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

Nature Reviews Molecular Cell Biology volume 9, pages 285–296 (2008)Cite this article

Key Points

  • Changes in oxygen (O2) tensions clearly have a role in patterning invertebrate and vertebrate embryos.

  • One of the first examples of the impact of O2 availability on developmental processes was demonstrated for the Drosophila melanogaster tracheal system. Here, O2-starved cells provide signals that promote increased branching morphogenesis of the O2-delivering tracheal network.

  • Genetic evidence now indicates that the differentiation of mammalian cardiovascular, placental, pulmonary, bone and haematopoietic cells and adipocytes is regulated by O2 availability.

  • Various pathways that mediate responses to O2 deprivation (hypoxia) have a role in embryonic development. The best genetic evidence is provided by animals that lack various subunits of the hypoxia inducible factor (HIF) heterodimeric transcription factors.

  • Recently, stem and progenitor cell phenotypes have been shown to be regulated by changes in O2 levels. Once again, HIFs have a crucial role in this process by interfacing with other stem cell signalling pathways such as those involving OCT4, Notch and Wnt.

Abstract

Low levels of oxygen (O2) occur naturally in developing embryos. Cells respond to their hypoxic microenvironment by stimulating several hypoxia-inducible factors (and other molecules that mediate O2 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 O2 regulates their differentiation. Recent work has revealed an important link between factors that are involved in regulating stem and progenitor cell behaviour and hypoxia-inducible factors, which provides a molecular framework for the 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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Figure 1: Branch morphogenesis during D. melanogaster tracheal development and mammalian blood vessel formation is regulated by O2 levels.
Figure 2: Oxygen gradients are generated in developing human and mouse placentas.
Figure 3: Distinct populations of stem cells occupy microenvironments that contain different O2 levels.
Figure 4: Models depicting O2 availability and transcriptional activity.
Figure 5: Multiple pathways responding to changes in O2 availability affect developmental processes as well as social behaviour.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    M. Celeste Simon & Brian Keith

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  1. M. Celeste Simon
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Correspondence to M. Celeste Simon.

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Glossary

Hypoxia

A state in which the level of O2 is decreased relative to the normal level (which is 2–9% in most mammalian cell types).

Normoxic

Although frequently defined in the literature as 21% O2, physiological normoxia is actually in the range of 2–9% O2 for most adult cells in vivo.

Ischaemia

A pathological condition resulting from blood vessel occlusion, involving deprivation of oxygen, nutrients and growth factors. This condition also usually leads to decreased tissue pH levels.

Niche

The natural anatomic environment that supports stem cell behaviour.

Ontogeny

The development of the fetus during embryogenesis.

ETS

The founding member of a family of oncogenes and proto-oncogenes. ETS refers to 'E26-specific'.

Ramification

The process of dividing or spreading into branches.

Vasculogenesis

The formation of nascent blood vessels from newly generated endothelial cells.

Angiogenesis

The remodelling of blood vessels into the large and small vessels that are typical of mature networks containing arteries, capillaries and veins.

Somite

The primordial tissue that generates the vertebrae, dermis and muscles.

Conceptus

An embryo or fetus.

Cytotrophoblast

An outer cell of the developing embryo that adheres to the endometrium.

Bradycardia

A slowing of heart rate, usually measured as fewer than 60 beats per minute in humans.

Catecholamine dysregulation

Mice lacking HIF-2α die in utero owing to decreased production of catecholamine (for example, L-3,4-dihydroxyphenylalanine) by chromaffin cells in the organ of Zuckerkandl. Catecholamines are required for normal cardiovascular function.

Arborize

To develop many branching parts or formations.

Retinopathy

An abnormal increase in retinal vascular networks.

Hepatic steatosis

The accumulation of lipid in the liver.

Cardiac hypertrophy

Overgrowth of the heart through increased cell size rather than increased cell number.

Skeletal myopathy

Any disease of the muscle tissues, such as muscular dystrophy.

Physiological hypoxia

The natural low O2 level that is encountered by cells within the developing embryo, in particular before establishment of the utero–placental network.

Adipogenesis

The differentiation of lipid-producing and storage cells known as adipocytes.

Inner cell mass

Early cells in the embryo that generate all lineages of the mature organism but do not give rise to the placenta.

Pluripotent

A cell that has the potential to differentiate into any of the cell lineages of the developing organism.

Embryoid body

A three-dimensional structure consisting of differentiated derivatives of embryonic stem cells.

Cancer stem cell

A cancer-initiating cell that can self-renew and generate distinct cell types.

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Simon, M., Keith, B. The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9, 285–296 (2008). https://doi.org/10.1038/nrm2354

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