Neural stem and progenitor cells in the aged subependyma are activated by the young niche.

Previous studies have demonstrated an age related decline in the size of the neural stem cell (NSC) pool and a decrease in neural progenitor cell proliferation, however, the mechanisms underlying these changes are unclear. In contrast to previous reports, we report that the numbers of NSCs is unchanged in the old age subependyma and the apparent loss is because of reduced proliferative potential in the aged stem cell niche. Transplantation studies reveal that the proliferation kinetics and migratory behavior of neural precursor cells are dependent on the age of the host animal and independent of the age of the donor cells suggesting that young and old age neural precursors are not intrinsically different.

Notch signaling imparts and preserves neural stem characteristics in the adult brain.

Although the role of Notch has been studied extensively in the developing nervous system, the embryonic lethality of Notch pathway mutants has hindered studies in the adult brain. The creation of cre/lox-mediated conditional gain- and loss-of-function mice has allowed us to investigate the role of Notch signaling in adult neural stem and progenitor cells. We have determined that Notch signaling is important for conferring stem cell characteristics upon neural precursor cells.

Wnt signaling regulates symmetry of division of neural stem cells in the adult brain and in response to injury.

Neural stem cells comprise a small population of subependymal cells in the adult brain that divide asymmetrically under baseline conditions to maintain the stem cell pool and divide symmetrically in response to injury to increase their numbers. Using in vivo and in vitro models, we demonstrate that Wnt signaling plays a role in regulating the symmetric divisions of adult neural stem cells with no change in the proliferation kinetics of the progenitor population. Using BAT-gal transgenic reporter mice to identify cells with active Wnt signaling, we demonstrate that Wnt signaling is absent in stem cells in conditions where they are dividing asymmetrically and that it is upregulated when stem cells are dividing symmetrically, such as (a) during subependymal regeneration in vivo, (b) in response to stroke, and (c) during colony formation in vitro.

Potential and pitfalls of stem cell therapy in old age.

Our increasing understanding of resident stem cell populations in various tissues of the adult body provides promise for the development of cell-based therapies to treat trauma and disease. With the sharp rise in the aging population, the need for effective regenerative medicine strategies for the aged is more important then ever. Yet, the vast majority of research fuelling our understanding of the mechanisms that control stem cell behaviour, and their role in tissue regeneration, is conducted in young animals.

Cyclooxygenase-2 inhibitors prevent the development of chemoresistance phenotype in a breast cancer cell line by inhibiting glycoprotein p-170 expression.

Breast cancer cells are usually sensitive to several chemotherapeutic regimens, but they can develop chemoresistance after prolonged exposure to cytotoxic drugs, acquiring a more aggressive phenotype. Drug resistance might involve the multi-drug resistance (MDR) 1 gene, encoding a transmembrane glycoprotein p-170 (P-gp), which antagonizes intracellular accumulation of cytotoxic agents, such as doxorubicin. We previously demonstrated that type 2 cyclooxygenase (COX-2) inhibitors can reverse the chemoresistance phenotype of a medullary thyroid carcinoma cell line by inhibiting P-gp expression and function.