scholarly journals AKT1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species

Blood ◽  
2010 ◽  
Vol 115 (20) ◽  
pp. 4030-4038 ◽  
Author(s):  
Marisa M. Juntilla ◽  
Vineet D. Patil ◽  
Marco Calamito ◽  
Rohan P. Joshi ◽  
Morris J. Birnbaum ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Function ◽  
Reactive Oxygen ◽  
Lymphoid Cells ◽  
Oxygen Species ◽  
Cellular Functions ◽  
Hematopoietic Stem ◽  
G0 Phase

Although AKT is essential for multiple cellular functions, the role of this kinase family in hematopoietic stem cells (HSCs) is unknown. Thus, we analyzed HSC function in mice deficient in the 2 isoforms most highly expressed in the hematopoietic compartment, AKT1 and AKT2. Although loss of either isoform had only a minimal effect on HSC function, AKT1/2 double-deficient HSCs competed poorly against wild-type cells in the development of myeloid and lymphoid cells in in vivo reconstitution assays. Serial transplantations revealed an essential role for AKT1 and AKT2 in the maintenance of long-term HSCs (LT-HSCs). AKT1/2 double-deficient LT-HSCs were found to persist in the G0 phase of the cell cycle, suggesting that the long-term functional defects are caused by increased quiescence. Furthermore, we found that the intracellular content of reactive oxygen species (ROS) is dependent on AKT because double-deficient HSCs demonstrate decreased ROS. The importance of maintaining ROS for HSC differentiation was shown by a rescue of the differentiation defect after pharmacologically increasing ROS levels in double-deficient HSCs. These data implicate AKT1 and AKT2 as critical regulators of LT-HSC function and suggest that defective ROS homeostasis may contribute to failed hematopoiesis.

FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation

Blood ◽  
2012 ◽  
Vol 120 (9) ◽  
pp. 1843-1855 ◽  
Author(s):  
Tomer Itkin ◽  
Aya Ludin ◽  
Ben Gradus ◽  
Shiri Gur-Cohen ◽  
Alexander Kalinkovich ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Reactive Oxygen ◽  
Receptor Activation ◽  
Oxygen Species ◽  
Hematopoietic Stem ◽  
Cell Engraftment ◽  
Stem And Progenitor Cells

Abstract Cytokine-induced expansion of hematopoietic stem and progenitor cells (HSPCs) is not fully understood. In the present study, we show that whereas steady-state hematopoiesis is normal in basic fibroblast growth factor (FGF-2)–knockout mice, parathyroid hormone stimulation and myeloablative treatments failed to induce normal HSPC proliferation and recovery. In vivo FGF-2 treatment expanded stromal cells, including perivascular Nestin+ supportive stromal cells, which may facilitate HSPC expansion by increasing SCF and reducing CXCL12 via mir-31 up-regulation. FGF-2 predominantly expanded a heterogeneous population of undifferentiated HSPCs, preserving and increasing durable short- and long-term repopulation potential. Mechanistically, these effects were mediated by c-Kit receptor activation, STAT5 phosphorylation, and reduction of reactive oxygen species levels. Mice harboring defective c-Kit signaling exhibited abrogated HSPC expansion in response to FGF-2 treatment, which was accompanied by elevated reactive oxygen species levels. The results of the present study reveal a novel mechanism underlying FGF-2–mediated in vivo expansion of both HSPCs and their supportive stromal cells, which may be used to improve stem cell engraftment after clinical transplantation.

Reactive oxygen species participate in acute renal vasoconstrictor responses induced by ETA and ETB receptors

2008 ◽  
Vol 294 (4) ◽  
pp. F719-F728 ◽  
Author(s):  
Armin Just ◽  
Christina L. Whitten ◽  
William J. Arendshorst
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Long Term Effects ◽  
Vasomotor Tone ◽  
Chronic Stimulation ◽  
Renal Vasoconstriction ◽  
Oxidase Inhibition

Reactive oxygen species (ROS) play important roles in renal vasoconstrictor responses to acute and chronic stimulation by angiotensin II and norepinephrine, as well as in long-term effects of endothelin-1 (ET-1). Little is known about participation of ROS in acute vasoconstriction produced by ET-1. We tested the influence of NAD(P)H oxidase inhibition by apocynin [4 mg·kg−1·min−1, infused into the renal artery (ira)] on ETA and ETB receptor signaling in the renal microcirculation. Both receptors were stimulated by ET-1, ETA receptors by ET-1 during ETB antagonist BQ-788, and ETB by ETB agonist sarafotoxin 6C. ET-1 (1.5 pmol injected ira) reduced renal blood flow (RBF) 17 ± 4%. Apocynin raised baseline RBF (+10 ± 1%, P < 0.001) and attenuated the ET-1 response to 10 ± 2%, i.e., 35 ± 9% inhibition ( P < 0.05). Apocynin reduced ETA-induced vasoconstriction by 42 ± 12% ( P < 0.05) and that of ETB stimulation by 50 ± 8% ( P < 0.001). During nitric oxide (NO) synthase inhibition ( Nω-nitro-l-arginine methyl ester), apocynin blunted ETA-mediated vasoconstriction by 60 ± 8% ( P < 0.01), whereas its effect on the ETB response (by 87 ± 8%, P < 0.001) was even larger without than with NO present ( P < 0.05). The cell-permeable superoxide dismutase mimetic tempol (5 mg·kg−1·min−1 ira), which reduces O2− and may elevate H2O2, attenuated ET-1 responses similar to apocynin (by 38 ± 6%, P < 0.01). We conclude that ROS, O2− rather than H2O2, contribute substantially to acute renal vasoconstriction elicited by both ETA and ETB receptors and to basal renal vasomotor tone in vivo. This physiological constrictor action of ROS does not depend on scavenging of NO. In contrast, scavenging of O2− by NO seems to be more important during ETB stimulation.

