Low oxygen tension inhibits osteogenic differentiation and enhances stemness of human MIAMI cells

D’Ippolito, Gianluca; Diabira, Sylma; Howard, Guy A.; Roos, Bernard A.; Schiller, Paul C.

doi:10.1016/j.bone.2006.02.061

Cited by 343 publications

(308 citation statements)

References 40 publications

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“…Accordantly, a recent report (26) suggested that ESC apoptosis is found to be dependent on the cel- lular differentiation and on the duration and degree of hypoxia. In this context, it is interesting to note that low O 2 tension inhibits differentiation of hESCs (27) and human marrow stromal cells (28). Notably, LIFR expression is low or absent in hESCs, indicating that the LIF-STAT3 signaling pathway does not appear to be involved in self-renewal of hESCs (29).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Jeong

Cha

et al. 2007

Journal of Biological Chemistry

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During mammalian embryogenesis, the early embryo grows in a relatively hypoxic environment due to a restricted supply of oxygen. The molecular mechanisms underlying modulation of self-renewal and differentiation of mouse embryonic stem cells (mESCs) under such hypoxic conditions remain to be established. Here, we show that hypoxia inhibits mESC self-renewal and induces early differentiation in vitro, even in the presence of leukemia inhibitory factor (LIF). These effects are mediated by down-regulation of the LIF-STAT3 signaling pathway. Under conditions of hypoxia, hypoxia-inducible factor-1␣ (HIF-1␣) suppresses transcription of LIF-specific receptor (LIFR) by directly binding to the reverse hypoxia-responsive element located in the LIFR promoter. Ectopic expression and small interference RNA knockdown of HIF-1␣ verified the inhibitory effect on LIFR transcription. Our findings collectively suggest that hypoxia-induced in vitro differentiation of mESCs is triggered, at least in part, by the HIF-1␣-mediated suppression of LIF-STAT3 signaling. Analysis of mESCs2 isolated from the inner cell mass of preimplantation embryos has aided in elucidating the early molecular events and mechanisms responsible for maintenance of ESC pluripotency (1). In contrast to human ESCs (hESCs), selfrenewal of mESCs can be sustained indefinitely in feeder-free conditions if supplemented with LIF (2). mESC lines can be derived directly from embryos in the presence of LIF, indicating that this factor is specifically required for the maintenance of pluripotency. Intracellular signaling cascades initiated by LIF are mediated through the heterodimerization of LIFR and glycoprotein 130 (gp130). This complex activates Janus-associated tyrosine kinase and the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Activation of STAT3 by LIF is crucial in mediating self-renewal signals in mESCs (3, 4).During mammalian development, oxygen needed for cellular metabolism in the early embryo is supplied by simple diffusion from fluids within the oviduct and uterus. Thus, the early embryo develops in a relatively hypoxic environment until the onset of vascularization after implantation (5). Actually, oxygen tension in the mammalian reproductive tract is reported to be less than half the atmospheric oxygen tension (6). Low oxygen tension triggers a wide range of cellular events centered on the regulation of hypoxia-inducible factor-1 (HIF-1) (7), which consists of a common ␤ subunit (HIF-1␤) and an oxygen-sensitive ␣ subunit (HIF-1␣). Under normoxia, HIF-1␣ is rapidly degraded via the von Hippel-Lindau protein-mediated ubiquitin-proteasome pathway (8). Although the role and biological relevance of HIF-1 during murine embryonic development have been established (9 -11), our understanding of how HIF-1 affects the early differentiation of mESCs at the molecular level is beginning to emerge.Our previous study demonstrated the presence of hypoxic regions during normal mouse development (12), which prompted us to study the role of hy...

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Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Jeong

Cha

et al. 2007

Journal of Biological Chemistry

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“…Low pO 2 protected hESCs by decreasing chromosomal damage, but also sensitized the hESCs to oxidative damage after a shift back to 20% O 2 [27]. MIAMI cell expansion was less extensive under 1% vs. 3-10% O 2 , although it was still greater than under 20% O 2 [31]. This was likely due to oxygen depletion under 1% O 2 and emphasizes the point that pO 2 experienced by cells in static cultures is less than that in the gas phase.…”

Section: Oxygen Tensionmentioning

confidence: 86%

“…After a short lag period, human MSCs grew more rapidly under 2% vs. 20% O 2 and exhibited greater retention of MSC markers and formation of CFU-F when cultured at 2% O 2 [30]. Bone-marrow-isolated adult multilineage-inducible (MIAMI) cells also exhibited greater expansion, retention of ESC markers, and decreased osteogenic differentiation under 3% vs. 20% O 2 [31]. Low pO 2 protected hESCs by decreasing chromosomal damage, but also sensitized the hESCs to oxidative damage after a shift back to 20% O 2 [27].…”

