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• W2084037323 abstract "The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering practices and furthermore elucidate an added dimension of stem cell control within the niche. The defining hallmark of stem cells is their ability to self-renew and maintain multipotency. This capacity depends on the balance of complex signals in their microenvironment. Low oxygen tensions (hypoxia) maintain undifferentiated states of embryonic, hematopoietic, mesenchymal, and neural stem cell phenotypes and also influence proliferation and cell-fate commitment. Recent evidence has identified a broader spectrum of stem cells influenced by hypoxia that includes cancer stem cells and induced pluripotent stem cells. These findings have important implications on our understanding of development, disease, and tissue-engineering practices and furthermore elucidate an added dimension of stem cell control within the niche. Early tissue and cell culture pioneers paid exquisite attention to the balance of nutrients, growth factors, and pH buffers used to grow cells in vitro (Carrel, 1912Carrel A. On the Permanent Life of Tissues Outside of the Organism.J. Exp. Med. 1912; 15: 516-528Crossref PubMed Google Scholar). Very little attention was given to the oxygen concentration present in culture media, as it was assumed that ambient air was adequate for cell growth (Shooter and Gey, 1952Shooter R.A. Gey G.O. Studies of the mineral requirements of mammalian cells.Br. J. Exp. Pathol. 1952; 33: 98-103PubMed Google Scholar). In contrast, direct measurements of tissue oxygen tensions in developing embryos revealed that these tissues demonstrated much lower oxygen tensions than had been presumed (Mitchell and Yochim, 1968Mitchell J.A. Yochim J.M. Intrauterine oxygen tension during the estrous cycle in the rat: its relation to uterine respiration and vascular activity.Endocrinology. 1968; 83: 701-705Crossref PubMed Google Scholar). Oxygen measurements of tissues known to harbor stem cells revealed even lower oxygen tensions, and raised the question of whether such an environment was necessary for the niche to maintain stem cells (Braun et al., 2001Braun R.D. Lanzen J.L. Snyder S.A. Dewhirst M.W. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents.Am. J. Physiol. Heart Circ. Physiol. 2001; 280: H2533-H2544PubMed Google Scholar, Cipolleschi et al., 1993Cipolleschi M.G. Dello Sbarba P. Olivotto M. The role of hypoxia in the maintenance of hematopoietic stem cells.Blood. 1993; 82: 2031-2037Crossref PubMed Google Scholar, Erecinska and Silver, 2001Erecinska M. Silver I.A. Tissue oxygen tension and brain sensitivity to hypoxia.Respir. Physiol. 2001; 128: 263-276Crossref PubMed Scopus (218) Google Scholar). Now that almost two decades have passed since these experiments were performed, hypoxia is appreciated to promote an undifferentiated state in several stem and precursor cell populations. The signaling cascade and transcriptional program activated in hypoxic conditions appear to be shared by many stem cells, at least to some degree, but also manifest different biological responses among specific stem cell lineages. The effects of hypoxia on development have been the subject of many reviews, but its direct effect on stem cell biology has received little attention (Simon and Keith, 2008Simon M.C. Keith B. The role of oxygen availability in embryonic development and stem cell function.Nat. Rev. Mol. Cell Biol. 2008; 9: 285-296Crossref PubMed Scopus (261) Google Scholar). This review aims to describe these responses and their signaling cascades in the context of the biology of several stem cell systems and their respective niches. Ever since the stem cell niche concept was proposed by Schofield in 1978, the term “niche” has been a source of confusion, controversy, and intrigue (Schofield, 1978Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell.Blood Cells. 