Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia

Parmar, Kalindi; Mauch, Peter; Vergilio, Jo‐Anne; Sackstein, Robert; Down, Julian D.

doi:10.1073/pnas.0701152104

Cited by 778 publications

(668 citation statements)

References 48 publications

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“…Examples of relatively hypoxic normal tissues include pericentral vein cells in the liver 12 , portions of the retina (in the dark) 13 , spinous layer of the epidermis 14 , the thymus 6,15 , renal tubular epithelium 16 , myocardium (particularly during exercise) 17 and subregions of the bone marrow that are enriched for stem cells 18 . Hypoxia has diverse roles in the function of these normal tissues.…”

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

“…In the bone marrow the role of hypoxia is reversed relative to what is observed in skin. Here, the most primitive stem cells are maintained in a hypoxic niche 18 . These cells are maintained in a quiescent state by hypoxia-regulated proteins, such as osteopontin (encoded by SPP1) 18,25 .…”

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

“…Here, the most primitive stem cells are maintained in a hypoxic niche 18 . These cells are maintained in a quiescent state by hypoxia-regulated proteins, such as osteopontin (encoded by SPP1) 18,25 . The stem cells are prone to use anaerobic metabolism, perhaps as a means to reduce genotoxic stress associated with reactive oxygen species generated from aerobic metabolism 18 .…”

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

“…These cells are maintained in a quiescent state by hypoxia-regulated proteins, such as osteopontin (encoded by SPP1) 18,25 . The stem cells are prone to use anaerobic metabolism, perhaps as a means to reduce genotoxic stress associated with reactive oxygen species generated from aerobic metabolism 18 . Oxygen electrode and hypoxia marker drug studies have demonstrated that the thymus of mice is heterogeneously hypoxic 6,15 , but in this tissue there is no evidence for HIF1-regulated gene expression 15 .…”

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

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Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

Section: Regulation Of Hif1 By Hypoxiamentioning

confidence: 99%

See 2 more Smart Citations

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…The partial pressure of O 2 in human bone marrow is lower than in peripheral blood and the architecture of medullary sinuses and arterial blood flow patterns generate an O 2 gradient. It has been proposed that HSCs and their proliferating progenitors are naturally distributed along this gradient, with the HSCs occupying the most hypoxic niches 54,55 . Furthermore, Danet et al demonstrated that bone marrow HSCs cultured at 1.5% O 2 promoted their ability to engraft and repopulate the haematopoietic organ of immunocompromised recipient mice 56 .…”

Section: O 2 Levels Regulate Hematopoietic and Embryonic Stem Cellsmentioning

confidence: 99%

The role of oxygen availability in embryonic development and stem cell function

Simon¹,

Keith²

2008

Nat Rev Mol Cell Biol

835

770

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Low levels of oxygen (O 2 ) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several hypoxia-inducible factors (and other molecules that mediate O 2 homeostasis), which then coordinate the development of the blood, vasculature, placenta, nervous system, and other organs. Furthermore, embryonic stem and progenitor cells frequently occupy hypoxic 'niches' and low O 2 regulates their differentiation. Recent work has revealed an important link between factors involved in regulating stem/progenitor cell behaviour and hypoxiainducible factors, which provides a molecular framework for hypoxic control of differentiation and cell fate. These findings have important implications for the development of therapies for tissue regeneration and disease.

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The paradox of metabolism in quiescent stem cells

Coller

2019

FEBS Letters

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The shift between a proliferating and a nonproliferating state is associated with significant changes in metabolic needs. Proliferating cells tend to have higher metabolic rates, and their metabolic profiles facilitate biosynthesis, as compared to those of nondividing cells of the same sort. Recent studies have elucidated specific molecules that control metabolic changes while cells shift between proliferation and quiescence. Embryonic stem cells, which are rapidly proliferating, tend to have metabolic patterns that are similar to those of nonstem cells in a proliferative state. Moreover, although adult stem cells tend to be quiescent, their metabolic profiles have been reported in multiple organs to more closely resemble those of proliferating than those of nondividing cells in some respects. The findings raise questions about whether there are metabolic profiles that are required for stemness, and whether these profiles relate to the metabolic properties that may be required for quiescence. Here, we review the literature on how metabolism changes upon commitment to proliferation and compare the proliferating and nonproliferating metabolic states of differentiated cells and embryonic and adult stem cells.

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Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia

Cited by 778 publications

References 48 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

The role of oxygen availability in embryonic development and stem cell function

The paradox of metabolism in quiescent stem cells

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