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Oxygen in our Bones

Vinogradov Nature imageEach day we take a breath about 20,000 times, bringing in oxygen that provides energy through a complicated reaction in the cell’s energy factory, the mitochondria. Just to break down one molecule of glucose – a basic reaction necessary for life -- into carbon dioxide and water takes six molecules of O2. On the other hand, a highly reactive form of oxygen called superoxide is created by immune cells from O2 to use against invading microbes. But, these reactive, charged oxygen molecules can be lethal to human tissues and are implicated in a host of diseases.

Sergei A. Vinogradov, PhD, associate professor of Biochemistry and Biophysics, at the Perelman School of Medicine, specializes in imaging of oxygen within the body using optical techniques.In 2008, his lab developed a new approach called two-photon phosphorescence lifetime microscopy (2PLM). This method allows him to look at oxygen distributions deep in tissue in three dimensions. The first applications of the method were in the brain.

Recently, working with many colleagues, the Penn team published in Nature the first application of 2PLM to directly quantify the physiological environment of blood stem cells, called haematopoietic stem cells, or HSCs. They asked: How can the marrow, which is highly permeated with blood capillaries, harbor blood stem cells in a low-oxygen microenvironment? Low oxygen levels in the HSC 'niche' keep stem cells in a quiescent state, protecting them against oxidative stress and maintaining their integrity until they are needed to make new cells, researchers surmise.

Why is knowing oxygen concentration of a stem cell niche important for a clinician? Simply put, as Vinogradov explains, “One needs to understand what is important to stem cells for successful bone marrow transplantation to cure leukemia. Oxygenation also affects the efficacy of cancer chemo and radiation treatment. Overall, quantitative measurements in vivo are the key to understanding the basic biochemistry and physiology of the cell - the foundation for all medical science."

Working with microscopist Charles Lin from the Wellman Center for Photomedicine at Massachusetts General Hospital and stem cell biologist David Scadden from the Harvard Stem Cell Institute, the investigators measured local oxygen concentration in the bone marrow of live mice. They proved that the absolute oxygen concentration around blood stem cells was indeed low, despite a very large density of the blood vessels.

The marrow is extremely densely populated by various cell types (not just HSCs), so that the oxygen concentration drops steeply just microns away from feeding capillaries. As a result, they also saw differences in local oxygenation, with the lowest deeper in the peri-sinusoidal regions, spaces between liver cells and capillaries. The endosteal region, connective tissue that lines bones, by contrast, is less hypoxic, because it is perfused with more oxygen-carrying arteries.

Support to date for the existence of an hypoxic niche in marrow blood stem cells came from indirect evidence such as expression of the hypoxia protein Hif-1 and related genes and staining with surrogate markers of hypoxia. Now, using the Vinogradov lab’s method, the team made the first direct measurement of fine oxygen concentration gradients in live bone marrow. “These findings generally support earlier hypotheses about the stem cell niche environment,” says Vinogradov. “But, this is the first unambiguous measurement of its kind performed directly in vivo. The 2PLM technique opens up possibilities to study how the environment changes upon application of therapies and drugs.”

The team's next step will be to image oxygen along with other metabolites and simultaneously visualize the haematopoietic stem cells themselves as they inhabit the niche.

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