1978; 4: 7-25PubMed Google Scholar). However, visualization of stem cell niches in worms (Kimble and White, 1981Kimble J.E. White J.G. On the control of germ cell development in Caenorhabditis elegans.Dev. Biol. 1981; 81: 208-219Crossref PubMed Google Scholar), flies (Xie and Spradling, 1998Xie T. Spradling A.C. decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary.Cell. 1998; 94: 251-260Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar), and eventually mammalian tissues (Doetsch et al., 1999Doetsch F. Caille I. Lim D.A. Garcia-Verdugo J.M. Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain.Cell. 1999; 97: 703-716Abstract Full Text Full Text PDF PubMed Scopus (2164) Google Scholar, Nilsson et al., 2001Nilsson S.K. Johnston H.M. Coverdale J.A. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches.Blood. 2001; 97: 2293-2299Crossref PubMed Scopus (315) Google Scholar, Quiñones-Hinojosa et al., 2006Quiñones-Hinojosa A. Sanai N. Soriano-Navarro M. Gonzalez-Perez O. Mirzadeh Z. Gil-Perotin S. Romero-Rodriguez R. Berger M.S. Garcia-Verdugo J.M. Alvarez-Buylla A. Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells.J. Comp. Neurol. 2006; 494: 415-434Crossref PubMed Scopus (244) Google Scholar) has slowly illuminated our view of the niche and helped us determine how it can be defined. The stem cell niche has come to refer to a defined anatomical compartment that includes cellular and acellular components that integrate both systemic and local cues to regulate the biology of stem cells (Jones and Wagers, 2008Jones D.L. Wagers A.J. No place like home: anatomy and function of the stem cell niche.Nat. Rev. Mol. Cell Biol. 2008; 9: 11-21Crossref PubMed Scopus (219) Google Scholar, Li and Xie, 2005Li L. Xie T. Stem cell niche: structure and function.Annu. Rev. Cell Dev. Biol. 2005; 21: 605-631Crossref PubMed Scopus (507) Google Scholar, Scadden, 2006Scadden D.T. The stem-cell niche as an entity of action.Nature. 2006; 441: 1075-1079Crossref PubMed Scopus (732) Google Scholar, Yin and Li, 2006Yin T. Li L. The stem cell niches in bone.J. Clin. Invest. 2006; 116: 1195-1201Crossref PubMed Scopus (361) Google Scholar). Cells, blood vessels, matrix glycoproteins, and the three-dimensional space that is formed from this architecture provide a highly specialized microenvironment for a stem cell (Scadden, 2006Scadden D.T. The stem-cell niche as an entity of action.Nature. 2006; 441: 1075-1079Crossref PubMed Scopus (732) Google Scholar). Contact and communication between these elements is critical for stem cell self-renewal and multipotency. While much interest has focused on identifying the structural and humoral factors that mediate this biology, an underexplored variable is the metabolic milieu of this highly specialized microenvironment (Scadden, 2006Scadden D.T. The stem-cell niche as an entity of action.Nature. 2006; 441: 1075-1079Crossref PubMed Scopus (732) Google Scholar). The ability to isolate and culture stem cells in vitro has greatly advanced our understanding of the role and makeup of the niche in some stem cell systems. Like all other established cell lines, stem cells were typically cultured under ambient oxygen tensions with very little attention paid to the metabolic milieu of the niche in which they were grown or normally resided. This practice led researchers to focus on identifying growth factors and signaling proteins while failing to explore equally as important metabolic factors of the niche (Scadden, 2006Scadden D.T. The stem-cell niche as an entity of action.Nature. 2006; 441: 1075-1079Crossref PubMed Scopus (732) Google Scholar). However, in time, scientists started manipulating oxygen concentrations and showed that lower oxygen tensions greatly influenced both embryonic and adult stem cell biology (Eliasson and Jonsson, 2010Eliasson P. Jonsson J.I. The hematopoietic stem cell niche: low in oxygen but a nice place to be.J. Cell. Physiol. 2010; 222: 17-22Crossref PubMed Scopus (111) Google Scholar, Panchision, 2009Panchision D.M. The role of oxygen in regulating neural stem cells in development and disease.J. Cell. Physiol. 2009; 220: 562-568Crossref PubMed Scopus (65) Google Scholar, Silvan et al., 2009Silvan U. Diez-Torre A. Arluzea J. Andrade R. Silio M. Arechaga J. Hypoxia and pluripotency in embryonic and embryonal carcinoma stem cell biology.Differentiation. 