Nitrate tolerance does not increase production of peroxynitrite in the heart

2002 ◽  
Vol 283 (1) ◽  
pp. H69-H76 ◽  
Author(s):  
Tamás Csont ◽  
Csaba Csonka ◽  
Annamária Ónody ◽  
Anikó Görbe ◽  
László Dux ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Vascular Dysfunction ◽  
Reactive Oxygen ◽  
Nitrate Tolerance ◽  
Oxygen Species ◽  
Mechanical Function ◽  
Nitrate Treatment

Clinical studies have suggested that long-term nitrate treatment does not improve and may even worsen cardiovascular mortality, and the possible role of nitrate tolerance has been suspected. Nitrate tolerance has been recently shown to increase vascular superoxide and peroxynitrite production leading to vascular dysfunction. Nevertheless, nitrates exert direct cardiac effects independent from their vascular actions. Therefore, we investigated whether in vivo nitroglycerin treatment leading to vascular nitrate tolerance increases cardiac formation of nitric oxide (NO), reactive oxygen species, and peroxynitrite, thereby leading to cardiac dysfunction. Nitrate tolerance increased bioavailability of NO in the heart without increasing formation of reactive oxygen species. Despite elevated myocardial NO, neither cardiac markers of peroxynitrite formation nor cardiac mechanical function were affected by nitroglycerin treatment. However, serum free nitrotyrosine, a marker for systemic peroxynitrite formation, was significantly elevated in nitroglycerin-treated animals. This is the first demonstration that, although the systemic effects of nitroglycerin may be deleterious due to enhancement of extracardiac peroxynitrite formation, nitroglycerin does not result in oxidative damage in the heart.

scholarly journals Human hematopoietic stem/progenitor cells display reactive oxygen species-dependent long-term hematopoietic defects after exposure to low doses of ionizing radiations

Haematologica ◽  
2019 ◽  
Vol 105 (8) ◽  
pp. 2044-2055 ◽  
Author(s):  
Elia Henry ◽  
Inès Souissi-Sahraoui ◽  
Margaux Deynoux ◽  
Andréas Lefèvre ◽  
Vilma Barroca ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Progenitor Cells ◽  
Reactive Oxygen ◽  
Low Doses ◽  
Oxygen Species ◽  
Hematopoietic Stem ◽  
Ionizing Radiations

scholarly journals TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species

2008 ◽  
Vol 205 (10) ◽  
pp. 2397-2408 ◽  
Author(s):  
Chong Chen ◽  
Yu Liu ◽  
Runhua Liu ◽  
Tsuneo Ikenoue ◽  
Kun-Liang Guan ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Mitochondrial Biogenesis ◽  
Reactive Oxygen ◽  
Mtor Pathway ◽  
Oxygen Species ◽  
Hematopoietic Stem ◽  
And Function

The tuberous sclerosis complex (TSC)–mammalian target of rapamycin (mTOR) pathway is a key regulator of cellular metabolism. We used conditional deletion of Tsc1 to address how quiescence is associated with the function of hematopoietic stem cells (HSCs). We demonstrate that Tsc1 deletion in the HSCs drives them from quiescence into rapid cycling, with increased mitochondrial biogenesis and elevated levels of reactive oxygen species (ROS). Importantly, this deletion dramatically reduced both hematopoiesis and self-renewal of HSCs, as revealed by serial and competitive bone marrow transplantation. In vivo treatment with an ROS antagonist restored HSC numbers and functions. These data demonstrated that the TSC–mTOR pathway maintains the quiescence and function of HSCs by repressing ROS production. The detrimental effect of up-regulated ROS in metabolically active HSCs may explain the well-documented association between quiescence and the “stemness” of HSCs.

scholarly journals Short Overview of ROS as Cell Function Regulators and Their Implications in Therapy Concepts

