Title

The regenerative potential of the subventricular zone in aging and injury

Date of Completion

January 2010

Keywords

Biology, Neurobiology|Health Sciences, Aging|Health Sciences, Human Development

Degree

Ph.D.

Abstract

The subventricular zone (SVZ) is a thin, highly proliferative region that lies subjacent to the lateral walls of the lateral ventricles in the adult mammalian brain. A subpopulation of astrocytes in the SVZ considered to be the neural stem cells contributes to active neurogenesis throughout adulthood. With aging, we detected signs of SVZ deterioration with a decline in cell proliferation, a reduction in the size of the neurogenic area and changes in the cytoarchitecture. However, in what remained of the elderly SVZ, key components typical of a younger neurogenic stem cell niche were still maintained. Surprisingly, in the aged SVZ we did observe increased numbers of astrocytes fully integrated within the ependyma, contacting the ventricle and possessing several characteristics of ependymal cells. To determine the origin of these inserted astrocytes, we labeled dividing astrocytes in the aged SVZ by consecutive BrdU injections for ten days. Three weeks later, we detected labeled astrocytes within the lateral wall ependyma, some of which co-expressed ependymal cell markers. No mature ependymal cells were BrdU + at this time point, indicating that ependymal cells were not dividing. However, after six and thirteen weeks, we detected an increase in the number of BrdU-retaining ependymal cells that coincided with decreased numbers of BrdU-retaining astrocytes within the ependymal monolayer, suggesting that a transition from astrocytes to ependymal-like cells occurred. To introduce a requirement for new ependymal cells in young mice, we created mild ependymal denudation by intraventricular injection of neuraminidase. We similarly observed dividing SVZ astrocytes that inserted into the neighboring ependyma and gradually converted to ependymal-like cells, mimicking the process seen in elderly mice. We further validated SVZ-mediated ependymal repair in an astrocyte lineage-tracking young mouse model GFAP-TV-A again using neuraminidase treatment to remove individual ependymal cells, followed by retroviral infections. One week later, we detected labeled astrocytes within the ependyma that also co-labeled with ependymal cell markers. Together, these results indicate that the adult SVZ not only contributes to neurogenesis, but also mediates ependymal repair in response to aging and moderate injury. ^