2009; 78: 159-168Crossref PubMed Scopus (23) Google Scholar). These observations, coupled with the direct tissue measurements of oxygen discussed above, fueled a hypothesis that perhaps low oxygen tensions were indeed critical to the metabolic milieu of stem cell niches. Furthermore, the identification of previously undescribed stem cells in compartments known to be notoriously hypoxic, as in the case of the kidney medulla/papilla, continues to drive the excitement behind this hypothesis (Oliver et al., 2004Oliver J.A. Maarouf O. Cheema F.H. Martens T.P. Al-Awqati Q. The renal papilla is a niche for adult kidney stem cells.J. Clin. Invest. 2004; 114: 795-804Crossref PubMed Google Scholar). Indeed, adult tissues experience a wide range of oxygen tensions that are considerably different from the inhaled ambient oxygen tensions of 21% (160 mm Hg) (Figure 1). The partial pressure oxygen (pO2) of inspired air progressively decreases after it enters the lungs and as it travels in the blood throughout the body. By the time it reaches organs and tissues, pO2 levels have dropped to 2%–9% (14–65 mm Hg) (Brahimi-Horn and Pouyssegur, 2007Brahimi-Horn M.C. Pouyssegur J. Oxygen, a source of life and stress.FEBS Lett. 2007; 581: 3582-3591Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). This pressure is a drastic departure from oxygen tensions in ambient air that are typically considered “normoxic” by conventional standards of cell-culture practice. However, oxygen concentrations between 2%–9% have recently been appreciated by some scientists to constitute physiologic normoxia (Simon and Keith, 2008Simon M.C. Keith B. The role of oxygen availability in embryonic development and stem cell function.Nat. Rev. Mol. Cell Biol. 2008; 9: 285-296Crossref PubMed Scopus (261) Google Scholar). Nonetheless, it is challenging to assay the precise oxygen pressures that a given cell might experience in vivo, and so physiologic normoxia for one cell may be higher or lower in different environments or tissues or even under different pathologic conditions. For example, adult tissues that exhibit unique vascular supply (i.e., the kidney medulla/papilla [Brezis et al., 1984Brezis M. Rosen S. Silva P. Epstein F.H. Renal ischemia: a new perspective.Kidney Int. 1984; 26: 375-383Crossref PubMed Google Scholar]) or low vascular density (such as the rat retina [Yu and Cringle, 2005Yu D.Y. Cringle S.J. Retinal degeneration and local oxygen metabolism.Exp. Eye Res. 2005; 80: 745-751Crossref PubMed Scopus (81) Google Scholar] and some areas of the brain [Erecinska and Silver, 2001Erecinska M. Silver I.A. Tissue oxygen tension and brain sensitivity to hypoxia.Respir. Physiol. 2001; 128: 263-276Crossref PubMed Scopus (218) Google Scholar]) can extend this gradient further and experience oxygen tensions as low as 1% (7.2 mm Hg), a relatively hypoxic environment when compared to other tissues. From a molecular perspective, physiologic normoxia is considered to be hypoxic because a conserved molecular response is deployed under oxygen tensions in the range of 2%–9%. This molecular response is discussed in more detail in other reviews and includes hypoxia-inducible transcriptions factors (HIFs), oxygen sensitive ion channels, the environmental sensing mammalian target of rapamycin (mTOR), and the endoplasmic reticulum (ER) stress response (Liu and Simon, 2004Liu L. Simon M.C. Regulation of transcription and translation by hypoxia.Cancer Biol. Ther. 2004; 3: 492-497PubMed Google Scholar, Semenza, 1999Semenza G.L. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1.Annu. Rev. Cell Dev. Biol. 1999; 15: 551-578Crossref PubMed Scopus (1148) Google Scholar, Wouters et al., 2005Wouters B.G. van den Beucken T. Magagnin M.G. Koritzinsky M. Fels D. Koumenis C. Control of the hypoxic response through regulation of mRNA translation.Semin. Cell Dev. Biol. 2005; 16: 487-501Crossref PubMed Scopus (90) Google Scholar). It has been hypothesized that the presence of low oxygen tensions in stem cell niches offers a selective advantage that is well suited to their particular biological roles (Cipolleschi et al., 1993Cipolleschi M.G. Dello Sbarba P. Olivotto M. The role of hypoxia in the maintenance of hematopoietic stem cells.Blood. 