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Diabetes Research Institute Demonstrates the Importance of Oxygen in Beta Cell Differentiation

Juan Dominguez-Bendala, Ph.D. heads the DRI's stem cell development program
Dr. Juan Dominguez-Bendala and his team have demonstrated the importance of oxygen for differentiating stem cells into fuctional beta cells.

DRI's Chris Fraker and Juan Domiguez-Bendala invented the "oxygen sandwich," an important cell culture device.
Drs. Dominguez-Bendala and Fraker invented the new culture device, called the "oxygen sandwich," which allows them to more closely replicate the cells' natural environment, which is optimal for their development into insulin-producing cells.

Scientists at the Diabetes Research Institute have shown for the first time that human embryonic stem cells can be turned into, or differentiated to, insulin-producing beta cells more efficiently by providing proper levels of oxygen at key points during their development. This significant finding, published online ahead of print in the journal Stem Cells Translational Medicine, opens the door to the design of protocols that significantly speed up this application for clinical (patient) use.

DRI researchers were the first to bring oxygen to the forefront in the diabetes field, showing, 1) that adequate oxygenation was key to maximize viability and function of human cultured islets; and, 2) that mimicking the patterns of oxygenation that beta cells experience during their development was key to induce their differentiation from stem cells. The latter work, originally performed on a mouse model, has now been replicated using human embryonic stem cells.

“We invented a new culture device, called the 'oxygen sandwich,' that is designed to tailor oxygen delivery to cultured cells”, said Dr. Juan Domínguez-Bendala, DRI’s director of stem cell development for translational research and lead author of the study together with Dr. Chris Fraker. “Thanks to the oxygen sandwich, we could cater to the specific oxygen requirements of beta cells as they developed from stem cells, and the results were quite impressive.”

Although islet transplantation is widely acknowledged as a promising therapy for type 1 diabetes, it will not become the treatment of choice for the disease until alternative sources of islets are found. Human embryonic stem cells represent a potentially unlimited supply of insulin-producing beta cells. However, limitations in the ability to grow and educate these cells in a dish along the pancreatic beta cell lineage are to blame for the poor efficiency of the process.

One of these limitations is proper oxygenation. While most investigators use extreme care to make sure that stem cells in culture receive the right amount of nutrients and remain at the adequate temperature and pH, paradoxically very few have looked at something as important as oxygen as a factor to take into account.

The “one size fits all” rule has been in place for decades when it comes to ensure that cells receive the oxygen they need. For instance, standard culture conditions do not distinguish between a neuron and a beta cell, despite the fact that each one has distinct requirements for oxygen.

Using this unique oxygenation method, the DRI team observed improved engraftment and rate of diabetes reversal in experimental models, and a higher yield of beta cells and insulin production in culture, among other findings. This study confirms the importance of oxygen and is another example of the importance of mimicking the native pancreas environment with the DRI BioHub and in designing future strategies to develop and sustain the function of adult cells for transplant.

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