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. Factors from the young stem cell niche rescue the numbers of NSC colonies derived from old age subependyma and enhance progenitor cell proliferation in vivo in old age mice. Finally, we report a loss of Wnt signaling in the old age stem cell niche that underlies the lack of expansion of the NSC pool after stroke.

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. Knocking-out Notch signaling in vivo results in neural progenitors, leaving the subependymal niche and migrating along the rostral migratory stream to the olfactory bulb, while overexpressing Notch results in retention of cells in the subependyma. Further, increased Notch signaling in progenitor cells resulted in the expression of stem cell markers in vivo as well as conferring the characteristics of self-renewal and multipotentiality upon subsequent isolation in vitro. Similar to what has been reported from the embryonic brain, the overexpression of Notch in neural precursor cells in vitro increased the numbers of neurospheres from the adult brain. Finally, overexpression of Notch1 in pure populations of progenitor cells (excluding neural stem cells) isolated by fluorescence activated cell sorting led to the formation of multipotent, self-renewing neurospheres from the non-neurosphere forming fraction. Hence, Notch overexpression confers stem cell properties upon progenitor cells and demonstrates that Notch signaling not only preserves stem cell characteristics, but that it can confer stem cell characteristics upon a subset of progenitor 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. Moreover, we demonstrate that blocking Wnt signaling in conditions where neural stem cells are dividing symmetrically inhibits neural stem cell expansion both in vivo and in vitro. Together, these findings reveal that the mechanism by which Wnt signaling modulates the size of the stem cell pool is by regulating the symmetry of stem cell division.

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. Evidence collected in the last several years indicates that, although stem cells remain active into old age, changes in the stem cells and their microenvironments inhibit their regenerative potential. An understanding of both the cell-intrinsic stem cell changes, as well as concomitant changes to the stem cell niche and the systemic environment, are crucial for the development of regenerative medicine strategies that might be successful in aged patients.