1993; 82: 2031-2037Crossref PubMed Google Scholar). That is, essentially all cells that undergo aerobic metabolism are subject to some degree of oxidative stress through the generation of reactive oxygen species that can damage DNA. This risk is supported by direct evidence that mouse embryonic fibroblasts accumulate more mutations and senesce faster when cultured under 20% O2 than cells cultured under 3% O2 (Busuttil et al., 2003Busuttil R.A. Rubio M. Dolle M.E. Campisi J. Vijg J. Oxygen accelerates the accumulation of mutations during the senescence and immortalization of murine cells in culture.Aging Cell. 2003; 2: 287-294Crossref PubMed Google Scholar). By residing in anatomical compartments that experience relatively low oxygen tensions (in the range of 1%–9%), stem cells may escape this damage and corresponding growth pressure (Figure 1). In addition, hypoxia has been shown to activate molecular pathways in multiple stem cell systems that appear to regulate Oct4 and Notch signaling, two important regulators of stemness (Simon and Keith, 2008Simon M.C. Keith B. The role of oxygen availability in embryonic development and stem cell function.Nat. Rev. Mol. Cell Biol. 2008; 9: 285-296Crossref PubMed Scopus (261) Google Scholar). Finally, oxygen tensions as low as 1% appear to decrease proliferation and maintain ESC pluripotency, while higher oxygen tensions (3%–5%) appear to maintain pluripotency with no effect on proliferation (Ezashi et al., 2005Ezashi T. Das P. Roberts R.M. Low O2 tensions and the prevention of differentiation of hES cells.Proc. Natl. Acad. Sci. USA. 2005; 102: 4783-4788Crossref PubMed Scopus (342) Google Scholar). These results suggest that proliferation and perhaps even stem cell quiescence may be regulated by gradients of oxygen tension supplied by their local niche. Embryogenesis is heavily influenced by oxygen gradients. Direct evidence for this finding was made available when oxygen tensions were measured in endometrial and trophoblastic tissues during early pregnancy (Mitchell and Yochim, 1968Mitchell J.A. Yochim J.M. Intrauterine oxygen tension during the estrous cycle in the rat: its relation to uterine respiration and vascular activity.Endocrinology. 1968; 83: 701-705Crossref PubMed Google Scholar, Rodesch et al., 1992Rodesch F. Simon P. Donner C. Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy.Obstet. Gynecol. 1992; 80: 283-285PubMed Google Scholar). Oxygen has a diffusion distance of approximately 150 μm (Folkman et al., 2000Folkman J. Hahnfeldt P. Hlatky L. Cancer: looking outside the genome.Nat. Rev. Mol. Cell Biol. 2000; 1: 76-79Crossref PubMed Google Scholar, Gatenby and Gillies, 2004Gatenby R.A. Gillies R.J. Why do cancers have high aerobic glycolysis?.Nat. Rev. Cancer. 2004; 4: 891-899Crossref PubMed Scopus (1286) Google Scholar). Thus, before establishment of the circulatory system, delivery of oxygen to the embryo is subject to the limits of diffusion and, as a result, early mammalian development occurs in a relatively oxygen-poor environment. The identification of hypoxia inducible factors (HIFs) helped explain many of hypoxia's direct effects on ESCs. HIFs belong to a family of transcription factors known for environmental sensing called bHLH-PAS (basic helix-loop-helix-Per-Arnt-Sim) transcription factors (Gu et al., 2000Gu Y.Z. Hogenesch J.B. Bradfield C.A. The PAS superfamily: sensors of environmental and developmental signals.Annu. Rev. Pharmacol. Toxicol. 2000; 40: 519-561Crossref PubMed Scopus (594) Google Scholar). The genes HIF-1α, HIF-2α, and HIF-3α encode HIF-α subunits that are stabilized under low oxygen tensions and exhibit tissue restricted expression (for review on the critical control mechanisms of these subunits, see Bruick, 2003Bruick R.K. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor.Genes Dev. 2003; 17: 2614-2623Crossref PubMed Scopus (229) Google Scholar). Upon stabilization, these subunits dimerize with the β-subunit, HIF-β (aryl hydrocarbon receptor nuclear translocator [ARNT]) and translocate to the nucleus to regulate a spectrum of genes necessary to maintain oxygen homeostasis, glucose metabolism, angiogenesis, erythropoiesis, and iron metabolism (Semenza, 1999Semenza G.L. