ISSCR 2017: Researchers say vitamin C keeps epigenome as well as stem cells happy – BioWorld Online
By Anette Breindl
Senior Science Editor
BOSTON – At the Thursday morning plenary of the annual meeting of the International Society for Stem Cell Research (ISSCR), those who came into the plenary room carrying their morning cup of orange juice turned out to be taking care of their own stem cells.
“Our data may begin to explain why people with low ascorbate levels get more cancer,” Sean Morrison told the plenary audience. “You need to get your daily requirement of ascorbate to maintain your epigenome.”
At the plenary session, whose topic was Stem Cells and Cancer, Morrison, professor and director of the Children’s Medical Research Institute at UT Southwestern, spoke on “the metabolic regulation of stem cell function and leukemogenesis.”
While the metabolic changes in cancer cells are a major area of research, much less is known about the metabolism of stem cells in particular.
There is excellent evidence that metabolite levels influence the activity of stem cells in cell culture. But finding out whether the same is true in the messier environs of the whole organism is a challenging endeavor.
“A remarkable amount of metabolomic knowledge comes from mashing up entire tissues, or studying large numbers of cells in culture,” Morrison said. “When people do metabolomics, they typically use around a million cells. And if you are carefully studying somatic stem cells, you can’t get a million cells.”
By maximizing the sensitivity of mass spectrometry, Morrison and his team are now at the point where they can accurately measure around 60 metabolites in populations of 10,000 cells. That still falls short of the 200 to 250 compounds that can be measured with a larger pool of cells, but is enough to “study any rare population, including stem cells,” he said.
When Morrison and his colleagues looked at the metabolism of blood-forming stem cells, they found that different types of pluripotent stem cells had different metabolic signatures, but that overall, one of the metabolites whose level was most different in stem cells compared to differentiated cells was ascorbate, colloquially known as vitamin C.
That, in turn, left them with the next experimental challenge. Because while humans and primates are dependent on dietary vitamin C, pretty much all other mammals – including lab mice – make their own.
Morrison’s team got around that challenge by studying mice with deleted gulonolactone oxidase – the final enzyme in the vitamin C synthesis pathway, and the same one that was somehow lost during primate evolution.
Such mice, like humans, are dependent on dietary vitamin C.
When Morrison and his team decreased the dietary levels of vitamin C to a level that did not lead to outright scurvy in the animals, but did leave them with abnormally low levels of vitamin C, the animals had more blood-forming stem cells than those who got their daily dose of fruit.
Increased numbers of stem cells “is what you get when you delete a tumor suppressor in the hematopoietic system,” Morrison said. Such cells, because they can’t differentiate, keep proliferating.
In another round of experiments, Morrison and his team demonstrated that low levels of vitamin C had similar cellular effects as mutations that reduced the activity of TET2, an epigenetic enzyme that plays an important role in the regulation of hematopoiesis, and is frequently mutated in many types of blood cancers.
The data may explain why TET2 is frequently mutated in the elderly, and is a tumor suppressor, but its mutation does not inevitably lead to cancer. If one copy of TET2 is mutated, the other copy may be sufficiently active to keep cells in line – if there is enough vitamin C around to keep it in good working order.