DNA damage response, redox status and hematopoiesis

Weiss, Cary N.; Ito, Keisuke

doi:10.1016/j.bcmd.2013.08.002

Cited by 18 publications

(13 citation statements)

References 98 publications

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“…This view changed when several studies observed the ability of H 2 O 2 to act as a cell signal, mainly through oxidation of specific target molecules. 5,[17][18][19] Therefore, the increase in ROS levels has been described as a key inducer of MSC proliferation and differentiation inductor, which are important steps in the regeneration of tissues and organs. 1 Previous studies demonstrated that MSCs remain in a quiescent state in low levels of endogenous H 2 O 2 .…”

Section: Discussionmentioning

confidence: 99%

Human adipose-derived stem cells obtained from lipoaspirates are highly susceptible to hydrogen peroxide mediated cytogenotoxicity

Machado

Homrich

Rodrigues

et al. 2019

Arch. Biosc. Health

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There is evidence that H2O2 can induce the proliferation, migration, and regeneration of stem cells, as well as that of adipose-derived stem cells (ASCs). This could be useful to expand the possible uses of ASCs in therapeutic applications. However, the safety profile of H2O2 use in stem cells is not clear yet. Therefore, the present study evaluated the acute cytotoxic, oxidative and genotoxic effects of different concentrations of H2O2 on ASCs obtained from human lipoaspirates. The ASCs were treated with 1–1000 μM H2O2 for two hours. Cell viability was evaluated by double-strand DNA determination. Apoptosis induction was analyzed measuring active levels of caspases 1, 3 and 8. Biochemical oxidative stress markers were analyzed and genotoxic effects were assessed by DNA comet assay. All H2O2 concentrations increased ASC mortality rates with approximately 100% mortality achieved at ≥ 200 μM. Active caspases 1, 3 and 8, oxidative stress, as well as oxidative damage as assessed by lipid peroxidation increased dose‐dependently. There was also an approximate 50% increase in catalase levels in cells exposed to all H2O2 tested concentrations. H2O2 concentrations of ≥ 10 μM were genotoxic. These results suggest that ASCs are highly sensitive to H2O2 exposition. In addition, DNA damage in the surviving cells may affect their proliferative and differentiation capacity, as well as their safety profile for therapeutic use.

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Section: Discussionmentioning

confidence: 99%

Human adipose-derived stem cells obtained from lipoaspirates are highly susceptible to hydrogen peroxide mediated cytogenotoxicity

Machado

Homrich

Rodrigues

et al. 2019

Arch. Biosc. Health

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“…HSCs are particularly vulnerable to the effects of oxidative stress, especially DNA damage, due to their longevity [17, 25, 26], and the ability of HSCs to self-renew and differentiate allows for accumulated damage to be spread throughout the entire hematopoietic system [27]. To avoid ROS generation and the associated damage, adult HSCs generally maintain a slow-cycling state [28, 29].…”

Section: Metabolism In Normal Hematopoietic Stem Cellsmentioning

confidence: 99%

The role of PML in hematopoietic and leukemic stem cell maintenance

2014

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The tumor suppressor promyelocytic leukemia (PML) was first identified as a component of PML–RARα fusion protein, one of the initiating cytogenetic abnormalities in acute promyelocytic leukemia. PML is now known to have diverse functions regulating the DNA-damage response, apoptosis, senescence, and angiogenesis. Recent investigations have identified PML as a regulator of metabolic pathways in stem cell compartments, including the hematopoietic system, and have provided researchers with new strategies for controlling stem cell maintenance and differentiation. Studies of PML in leukemia-initiating cells demonstrate that PML is also an essential component of their maintenance, which has drawn tremendous attention to PML from scientists in various stem cell fields. Here, we review research into PML and its associated pathways, including recent studies of PML as it relates to stem cell biology, as well as our finding that PML regulates fatty acid oxidation, which is essential to the maintenance of normal hematopoietic stem cells. We also discuss the therapeutic potential of controlling PML-associated pathways. In particular, we describe promising evidence for the use of arsenic trioxide in the treatment of chronic myeloid leukemia.

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“…However, much evidence suggests an opposing hypothesis—the consequences of erroneous DNA damage repair in an HSC could be so severe that it is preferable for an HSC faced with oxidative or other genotoxic stress to differentiate, removing it from the stem cell pool and preventing the dissemination of deleterious mutations. The pathways that underlie this decision have been coined the “ROS rheostat [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]”.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reviewed the effects of cellular metabolism and oxidative stress, and of the DNA damage response on HSC maintenance [ 20 , 26 ]. In this review, we will investigate three recent papers that have led us to reexamine the contributions of DNA damage repair to the development of malignancy, and also to reconsider the notion that HSCs are privileged to avoid genotoxic stress and the accumulation of DNA damage [ 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the first, Santos, et al , the authors explored a role for the DNA damage response and DNA damage resistance in promoting the development of hematological malignancy [ 27 ]. This work is the culmination of accumulated evidence that has suggested a mechanism through which HSCs differentiate when faced with genotoxic stressors, likely to avoid the propagation of mutations in a population capable of self-renewal [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The second publication, Beerman, et al , describes the accumulation of DNA damage with age in quiescent HSCs due to an inefficient response to DNA damage [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

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DNA Damage: A Sensible Mediator of the Differentiation Decision in Hematopoietic Stem Cells and in Leukemia

Weiss

Ito

2015

IJMS

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In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche.

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DNA damage response, redox status and hematopoiesis

Cited by 18 publications

References 98 publications

Human adipose-derived stem cells obtained from lipoaspirates are highly susceptible to hydrogen peroxide mediated cytogenotoxicity

Human adipose-derived stem cells obtained from lipoaspirates are highly susceptible to hydrogen peroxide mediated cytogenotoxicity

The role of PML in hematopoietic and leukemic stem cell maintenance

DNA Damage: A Sensible Mediator of the Differentiation Decision in Hematopoietic Stem Cells and in Leukemia

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