HIF-2α Protects Human Hematopoietic Stem/Progenitors and Acute Myeloid Leukemic Cells from Apoptosis Induced by Endoplasmic Reticulum Stress

Rouault-Pierre, Kevin; López-Onieva, Lourdes; Foster, Katie; Anjos-Afonso, Fernando; Lamrissi-Garcia, Isabelle; Serrano-Sanchez, Martin; Mitter, Richard; Ivanović, Zoran; Verneuil, Hubert de; Gribben, John G.; Taussig, David; Rezvani, Hamid Reza; Mazurier, Frédéric; Bonnet, Dominique

doi:10.1016/j.stem.2013.08.011

Cited by 170 publications

(178 citation statements)

References 48 publications

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“…The dependence on glycolysis and the pentose phosphate pathway of adult stem cells, and more specifically of HSCs, may be due to multiple factors, such as their location within a hypoxic niche, the low energy requirements of quiescence and the need to minimize oxidative stress from mitochondrial ROS (Jang and Sharkis, 2007;Kunisaki et al, 2013). Evidence of this comes from genetic ablation of HIFs, which causes activation of oxidative phosphorylation and an increase in ROS, resulting in the subsequent loss of quiescence and the self-renewal properties of HSCs (Rouault-Pierre et al, 2013;Takubo et al, 2010). In HSCs, MEIS1 regulates both HIF1α and HIF2α (Simsek et al, 2010;Kocabas et al, 2012).…”

Section: Adult Stem Cellsmentioning

confidence: 99%

Stem cells and the impact of ROS signaling

2014

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An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.

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Section: Adult Stem Cellsmentioning

confidence: 99%

Stem cells and the impact of ROS signaling

2014

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“…2 Additionally, HIF-2a was shown to promote proliferation in primary mouse embryo fibroblasts as well as NIH3T3 cells, 2 and in human haematopoietic stem and progenitor cells, HIF-2a was shown to promote survival. 4 We, on the other hand, saw no significant differences in b cell proliferation in HIF-2a OE mice after both chow and HFD compared to WT littermate controls. In addition, our HFD fed mice had no detectable differences in apoptosis between HIF-2a OE and WT littermates as assessed by TUNEL following prolonged HFD.…”

Section: Pancreas Specific Overexpression Of Hif-2a Does Not Alter Glmentioning

confidence: 55%

“…Activation of this pathway increases the expression of numerous genes that are involved in multiple cellular processes such as angiogenesis, energy metabolism, apoptosis, and proliferation. [1][2][3][4] HIFs belong to the basic helix-loop-helix PAS (Per-ARNT (aryl-hydrocarbonreceptor nuclear translocator)-SIM) family of transcription factors. 5,6 In its active form, HIFs are heterodimers consisting of an oxygen-sensing a subunit and constitutively expressed b subunit.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Brunt

Shi

Schroer

et al. 2014

Islets

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Keywords: Hypoxia inducible factor b cell glucose homeostasis diabetes mellitus pancreas Abbreviations: ARNT, aryl hydrocarbon receptor nuclear translocator; EPAS1, endothelial PAS domain protein 1; GLUT1 glucose transporter 1; GTT, glucose tolerance test; HFD, high fat diet; HIF, hypoxia inducible factor; HIF-1a, hypoxia inducible factor-1 a; HIF-1b, hypoxia inducible factor-1 b; HIF-2a, hypoxia inducible factor-2 a; i.p., intraperitoneal; ITT, insulin tolerance test; OE, overexpression; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; WT, wild-type.Both type 1 and type 2 diabetes are associated with insufficient functional b-cell mass. Understanding intracellular signaling pathways associated with this decline is important in broadening our understanding of the disease and potential therapeutic strategies. The hypoxia inducible factor pathway (HIF) plays a critical role in cellular adaptation to hypoxic conditions. Activation of this pathway increases expression of numerous genes involved in multiple cellular processes and has been shown to impact the regulation of b-cell function. Previously, deletion of HIF-1a or HIF-1b in pancreatic b-cells, as well as constitutive activation of the HIF pathway in b-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2a overexpression in pancreatic b-cells in vivo. We overexpressed HIF-2a in pancreatic b-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2a overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or b-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2a in the pancreatic b-cells does not play a significant role in b-cell function and glucose homeostasis.

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“…Following that, the apoptotic stimuli induced by hypoxia appear to be inhibited at 72 h, where the percentage of apoptotic cells was not identified to be significantly different in hypoxia compared with normoxia. It is hypothesized that, in the early stages, additional mechanisms of protection against oxygen deprivation-induced cell death may occur (47,48).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia mediates osteocyte ORP150 expression and cell death in vitro

Montesi

Jähn

Bonewald

et al. 2016

Molecular Medicine Reports

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Abstract. Skeletal unloading leads to hypoxia in the bone microenvironment, resulting in imbalanced bone remodeling that favors bone resorption. Osteocytes, the mechanosensors of bone, have been demonstrated to orchestrate bone homeostasis. Hypoxic osteocytes either undergo apoptosis or actively stimulate osteoclasts to remove bone matrix during hypoxia. Oxygen-regulated protein 150 (ORP150) is an endoplasmic reticulum-associated chaperone that has been observed to serve an important role in the cellular adaptation to hypoxia and in preventing cellular apoptosis in various tissue types. The current study hypotheses that expression of ORP150 would be increased in osteocytes under hypoxic conditions (1% O 2 ). The MLO-Y4 osteocyte cell line was cultured under normoxic or hypoxic conditions for up to 72 h. It was demonstrated that 1% O 2 significantly induced hypoxia after 16 h and up to 72 h, significantly reduced cell number at 8 and 48 h, induced cell death at 8, 24 and 48 h and induced apoptosis at 16, 24 and 48 h. Significant differences in ORP150 mRNA were observed at 72 h, however no differences were observed in the protein expression levels. The relative increase in ORP150 mRNA observed in hypoxia, compared with normoxia, may support its cytoprotective role in oxygen-deprived conditions.

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HIF-2α Protects Human Hematopoietic Stem/Progenitors and Acute Myeloid Leukemic Cells from Apoptosis Induced by Endoplasmic Reticulum Stress

Cited by 170 publications

References 48 publications

Stem cells and the impact of ROS signaling

Stem cells and the impact of ROS signaling

Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Hypoxia mediates osteocyte ORP150 expression and cell death in vitro

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