions between myelinating cells and axons. The recognition cell-adhesion molecule L1, a member of the immunoglobulin superfamily has been shown to play important roles in neuronal migration and survival, and in PNS myelination. We have investigated the role of axonally expressed L1 in CNS myelination. In co-cultures of myelinating oligodendrocytes and neurons derived from murine brain, we demonstrate that, before myelination, L1 immunoreactivity is confined to neurites. After myelination commences, L1 expression is downregulated on myelinated axons and adjacent, but not yet myelinated, internodes. Interfering with L1 before the onset of myelination, by adding either anti-L1 antibody or L1-Fc fusion proteins to the culture medium, inhibits myelination. In addition, in purified cultures of oligodendrocytes, L1-Fc fusion protein prevents lysophosphatidic acid-induced activation of the mitogen-activated kinase (MAP)-kinase pathway. Together, our data indicate that L1 is involved in the initiation of CNS myelination, and that this effect might involve the dephosphorylation of oligodendroglial phosphoproteins.

Oligodendrocytes, derived from stem cell precursors which arise in subventricular zones of the developing central nervous system, have as their specialist role the synthesis and maintenance of myelin. Astrocytes contribute to the cellular architecture of the central nervous system and act as a source of growth factors and cytokines; microglia are bone-marrow derived macrophages which function as primary immunocompetent cells in the central nervous system. Myelination depends on the establishment of stable relationships between each differentiated oligodendrocyte and short segments of several neighbouring axons. There is growing evidence, especially from studies of glial cell implantation, that oligodendrocyte precursors persist in the adult nervous system and provide a limited capacity for the restoration of structure and function in myelinated pathways damaged by injury or disease.

This review summarises some of the major findings derived from studies using the model of a glia-depleted environment developed and characterised in this laboratory. Glial depletion is achieved by exposure of the immature rodent spinal cord to x-radiation which markedly reduces both astrocyte and oligodendrocyte populations and severely impairs myelination. This glia-depleted, hypomyelinated state presents a unique opportunity to examine aspects of spinal cord maturation in the absence of a normal glial population. An associated sequela within 2–3 wk following irradiation is the appearance of Schwann cells in the dorsal portion of the spinal cord. Characteristics of these intraspinal Schwann cells, their patterns of myelination or ensheathment, and their interrelations with the few remaining central glia have been examined. A later sequela is the development of Schwann cells in the ventral aspect of the spinal cord where they occur predominantly in the grey matter. Characteristics of these ventrally situated intraspinal Schwann cells are compared with those of Schwann cells located dorsally. Recently, injury responses have been defined in the glia-depleted spinal cord subsequent to the lesioning of dorsal spinal nerve roots. In otherwise normal animals, dorsal nerve root injury induces an astrocytic reaction within the spinal segments with which the root(s) is/are associated. Lesioning of the 4th lumbar dorsal root on the right side in irradiated or nonirradiated animals results in markedly different glial responses with little astrocytic scarring in the irradiated animals. Tracing studies reveal that these lesioned dorsal root axons regrow rather robustly into the spinal cord in irradiated but not in nonirradiated animals. To examine role(s) of glial cells in preventing this axonal regrowth, glial cells are now being added back to this glia-depleted environment through transplantation of cultured glia into the irradiated area. Transplanted astrocytes establish barrier-like arrangements within the irradiated cords and prevent axonal regrowth into the cord. Studies using other types of glial cultures (oligodendrocyte or mixed) are ongoing.