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1.Annu. Rev. Cell Dev. Biol. 1999; 15: 551-578Crossref PubMed Scopus (1148) Google Scholar). Homozygous knockouts of HIF-1α, HIF-2α, and HIF-β subunits are embryonically lethal, thus identifying an essential role for this pathway during development. HIF-β-deficient embryos demonstrated lethality by day E10.5, with prominent defects in vascularization of the yolk sac, placenta, brachial arches, cranium, and somites (Ramirez-Bergeron et al., 2006Ramirez-Bergeron D.L. Runge A. Adelman D.M. Gohil M. Simon M.C. HIF-dependent hematopoietic factors regulate the development of the embryonic vasculature.Dev. Cell. 2006; 11: 81-92Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Similar to HIF-β knockouts, HIF-1α-deficient animals were also embryonically lethal and exhibited pathologies in neural-fold closure and blood vessel formation (Iyer et al., 1998Iyer N.V. Kotch L.E. Agani F. Leung S.W. Laughner E. Wenger R.H. Gassmann M. Gearhart J.D. Lawler A.M. Yu A.Y. et al.Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha.Genes Dev. 1998; 12: 149-162Crossref PubMed Google Scholar, Ryan et al., 1998Ryan H.E. Lo J. Johnson R.S. HIF-1 alpha is required for solid tumor formation and embryonic vascularization.EMBO J. 1998; 17: 3005-3015Crossref PubMed Scopus (986) Google Scholar). It has been well documented that even in the presence of feeder layers in vitro human ESCs differentiate spontaneously when cultured under 21% oxygen. Remarkably, the rate of differentiation is significantly reduced when hESCs are cultured under 3% or 5% O2 (Ezashi et al., 2005Ezashi T. Das P. Roberts R.M. Low O2 tensions and the prevention of differentiation of hES cells.Proc. Natl. Acad. Sci. USA. 2005; 102: 4783-4788Crossref PubMed Scopus (342) Google Scholar). Culture under these hypoxic conditions (also considered “physiologically normoxic,” as discussed above) is necessary to maintain full pluripotency and enhanced formation of embryoid bodies with no compromise in proliferation rates (Ezashi et al., 2005Ezashi T. Das P. Roberts R.M. Low O2 tensions and the prevention of differentiation of hES cells.Proc. Natl. Acad. Sci. USA. 2005; 102: 4783-4788Crossref PubMed Scopus (342) Google Scholar). Interestingly, culturing under lower oxygen tensions (1%), maintains pluripotency but significantly reduces proliferation, suggesting that gradients of oxygen tensions can modulate proliferation and quiescence in stem cells (Ezashi et al., 2005Ezashi T. Das P. Roberts R.M. Low O2 tensions and the prevention of differentiation of hES cells.Proc. Natl. Acad. Sci. USA. 2005; 102: 4783-4788Crossref PubMed Scopus (342) Google Scholar). Recent findings support not only a direct role for low oxygen tensions in maintaining stem cell phenotypes but also potentially an indirect role through modifying nearby stromal elements. Although ESC niches remain largely ill-defined, Ji et al. have recently demonstrated that activation of hypoxia signaling pathways by overexpression of HIF-1α in human fetal liver stromal cells maintained self-renewal and pluripotency of cocultured hESCs (Ji et al., 2009Ji L. Liu Y.X. Yang C. Yue W. Shi S.S. Bai C.X. Xi J.F. Nan X. Pei X.T. Self-renewal and pluripotency is maintained in human embryonic stem cells by co-culture with human fetal liver stromal cells expressing hypoxia inducible factor 1alpha.J. Cell. Physiol. 2009; 221: 54-66Crossref PubMed Scopus (14) Google Scholar). These observations support the hypothesis that low oxygen tensions play a critical role in regulating ESCs directly and that surrounding stromal cells of the niche may be influenced to secrete factors that support stem cell pluripotency. One of the most well-characterized stem cell niches is that of the hematopoietic stem cell (HSC) (Yin and Li, 2006Yin T. Li L. The stem cell niches in bone.J. Clin. Invest. 