The goal of this grant is to test the hypothesis that hESCs and iPSCs acquire specific metabolic signatures important for stemness through a common means, possibly by an exposure to stabilized HIF activity. Recent data support this hypothesis;HIFs have shown to play a role in ESC fate and ESCs have shown to sustain highly unsaturated metabolome. However, it is not yet clear how ESCs acquire their metabolic state, how the state is maintained and further, how the metabolic state of differentiation is obtained. We have showed that hypoxia is involved specifically in the acquisition state of stemness since hypoxia alone can de-differentiate committed cells back to stem cell fate. The de-differentiated cells re-activate Oct4 promoter analyzed by Oct4- GFP. These hypoxia induced stem like cells also mimic hESCs by their colony morphology, long-term self- renewal capacity, capability to replicate both in hypoxia and normoxia, genome wide mRNA and miRNA profiles, cell surface marker, TRA1 and SSEA expression and capacity to form teratomas. Furthermore, we have observed a specific metabolic signature in ESCs. We will now test whether hypoxia induced transcription factor, HIF is sufficient to induce the ESC specific metabolic pattern. We will first analyze glycolytic and oxidative phosphorylation responses to hypoxia using a panel of stem cells with different stages of pluripotency (piSC, diSC, EpiSC, HiPSC) and differentiated cells, followed by detailed assessment of redox poise within the mitochondrial electron transport chain (ETC) and metabolic pathway flux. Secondly, we will define the contribution of HIF activity for induction of unique stemness signatures (metabolism, mtDNA copy number) using hypoxia de-differentiation paradigms (HiPSC). Paradoxically, hypoxia has shown to affect both stemness and differentiation, suggesting that HIF might be differentially regulated to obtain the desired cellular outcomes. Therefore, we will devise high throughput screens to identify molecules that specifically affect HIF- induced stemness by promoting or interfering with stem cell-associated metabolic pathways. These studies will beget a new level of understanding of the acquisition of stemness and cancer and as such are bound to result in new approaches both in re-generative and cancer medicine.
The goal of this grant is to test the hypothesis that stem cells (in normal or cancer development) acquire a common characteristic metabolic signature through exposure to stabilized hypoxia-inducible factor (HIF) activity. Further, this metabolic signature may be determinative for stemness. Metabolites that are enriched in stem cells will be tested for their ability to reverse ESC differentiation in a high throughput format. These studies will spur improvements in regenerative medicine and potential therapies against cancer stem cells.
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|Moody, James D; Levy, Shiri; Mathieu, Julie et al. (2017) First critical repressive H3K27me3 marks in embryonic stem cells identified using designed protein inhibitor. Proc Natl Acad Sci U S A 114:10125-10130|
|Mathieu, Julie; Ruohola-Baker, Hannele (2017) Metabolic remodeling during the loss and acquisition of pluripotency. Development 144:541-551|
|Ellen Kreipke, Rebecca; Wang, Yuliang; Miklas, Jason Wayne et al. (2016) Metabolic remodeling in early development and cardiomyocyte maturation. Semin Cell Dev Biol 52:84-92|
|Xu, Zhuojin; Robitaille, Aaron M; Berndt, Jason D et al. (2016) Wnt/?-catenin signaling promotes self-renewal and inhibits the primed state transition in naïve human embryonic stem cells. Proc Natl Acad Sci U S A 113:E6382-E6390|
|Kuppusamy, Kavitha T; Jones, Daniel C; Sperber, Henrik et al. (2015) Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes. Proc Natl Acad Sci U S A 112:E2785-94|
|Sperber, Henrik; Mathieu, Julie; Wang, Yuliang et al. (2015) The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol 17:1523-35|
|Xing, Yalan; Su, Tin Tin; Ruohola-Baker, Hannele (2015) Tie-mediated signal from apoptotic cells protects stem cells in Drosophila melanogaster. Nat Commun 6:7058|
|Mathieu, Julie; Zhou, Wenyu; Xing, Yalan et al. (2014) Hypoxia-inducible factors have distinct and stage-specific roles during reprogramming of human cells to pluripotency. Cell Stem Cell 14:592-605|
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