Browsing by Subject "Adult Stem Cells"
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Item Malignant Gliomas Originate From Neural Stem/Progenitor Cells and Are Maintained By Cancer Stem Cells(2011-12-12) Chen, Jian; Parada, Luis F.Malignant glioma is one of the most aggressive cancers. To study the biology of glioma, our lab previously developed a series of mouse models that phenocopy both tumor initiation and progression through stochastic tumor suppressor loss-of-heterozygosity (LOH). To determine whether the mouse models recapitulate human glioma at the molecular level, we have performed gene set enrichment analysis (GSEA) comparing the molecular signature of tumors that develop in our mouse glioma models to the gene expression profiles of a number of human tumors. Our mouse glioma models share high similarity with human GBM and showed a generally proneural marker gene expression profile. We also found that tumors from the same initial genetic mutations can be further divided into several subtypes. Previous studies suggested a neural stem/progenitor cell (NSC) origin for gliomas, however strict exprimental evidence was still lacking. To examine the role of NSCs in glioma, we developed an NSC-specific tamoxifen-inducible nestin-cre driver mouse. When crossed to the NF/p53/Pten flox mice and induced with tamoxifen at E13.5, the Nes-Cre;Nf/p53/Pten mutant mice exhibited tumor initiation and progression similar to our previous mouse model using hGFAP-cre, with complete penetrance. All analyzed mice that were induced at 4 weeks such that only adult neural stem cells were targeted, developed malignant astrocytoma 7 - 12 months after induction. These findings indicate that despite their rarity, neural stem/progenitor cells are sufficient targets for the accumulation of mutations that initiate malignant astrocytomas. Our highly physiological relevant mouse model also allowed us to address the question of how glioma is maintained in vivo: whether tumors are maintained by a subpopulation of cells with self-renewal capacity that supplies tumor bulk, or whether the majority of tumor cells have the capacity to maintain the tumor. In our spontaneous somatic mouse model of glioma, a Nestin-¦¤TK-IRES-GFP transgene labels the primary tumor cells that are required for tumorigenicity in allograft assays. Ablating endogenous Nes-¦¤TK-positive cells significantly extended the survival of tumor-bearing mice by decreasing tumor proliferation and infiltration. We show that the glioma drug, temozolomide, selectively targets endogenous CSC-derived proliferating cells. Furthermore, a combination therapy targeting both dividing cells and the CSCs arrests tumor progression.Item Roles of HDACs and MEF2 in Adult Hippocampal Neurogenesis(2014-11-17) Jiang, Yindi; Zhang, Chun-Li; Olson, Eric N.; Johnson, Jane E.; Hsieh, JennyThe maintenance of the resident adult neural stem/progenitor cell (NSPC) pool depends on the precise balance of proliferation, differentiation, and maintenance of the undifferentiated state. Identifying the mechanisms that regulate this balance in adult hippocampal NSPCs can provide insight into basic neurogenesis principles important for tissue homeostasis and preventing tumor formation. Pharmacological inhibition of histone deacetylases (HDACs), a class of histone-modifying enzymes, have promising effects in cancer cells, yet the specific roles of individual HDACs in adult NSPCs are unclear. In this dissertation, I focus on dissecting the roles of two different HDACs in adult hippocampal neurogenesis: the Class I HDAC, HDAC3 and the Class IIa HDAC, HDAC5 as well as the Class IIa HDAC binding partner, myocyte enhancer factor 2 (MEF2). Using conditional knockout (cKO) mice and in vitro cell culture, I show that histone deacetylase 3 (HDAC3) is required for the proliferation of adult NSPCs. Detailed cell cycle analysis of NSPCs from Hdac3 cKO mice reveals a defect in cell cycle progression through G2/M phase, but not S phase. Moreover, HDAC3 controls G2/M phase progression mainly through post-translational stabilization of the G2/M cyclin- dependent kinase-1 (CDK1). These results demonstrate that HDAC3 plays a critical role in NSPC proliferation. HDAC5 is the most abundant Class IIa HDAC in adult dentate gyrus. HDAC5 is only expressed in immature and mature neurons. Using Hdac5 knockout mice and in vitro cell culture, I show that HDAC5 is necessary and sufficient to restrict the neuronal differentiation of NSPCs. However, the detailed mechanisms are yet to be determined. Class IIa HDACs bind to myocyte enhancer factor 2 (MEF2) in the nucleus to repress transcription of pro-neuronal genes. Thus, we also examined the function of Mef2 genes in adult hippocampal neurogenesis. In adult hippocampus, the three most highly expressed MEF2 proteins are MEF2A, 2C, and 2D, which are expressed in immature and mature neurons similar to HDAC5. We have shown that one synthetic small molecule, Isoxazole-9 (Isx-9) could trigger neuronal differentiation robustly in vitro and in vivo. Inducible knockout of all three Mef2 genes specifically in NSPCs and their progeny revealed their critical roles in mediating Isx-9 induced neurogenesis and baseline neurogenesis. In summary, these results demonstrate that HDACs and MEF2 control different stages of adult hippocampal neurogenesis and suggest that strategies aimed at pharmacological modulation of these proteins may be beneficial for tissue regeneration and controlling tumor cell growth in mammalian brain.