2006; 116: 1195-1201Crossref PubMed Scopus (361) Google Scholar). With the ability to purify and modify HSCs and reintroduce them to the in vivo setting, new experimental tools have allowed for direct investigation of their native niche. Tracer studies of transplanted HSCs reveal that they most likely reside in bone cavities specifically adjacent to endosteal bone lined by osteoblast cells (Jones and Wagers, 2008Jones D.L. Wagers A.J. No place like home: anatomy and function of the stem cell niche.Nat. Rev. Mol. Cell Biol. 2008; 9: 11-21Crossref PubMed Scopus (219) Google Scholar, Li and Xie, 2005Li L. Xie T. Stem cell niche: structure and function.Annu. Rev. Cell Dev. Biol. 2005; 21: 605-631Crossref PubMed Scopus (507) Google Scholar). HSCs share an important relationship with osteablasts and other stromal elements of the bone marrow niche critical to their maintenance and protection (Jones and Wagers, 2008Jones D.L. Wagers A.J. No place like home: anatomy and function of the stem cell niche.Nat. Rev. Mol. Cell Biol. 2008; 9: 11-21Crossref PubMed Scopus (219) Google Scholar, Li and Xie, 2005Li L. Xie T. Stem cell niche: structure and function.Annu. Rev. Cell Dev. Biol. 2005; 21: 605-631Crossref PubMed Scopus (507) Google Scholar, Qian et al., 2007Qian H. Buza-Vidas N. Hyland C.D. Jensen C.T. Antonchuk J. Mansson R. Thoren L.A. Ekblom M. Alexander W.S. Jacobsen S.E. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells.Cell Stem Cell. 2007; 1: 671-684Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, Yoshihara et al., 2007Yoshihara H. Arai F. Hosokawa K. Hagiwara T. Takubo K. Nakamura Y. Gomei Y. Iwasaki H. Matsuoka S. Miyamoto K. et al.Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche.Cell Stem Cell. 2007; 1: 685-697Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar). However, in a series of papers published in the early 1990s, it was postulated that the bone marrow niche was hypoxic relative to other tissues (Cipolleschi et al., 1993Cipolleschi M.G. Dello Sbarba P. Olivotto M. The role of hypoxia in the maintenance of hematopoietic stem cells.Blood. 1993; 82: 2031-2037Crossref PubMed Google Scholar, Dello Sbarba et al., 1987Dello Sbarba P. Cipolleschi M.G. Olivotto M. Hemopoietic progenitor cells are sensitive to the cytostatic effect of pyruvate.Exp. Hematol. 1987; 15: 137-142PubMed Google Scholar). This model was based on the observation that quiescent HSCs localized to regions of the bone marrow that were several cells away from blood vessels. Oxygen tension of bone marrow blood is lower than other tissues and is equivalent to that of blood in the jugular vein (Grant and Root, 1947Grant W.C. Root W.S. The relation of O2 in bone marrow blood to post-hemorrhagic erythropoiesis.Am. J. Physiol. 1947; 150: 618-627PubMed Google Scholar). With several stromal cells and progenitor cells observed to physically reside between the HSCs and the closest blood vessel, it was postulated that this niche was relatively hypoxic when compared to other tissues, as these cells competed for the already scarce nutrient and oxygen supply (Figure 1). Mathematical models based on animal data supported this hypothesis and predicted oxygen tensions to be as low as 1% (Chow et al., 2001Chow D.C. Wenning L.A. Miller W.M. Papoutsakis E.T. Modeling pO(2) distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models.Biophys. J. 2001; 81: 685-696Abstract Full Text Full Text PDF PubMed Google Scholar). It is now widely accepted that gradients of oxygen from below 1% in hypoxic niches to 6% in the sinusoidal cavity exist within the human bone marrow (Eliasson and Jonsson, 2010Eliasson P. Jonsson J.I. The hematopoietic stem cell niche: low in oxygen but a nice place to be.J. Cell. Physiol. 2010; 222: 17-22Crossref PubMed Scopus (111) Google Scholar). As the role of hypoxia on HSC maintenance is a subject of other reviews (Eliasson and Jonsson, 2010Eliasson P. Jonsson J.I. The hematopoietic stem cell niche: low in oxygen but a nice place to be.J. Cell. Physiol. 