ScienceDaily (June 11, 2012) When most groups of mammalian cells are faced with a shortage of nutrients or oxygen, the phrase "every man for himself" is more apt than "all for one, one for all." Unlike colonies of bacteria, which often cooperate to thrive as a group, mammalian cells have never been observed to help one another out. But a new study led by a researcher at the Stanford University School of Medicine has shown that certain human embryonic stem cells, in times of stress, produce molecules that not only benefit themselves, but also help nearby cells survive.

"Altruism has been reported among bacterial populations and among humans and other animals, like monkeys and elephants," said Stanford postdoctoral scholar Bikul Das, MBBS, PhD. "But in mammalian cells -- at the cellular level -- the idea of altruism has never been described before." Das is the lead author of a paper, published online June 11 in Stem Cells, documenting altruistic behavior by human embryonic stem cells, or hESCs.

While altruism is generally thought of as a virtue, it can have a downside for hESCs: The altruistic cells appear to be more prone to accumulating mutations, a sign that they could lead to cancers. A better understanding of hESC altruism could provide new insights into cancer therapies, as well as improving scientists' ability to develop safe and effective stem cell treatments for other diseases.

The finding arose from Das' research into how hESCs react to low-oxygen environments, important because many cancerous tumors are low in oxygen. Embryonic stem cells have the capability to develop into many different cell types through a process called differentiation. Das found that when hESCs were placed for 24 hours in an environment with only one-tenth of a percent of oxygen (the air we breathe, by comparison, is almost 21 percent oxygen), free-radical molecules were generated that began causing internal damage in some cells. Ninety percent of the hESCs differentiated into other cell types or died, with only 10 percent maintaining their so-called "stemness," meaning they retained their ability to develop into any type of cell.

Das wanted to know what set these more hearty cells apart and so began sorting them based on what molecules they contained.

Das and his colleagues discovered that of the embryonic stem cells that had survived the oxygen deprivation, half had high levels of HIF2-alpha (a protein that turns up the production of antioxidant molecules) and low levels of p53 (a protein that normally encourages cells to die when they have too much DNA damage). These levels of HIF2-alpha and p53 are enough, Das showed, to keep the cells from differentiating by turning off cellular pathways typically involved in the process.

But the other half of the stem cells that had kept their "stemness" had relatively normal levels of HIF2-alpha and p53, he and his colleagues report in their paper. There was no clear explanation as to how they would remain undifferentiated without the help of high HIF2-alpha and low p53 -- unless the other cells were helping them out.

"When I saw this data, I began to suspect that maybe there was altruism going on," said Das.

To test the theory, Das and his colleagues at the University of Toronto, where he began the work as a graduate student, let the cells with high levels of HIF2-alpha and low levels of p53 soak in a cell culture medium for 24 hours. Then, he removed the cells and added the other half -- those that didn't have high HIF2-alpha and low p53. Sure enough, when the mixture was deprived of oxygen, the cells retained their stemness. Molecules in the liquid had some property that kept them from differentiating. The team discovered that the important molecule in the liquid is an antioxidant called glutathione.

Scientists had previously shown that when embryonic stem cells are under stress, levels of HIF2-alpha and p53 increase and most cells differentiate or die. What makes this study unusual is that Das and colleagues were able to isolate the altruistic cells that exhibit low levels of p53, which helps them to escape death or differentiation.

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Unusual 'altruistic' stem cell behavior with possible link to cancer identified