Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, with a median survival of about one year1. This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal. Precisely how recurrence occurs is unknown. Using a genetically-engineered mouse model of glioma, we identify a subset of endogenous tumor cells that are the source of new tumor cells after the drug, temozolomide (TMZ), is administered to transiently arrest tumor growth. A Nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumor cells. Upon arrest of tumor cell proliferation with TMZ, pulse-chase experiments demonstrate a tumor re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumor growth and combined TMZ-ganciclovir treatment impeded tumor development. These data indicate the existence of a relatively quiescent subset of endogenous glioma cells that are responsible for sustaining long-term tumor growth through the production of transient populations of highly proliferative cells.

It is becoming increasingly clear that brain injuries from a variety of causes stimulate neurogenesis within the hippocampus. It remains unclear, however, how robust this response may be and what primary cell types are involved. Here, using a controlled cortical impact model of traumatic brain injury on a previously characterized transgenic mouse line that expresses enhanced green fluorescent protein (eGFP) under the control of the nestin promoter, we demonstrate that it is the earliest type-1 quiescent progenitor cells that are induced to proliferate and migrate outside the subgranular layer of the dentate gyrus. This type-1 cell activation occurs at the same time that we observe adjacent but more differentiated doublecortin-expressing progenitors (type-2 cells) being eliminated. Also, although type-2 cells remain intact in the contralateral (uninjured) dentate gyrus, the type-1 cells there are also activated and result in increased numbers of the doublecortin-expressing type-2 cells. In addition, we have generated a novel mouse transgenic that expresses a modified version of the herpes simplex virus thymidine kinase along with eGFP that allows for the visualization and inducible ablation of early dividing progenitors by exposing them to ganciclovir. Using this transgenic in the context of traumatic brain injury, we demonstrate that these early progenitors are required for injury-induced remodeling to occur. This work suggests that injury-induced hippocampal remodeling following brain injury likely requires sustained activation of quiescent early progenitors.

Significant spontaneous recovery occurs following essentially all forms of serious brain injury, though the mechanisms underlying this recovery are unknown. Given that many forms of brain injury such as traumatic brain injury (TBI) induce hippocampal neurogenesis, we investigated whether these newly generated neurons might play a role in recovery. By modeling TBI in transgenic mice, we determined that injury-induced newly generated neurons persisted over time and elaborated extensive dendritic trees that stably incorporated themselves throughout all neuronal layers of the dentate gyrus. When we selectively ablated dividing stem/progenitors at the time of injury with ganciclovir in a nestin-HSV-TK transgenic model, we eliminated injury-induced neurogenesis and subsequently diminished the progenitor pool. Moreover, using hippocampal-specific behavioral tests, we demonstrated that only injured animals with neurogenesis ablated at the time of injury lost the ability to learn spatial memory tasks. These data demonstrate a functional role for adult neurogenesis following brain injury and offer compelling and testable therapeutic options that might enhance recovery.

Different places may share common features, but are coded by distinct populations of CA3 neurons in the hippocampus. Here we show that chemical or genetic suppression of adult neurogenesis in the hippocampus impairs this population-based coding of similar (but not dissimilar) contexts. These data provide a neural basis for impaired spatial discrimination following ablation of adult neurogenesis, and support the proposal that adult neurogenesis regulates the efficiency of a pattern separation process in the hippocampus.