Stem and progenitor cells of the postnatal CNS

One of the big surprises in neurobiology recently has been the realization that there are pockets of stem cells in the adult brain that continuously generate new neurons throughout life, both in rodents and humans. The majority of ?adult-born? neurons populate the olfactory bulb (a brain structure required for recognition and memory of odors) and the hippocampus (an enigmatic structure involved in laying down memories of places and events). We are still in the dark about the precise role of the new neurons. Nevertheless, there is widespread excitement that, because stem cells can generate some types of neurons under normal conditions, they might have a wider potential to generate neurons to replace those that are lost through injury or neurodegenerative diseases like Parkinson?s or Alzheimer?s. This is a challenging idea because, as far as we know, the stem cells do not normally make the kinds of neurons that are destroyed in these diseases. The question is, do they have the potential to make the neurons we want, if only we could learn how to ?tweak? them?

We and others recently discovered that there is not just one kind of stem cell in the healthy brain but several, possibly many, that have slightly different properties and that specialize in making different kinds of neurons in the olfactory bulb. This is encouraging because it implies that there might be yet more types of stem cells that we don?t know about yet, perhaps some with the properties we are looking for. On the other hand, it complicates the picture because we now have more cells to sort through. In the programme of work we describe here we make a start towards understanding the different behaviours we might expect from different stem cell subtypes when they are confronted with different forms of damage such as ischemia (interruption of blood supply such as occurs during stroke) or demyelination (loss of the insulating layer around nerve fibres, such as happens in multiple sclerosis) or in a genetic form of motor neuron disease (in which spinal motor neurons die, leading to paralysis. We will do this by genetically manipulating mice to mark one stem cell subtype or the other with a fluorescent label, so that we can follow their behaviour separately in the intact brain. The fluorescent label also allows us to purify and study them separately in a culture dish.

We showed recently that the adult forebrain subventricular zone (SVZ) contains a mixture of stem cells that have spatially diverse origins in the embryonic telencephalon and different neurogenic properties in the adult. We shall use genetically manipulated mice to dissect the roles of these different SVZ stem cell sub-populations in adult olfactory neurogenesis and olfactory behaviour, and their possibly distinct regenerative responses to damage. There are also stem cells in the adult spinal cord ependymal zone (EZ) surrounding the central canal. By analogy with the SVZ, the EZ might be expected to inherit the spatially patterned cell fate restrictions of the embryonic neuroepithelium. We will test this by mapping the embryonic origins of the EZ and asking whether embryonic ancestry predicts adult stem cell response to degenerative disease (a genetic model of motor neuron disease), demyelination or physical injury. Finally, we shall examine the role of ?NG2 cells? ? an abundant and ubiquitous population of progenitor cells in the adult CNS ? in adult gliogenesis and cortical neurogenesis, testing the ideas that de novo myelination of previously naked axons contributes to neural plasticity and that adult-born cortical projection neurons likewise have a significant functional role.