Achieving tissue homeostasis in the adult organism requires the continual replacement of cells which have died due to aging, damage or disease. While it was once thought that the adult brain was an exception to this aspect of tissue regulation, it is now known that the brain contains several regions where neurogenesis occurs throughout life. This laboratory recently described a series of new sites in the brain, found in the adult circumventricular organs (CVOs), that contains cells expressing stem cell-like traits. Traditionally, CVOs have been referred to as the "windows of the brain" because of their unique ability to sense physiological stimuli in blood and secrete factors into cerebrospinal fluid. These properties of the CVOs, and their cells with stem cell-like properties, raise the intriguing hypothesis that CVOs represent novel niches for cell genesis important for homeostasis in the adult brain. This project is designed to characterize further the putative stem cells residing in the CVOs of mice. The PI's laboratory has generated genetically engineered CVO stem cells that are tagged and can be tracked allowing their survival, migration and differerentiation to be followed in the adult brain. In addition, this project will explore whether the fate of tagged CVO stem cells can be re-directed following their transplantation to distinct CVO niches. The overall goal of these studies is the discovery and characterization of new sites for cell genesis in the adult brain that are important for maintaining brain homeostasis in response to changing physiological, environmental, and/or pathological stimuli. Moreover, by training both undergraduate and graduate students, this project will foster the development of the next generation of scientists in stem cell biology, an important new area of scientific inquiry.
In the adult brain, there are only two sites that are widely accepted as regions where new neurons can arise from stem cells throughout the life of the organism. These stem cell niches are known as the subventricular (SVZ) and subgranular (SGZ) zones. Work from our laboratory and this grant further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). Since in the quiescent rat brain, NSC proliferation remains low in all of these sites, we wondered whether injury to the nervous system as during a stroke would induce neurogenesis in these sites. Using an experimental model of stroke in rats, we found a dramatic rise in the number of stem cells proliferating and differentiating into brain cells in known and even several novel niche sites. Importantly, we found that these niche sites possess a rich vasculature with a highly permeable blood-brain-barrier (BBB) not found elsewhere in the brain. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites, consistent with the potential for widespread neurogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, adult stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem cell-mediated brain repair. In so doing, we hope to unleash the full reparative potential of brain stem cells after injury.