Section: Oxygen Tensionmentioning

confidence: 99%

Bioreactor development for stem cell expansion and controlled differentiation

King

Miller

2007

Current Opinion in Chemical Biology

219

154

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Widespread use of embryonic and adult stem cells for therapeutic applications will require reproducible production of large numbers of well-characterized cells under well-controlled conditions in bioreactors. During the last two years, substantial progress has been made towards this goal. Human mesenchymal stem cells expanded in perfused scaffolds retained multi-lineage potential. Mouse neural stem cells were expanded as aggregates in serum-free medium for 44 days in stirred bioreactors. Mouse embryonic stem cells expanded as aggregates and on microcarriers in stirred vessels retained expression of stem cell markers and could form embryoid bodies. Embryoid body formation from dissociated mouse embryonic stem cells, followed by embryoid body expansion and directed differentiation, was scaled-up to gas-sparged, 2-liter instrumented bioreactors with pH and oxygen control.

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“…Jaworski and others (17,42) have suggested that the oxygen supply regulates cutting cone formation and diameter. We, and others, have previously demonstrated that the oxygen supply regulates the phenotype of both osteoblasts and preosteocytes (6,28,32,36,41,47). From this perspective, the oxygen supply may limit the maximal diameter of functional osteons by regulating cell activity and differentiation in both the cutting and closing cones.…”

Section: C926 Numerical Modeling Of Oxygen In Bonementioning

confidence: 88%

Numerical modeling of oxygen distributions in cortical and cancellous bone: oxygen availability governs osteonal and trabecular dimensions

Zahm

Bucaro

Ayyaswamy

et al. 2010

American Journal of Physiology-Cell Physiology

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has demonstrated the role of oxygen tension in the regulation of skeletal cell function and viability, the microenvironmental oxemic status of bone cells remains unknown. In this study, we have employed the Krogh cylinder model of oxygen diffusion to predict the oxygen distribution profiles in cortical and cancellous bone. Under the assumption of saturation-type Michaelis-Menten kinetics, our numerical modeling has indicated that, under steady-state conditions, there would be oxygen gradients across mature osteons and trabeculae. In Haversian bone, the calculated oxygen tension decrement ranges from 15 to 60%. For trabecular bone, a much shallower gradient is predicted. We note that, in Haversian bone, the gradient is largely dependent on osteocyte oxygen utilization and tissue oxygen diffusivity; in trabecular bone, the gradient is dependent on oxygen utilization by cells lining the bone surface. The Krogh model also predicts dramatic differences in oxygen availability during bone development. Thus, during osteon formation, the modeling equations predict a steep oxygen gradient at the initial stage of development, with the gradient becoming lesser as osteonal layers are added. In contrast, during trabeculum formation, the oxygen gradient is steepest when the diameter of the trabeculum is maximal. Based on these results, it is concluded that significant oxygen gradients exist within cortical and cancellous bone and that the oxygen tension may regulate the physical dimensions of both osteons and bone trabeculae. osteon; bone trabeculum; kinetics; Krogh; H; aversian OXYGEN DELIVERY governs the form and function of both soft and hard tissues (25). In the bone, a decrease in the rate of oxygen transport can severely impact skeletal health causing delays in bone healing, a change in the rate of bone turnover, and a raised incidence of vertebral and cranial malformations (7,26,31,33,40). Most commonly, oxemic stress is thought to be caused by a decrease in fluid flow during biomechanical unloading (8,13,22,34); when this occurs, there is a reduction in the oxygen transport rate in the lacunocanalicular system and impaired osteocyte function (29). While it is clear that the local oxygen tension (PO 2 ) is a potent regulator of skeletal cell metabolism and viability (1, 38, 41, 43), the oxygen distribution profile in the bone is currently unknown.The viability and function of cells in complex tissues is dependent on the delivery of oxygen and nutrients. Several numerical studies have attempted to model nutrient exchange by stress-induced fluid flow and diffusion within the lacunocanalicular system of the bone (22,29,34,45). While these studies have provided values for low-molecular-weight solutes, oxygen transport in the bone has not been addressed. In an earlier investigation, we have employed the Krogh cylinder assumption to model the oxygen supply to avian femoral growth cartilage (16); this same model has been used to predict the oxygen tension in skeletal muscle (24), brain (21), and bone marrow (3, 4).The Krogh cy...

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Low oxygen tension inhibits osteogenic differentiation and enhances stemness of human MIAMI cells

Cited by 343 publications

References 40 publications

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Hypoxia-inducible Factor-1α Inhibits Self-renewal of Mouse Embryonic Stem Cells in Vitro via Negative Regulation of the Leukemia Inhibitory Factor-STAT3 Pathway

Bioreactor development for stem cell expansion and controlled differentiation

Numerical modeling of oxygen distributions in cortical and cancellous bone: oxygen availability governs osteonal and trabecular dimensions

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