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 793 ◽  
Author(s):  
Lidija Milkovic ◽  
Ana Cipak Gasparovic ◽  
Marina Cindric ◽  
Pierre-Alexis Mouthuy ◽  
Neven Zarkovic
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Function ◽  
Reactive Oxygen ◽  
Redox Signaling ◽  
Oxygen Species ◽  
Cellular Functions ◽  
Short Overview ◽  
Ros Formation

The importance of reactive oxygen species (ROS) has been gradually acknowledged over the last four decades. Initially perceived as unwanted products of detrimental oxidative stress, they have been upgraded since, and now ROS are also known to be essential for the regulation of physiological cellular functions through redox signaling. In the majority of cases, metabolic demands, along with other stimuli, are vital for ROS formation and their actions. In this review, we focus on the role of ROS in regulating cell functioning and communication among themselves. The relevance of ROS in therapy concepts is also addressed here.

scholarly journals Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress

Blood ◽  
2012 ◽  
Vol 120 (25) ◽  
pp. 4973-4981 ◽  
Author(s):  
Zeenath Unnisa ◽  
Jason P. Clark ◽  
Jayeeta Roychoudhury ◽  
Elizabeth Thomas ◽  
Lino Tessarollo ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Hematopoietic Stem ◽  
Knock Out ◽  
Von Hippel Lindau ◽  
Expression Of Genes

Abstract The transcription factor Meis1 is expressed preferentially in hematopoietic stem cells (HSCs) and overexpressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. In the present study, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over the long term, whereas steady-state hematopoiesis was sustained in the absence of Meis1 in inducible knock-out mice. BM cells of Meis1-deficient mice showed reduced colony formation and contained significantly fewer numbers of long-term HSCs, which exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species in HSCs and decreased expression of genes implicated in hypoxia response. Finally, reactive oxygen species scavenging by N-acetyl cysteine or stabilization of hypoxia signaling by knockdown of the von-Hippel-Lindau (VHL) protein led to reversal of the effects of Meis1 deletion. The results of the present study demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism.

scholarly journals Reactive Oxygen Species Initiate a Metabolic Collapse in Hippocampal Slices: Potential Trigger of Cortical Spreading Depression

2014 ◽  
Vol 34 (9) ◽  
pp. 1540-1549 ◽  
Author(s):  
Anton Malkov ◽  
Anton I lvanov ◽  
Irina Popova ◽  
Marat Mukhtarov ◽  
Olena Gubkina ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Hippocampal Slices ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cellular Functions ◽  
Ros Accumulation ◽  
Potential Trigger

Excessive accumulation of reactive oxygen species (ROS) underlies oxidative damage. We find that in hippocampal slices, decreased activity of glucose-based antioxidant system induces a massive, abrupt, and detrimental change in cellular functions. We call this phenomenon metabolic collapse (MC). This collapse manifested in long-lasting silencing of synaptic transmission, abnormal oxidation of NAD(P)H and FADH2 associated with immense oxygen consumption, and massive neuronal depolarization. MC occurred without any preceding deficiency in neuronal energy supply or disturbances of ionic homeostasis and spread throughout the hippocampus. It was associated with a preceding accumulation of ROS and was largely prevented by application of an efficient antioxidant Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl). The consequences of MC resemble cortical spreading depression (CSD), a wave of neuronal depolarization that occurs in migraine, brain trauma, and stroke, the cellular initiation mechanisms of which are poorly understood. We suggest that ROS accumulation might also be the primary trigger of CSD. Indeed, we found that Tempol strongly reduced occurrence of CSD in vivo, suggesting that ROS accumulation may be a key mechanism of CSD initiation.

scholarly journals Arsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Na Kong ◽  
Hanjie Zhang ◽  
Chan Feng ◽  
Chuang Liu ◽  
Yufen Xiao ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cancer Therapy ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Non Invasive ◽  
Ros Burst ◽  
Imaging Properties

AbstractThe modulation of intracellular reactive oxygen species (ROS) levels is crucial for cellular homeostasis and determination of cellular fate. A sublethal level of ROS sustains cell proliferation, differentiation and promotes tumor metastasis, while a drastic ROS burst directly induces apoptosis. Herein, surface-oxidized arsenene nanosheets (As/AsxOy NSs) with type II heterojunction are fabricated with efficient ·O2− and 1O2 production and glutathione consumption through prolonging the lifetime of photo-excited electron-hole pairs. Moreover, the portion of AsxOy with oxygen vacancies not only catalyzes a Fenton-like reaction, generating ·OH and O2 from H2O2, but also inactivates main anti-oxidants to cut off the “retreat routes” of ROS. After polydopamine (PDA) and cancer cell membrane (M) coating, the engineered As/AsxOy@PDA@M NSs serve as an intelligent theranostic platform with active tumor targeting and long-term blood circulation. Given its narrow-band-gap-enabled in vivo fluorescence imaging properties, As/AsxOy@PDA@M NSs could be applied as an imaging-guided non-invasive and real-time nanomedicine for cancer therapy.

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