2010; 222: 17-22Crossref PubMed Scopus (111) Google Scholar), we will limit our discussion to important findings that might be pertinent to other stem cell lineages that have received less attention to date. Several investigators have demonstrated that slow-cycling HSCs are more likely to localize in the low oxygen areas of the marrow, away from blood vessels, whereas fast cycling neutrophilic/monocytic colony-forming units (CFU-NM) and day 7 colony forming units in spleen (CFU-S) (both examples of early hematopoietic progenitors with limited capacity for self-renewal) reside in areas much closer to vasculature (Kubota et al., 2008Kubota Y. Takubo K. Suda T. Bone marrow long label-retaining cells reside in the sinusoidal hypoxic niche.Biochem. Biophys. Res. Commun. 2008; 366: 335-339Crossref PubMed Scopus (58) Google Scholar, Lord et al., 1975Lord B.I. Testa N.G. Hendry J.H. The relative spatial distributions of CFUs and CFUc in the normal mouse femur.Blood. 1975; 46: 65-72Crossref PubMed Google Scholar). Although hypoxic cultivation of bone marrow cells has been shown to increase their ability to repopulate and engraft, it is still unclear whether these effects are due to direct action on HSCs or other stromal elements, as many of these experiments were performed with whole marrow or partially purified cell populations (Eliasson and Jonsson, 2010Eliasson P. Jonsson J.I. The hematopoietic stem cell niche: low in oxygen but a nice place to be.J. Cell. Physiol. 2010; 222: 17-22Crossref PubMed Scopus (111) Google Scholar). Hypoxia appears to maintain an immature blast-like quality in mouse HSCs with a primitive phenotype and enhanced engraftment capabilities (Eliasson and Jonsson, 2010Eliasson P. Jonsson J.I. The hematopoietic stem cell niche: low in oxygen but a nice place to be.J. Cell. Physiol. 2010; 222: 17-22Crossref PubMed Scopus (111) Google Scholar). One of the advantages of residing in a hypoxic niche is that stem cells can maintain slow-cycling proliferation rates while avoiding the oxidative stress associated with more well-oxygenated tissue (Busuttil et al., 2003Busuttil R.A. Rubio M. Dolle M.E. Campisi J. Vijg J. Oxygen accelerates the accumulation of mutations during the senescence and immortalization of murine cells in culture.Aging Cell. 2003; 2: 287-294Crossref PubMed Google Scholar, Cipolleschi et al., 1993Cipolleschi M.G. Dello Sbarba P. Olivotto M. The role of hypoxia in the maintenance of hematopoietic stem cells.Blood. 1993; 82: 2031-2037Crossref PubMed Google Scholar, Eliasson and Jonsson, 2010Eliasson P. Jonsson J.I. The hematopoietic stem cell niche: low in oxygen but a nice place to be.J. Cell. Physiol. 2010; 222: 17-22Crossref PubMed Scopus (111) Google Scholar, Lekli et al., 2009Lekli I. Gurusamy N. Ray D. Tosaki A. Das D.K. Redox regulation of stem cell mobilization.Can. J. Physiol. Pharmacol. 2009; 87: 989-995Crossref PubMed Scopus (15) Google Scholar). HIF-1 has emerged as a likely candidate of this regulatory mechanism, as several groups have demonstrated that HIF can mediate cell-cycle arrest in several cell lines (Koshiji et al., 2004Koshiji M. Kageyama Y. Pete E.A. Horikawa I. Barrett J.C. Huang L.E. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.EMBO J. 2004; 23: 1949-1956Crossref PubMed Scopus (278) Google Scholar). In addition, mice with defective HIF signaling exhibit numerous hematopoietic pathologies with prominent defects in hematopoiesis that are embryonically lethal (Eliasson and Jonsson, 2010Eliasson P. Jonsson J.I. The hematopoietic stem cell niche: low in oxygen but a nice place to be.J. Cell. Physiol. 2010; 222: 17-22Crossref PubMed Scopus (111) Google Scholar). HSCs present in the hypoxic niche express higher levels of Notch-1, telomerase, and the cell-cycle inhibitor p21 than cells closer to the vasculature (Jang and Sharkis, 2007Jang Y.Y. Sharkis S.J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche.Blood. 2007; 110: 3056-3063Crossref PubMed Scopus (223) Google Scholar). This observation was recently supported when work on xenotra" @default.
• W2084037323 created "2016-06-24" @default.
• W2084037323 creator A5019691833 @default.
• W2084037323 creator A5029294194 @default.
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• W2084037323 date "2010-08-01" @default.
• W2084037323 modified "2023-10-17" @default.
• W2084037323 title "Oxygen in Stem Cell Biology: A Critical Component of the Stem Cell Niche" @default.
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