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Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain

Final Report Summary - STEMRENEWAL (Identification of a new mechanism of stem cell self-renewal; direct implications on self-repair and tumor initiating cells in the brain)

The importance of understanding cellular mechanisms of stem and principles governing their differentiation into specialized cells cannot be overestimated. Such knowledge will improve knowledge on the strategies for stem cell based therapies in regenerative medicine and for development of novel treatments of cancer. Stem cells reside in specific anatomical locations, stem cell niches, which regulate how stem cells participate in tissue generation, maintenance and repair. Understanding the stem cell identity and molecular mechanisms underlying the renewal and maintenance of stem cell niches and their differentiation into functional neurons and cells of varying types will be instrumental for harnessing the power of stem cells for therapeutic approaches. Similarly, identifying and understanding unique properties of cancer stem cells should open for entirely new strategies to combat cancer which hopefully should minimize disease recurrence. In this project, we have made a number of achievements that have improved the knowledge of mechanisms which participate in maintenance and differentiation of stem/progenitor cells into specific cellular types. These processes require a hierarchical specification of progenitor cells dependent on factors stimulating the cells following interactions with the environment. We have identified a new type of stem cell, the glial-like immature cell type called Schwann cell precursor, which by a process of inductive recruitment determines skin pigmentation by providing pigmentation cells. We have also identified soluble factors and gene programs determining development of pigment cells from these stem/progenitor cells. These immature glial cells have been shown to be true stem cells with potential to differentiate into numerous cell types and the entire parasympathetic nervous system were also found to arise from these cells as well as odontoblasts in the tooth during development and regeneration in the adult. Hence, in contrast to earlier belief, we have shown that the tooth, parasympathetic nervous system and pigment cells arise from immature glial-like stem cells dwelling in nerves.

In the adult brain, stem cell cells reside in the subventricular zone in a defined microenvironment (or stem cell niche) consisting of ependymal cells, transit amplifying progenitors and neuroblasts and in the subgranular zone of the hippocampus. Neurogenesis continues in the adult brain throughout life and may play important roles of learning and memory, as well as in diseases such as anxiety and depression. We have reported a new mechanism regulating stem cell numbers in the adult brain. This mechanism is highly unexpected and unconventional as it involves GABAA receptor signaling in neural stem cells resulting in modifications of histone H2AX which controls proliferation of the stem cells in the S-phase of the cell cycle. Our data supports a view where this mechanism underlies a homeostatic suppression of neural stem cell proliferation that may contribute to changes in stem cell numbers and neurogenesis associated with neurological diseases as well as the limited self-repair capacity of the damaged brain. We have also identified a similar mechanism in brain cancer stem cells (i.e. glioblastoma cells) and this signaling significantly affects survival and disease outcome. In a large effort spanning five years, glioblastoma cells were also found vulnerable to macropinocytic vacuolization and death. We hypothesized that gain- and loss-of-function mutations lead to acquired functions also in cellular pathways not necessarily involved in cell transformation. Such properties could be exploited for development of conceptually new therapeutic strategies. Based on this assumption, we performed a small molecule screen and identified the selective vulnerability of human glioblastoma stem-like cells to catastrophic vacuolization and necrotic-like death. These results exemplifies to our knowledge for the first time that the marked changes in biology underlying cell transformation also can lead to gained functions resulting in a vulnerability of the cancer cell. We have showed that this mechanism readily can be targeted by a small molecule with excellent in vivo pharmacokinetics and brain exposure, and that when administered by orally (by ingestion), it significantly attenuates infiltration, tumor growth and markedly extends survival in glioblastoma animal models. These results point to the possible exploitation of this cellular process in the design of anticancer therapies.