HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition

Zhou, Wenyu; Choi, Minyoung; Margineantu, Daciana; Margaretha, Lilyana; Hesson, Jennifer; Blau, C. Anthony; Horwitz, Marshall S.; Hockenbery, David M.; Ware, Carol B.; Ruohola‐Baker, Hannele

doi:10.1038/emboj.2012.71

Cited by 492 publications

(573 citation statements)

References 59 publications

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“…4E). This is consistent with previous observations in mice in which mouse ESCs used oxidative phosphorylation, and EpiSCs showed low mitochondrial respiratory capacity [27].…”

Section: Genome-wide Expression Analysis Of Patient-specific Naïve Ipscssupporting

confidence: 82%

Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9

Yang

Zhang

et al. 2015

Stem Cells Translational Medicine

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Conventional primed human embryonic stem cells and induced pluripotent stem cells (iPSCs) exhibit molecular and biological characteristics distinct from pluripotent stem cells in the naïve state. Although naïve pluripotent stem cells show much higher levels of self-renewal ability and multidifferentiation capacity, it is unknown whether naïve iPSCs can be generated directly from patient somatic cells and will be superior to primed iPSCs. In the present study, we used an established 5i/L/FA system to directly reprogram fibroblasts of a patient with b-thalassemia into transgene-free naïve iPSCs with molecular signatures of ground-state pluripotency. Furthermore, these naïve iPSCs can efficiently produce cross-species chimeras. Importantly, using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 nuclease genome editing system, these naïve iPSCs exhibit significantly improved gene-correction efficiencies compared with the corresponding primed iPSCs. Furthermore, human naïve iPSCs could be directly generated from noninvasively collected urinary cells, which are easily acquired and thus represent an excellent cell resource for further clinical trials. Therefore, our findings demonstrate the feasibility and superiority of using patient-specific iPSCs in the naïve state for disease modeling, gene editing, and future clinical therapy. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:8-19 SIGNIFICANCEIn the present study, transgene-free naïve induced pluripotent stem cells (iPSCs) directly converted from the fibroblasts of a patient with b-thalassemia in a defined culture system were generated. These naïve iPSCs, which show ground-state pluripotency, exhibited significantly improved singlecell cloning ability, recovery capacity, and gene-targeting efficiency compared with conventional primed iPSCs. These results provide an improved strategy for personalized treatment of genetic diseases such as b-thalassemia.

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“…4E). This is consistent with previous observations in mice in which mouse ESCs used oxidative phosphorylation, and EpiSCs showed low mitochondrial respiratory capacity [27].…”

Section: Genome-wide Expression Analysis Of Patient-specific Naïve Ipscssupporting

confidence: 82%

Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9

Yang

Zhang

et al. 2015

Stem Cells Translational Medicine

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“…mESCs are bivalent and can convert between mitochondrial and glycolytic metabolism depending on culture conditions, whereas mEpiSCs and hESCs are dependent primarily on aerobic glycolysis (14). Consistent with the mouse data, expression of cytochrome c oxidase assembly protein and estrogen receptorrelated receptor B were significantly higher in the naïve Elf1 cultures relative to primed Elf1 (P < 1 × 10 −4 and P < 0.01, respectively; Agilent array data), signifying effective mitochondrial oxidative metabolism.…”

Section: Mitochondrial Metabolism As a Functional Marker Of Pluripotencysupporting

confidence: 73%

“…Reflective of the mouse naïve vs. primed cells (14), naïve Elf1 mitochondria appeared less mature, in that they were generally round with few cristae, whereas mitochondria in primed cells were elongated with somewhat more developed cristae (Fig. 3E).…”

Section: Mitochondrial Metabolism As a Functional Marker Of Pluripotencymentioning

confidence: 99%

Derivation of naïve human embryonic stem cells

Ware¹,

Nelson

Mecham

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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412

433

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The naïve pluripotent state has been shown in mice to lead to broad and more robust developmental potential relative to primed mouse epiblast cells. The human naïve ES cell state has eluded derivation without the use of transgenes, and forced expression of OCT4, KLF4, and KLF2 allows maintenance of human cells in a naïve state [Hanna J, et al. (2010) Proc Natl Acad Sci USA 107 (20):9222-9227]. We describe two routes to generate nontransgenic naïve human ES cells (hESCs). The first is by reverse toggling of preexisting primed hESC lines by preculture in the histone deacetylase inhibitors butyrate and suberoylanilide hydroxamic acid, followed by culture in MEK/ERK and GSK3 inhibitors (2i) with FGF2. The second route is by direct derivation from a human embryo in 2i with FGF2. We show that human naïve cells meet mouse criteria for the naïve state by growth characteristics, antibody labeling profile, gene expression, X-inactivation profile, mitochondrial morphology, microRNA profile and development in the context of teratomas. hESCs can exist in a naïve state without the need for transgenes. Direct derivation is an elusive, but attainable, process, leading to cells at the earliest stage of in vitro pluripotency described for humans. Reverse toggling of primed cells to naïve is efficient and reproducible.

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“…Mouse ESCs possess bivalent metabolic traits (glycolysis and oxidative phosphorylation) to regulate pluripotency, proliferation, and differentiation (35). Because Cited2 deletion did not affect pluripotency in undifferentiated ESCs from our previous study (22), we tested whether enhanced glycolysis in Cited2…”

Section: Enhanced Aerobic Glycolysis and Reduced Glucose Oxidation Inmentioning

confidence: 99%

Cited2, a Transcriptional Modulator Protein, Regulates Metabolism in Murine Embryonic Stem Cells

Hakimi

Liu

et al. 2014

Journal of Biological Chemistry

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Background:The function of HIF-1, a master regulator of metabolism, is in part modulated by Cited2. The role of Cited2 in murine embryonic stem cell (mESC) glucose metabolism remains unknown. Results: Deletion of Cited2 in mESCs results in impaired mitochondria morphology, reduced glucose oxidation, increased glycolysis, and defective mESC differentiation. Conclusion: Cited2 coordinates glucose metabolism to regulate mESC differentiation. Significance: Cited2 is a potential target for metabolic reprogramming in mESCs.

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HIF1α induced switch from bivalent to exclusively glycolytic metabolism during ESC-to-EpiSC/hESC transition

Cited by 492 publications

References 59 publications

Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9

Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9

Derivation of naïve human embryonic stem cells

Cited2, a Transcriptional Modulator Protein, Regulates Metabolism in Murine Embryonic Stem Cells

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