Not much is known about stem cell metabolism, but a new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia.
“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why. Our research provides part of the explanation, at least for the blood-forming system,” said Dr. Sean Morrison, the Director of CRI.
The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published inNature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells.
The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures — taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) — a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate.
Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans. At these levels, researchers expected depletion of ascorbate might lead to loss of stem cell function but were surprised to find the opposite was true — stem cells actually gained function. However, this gain came at the cost of increased instances of leukemia.
“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said Dr. Michalis Agathocleous, lead author of the study, an Assistant Instructor at CRI, and a Royal Commission for the Exhibition of 1851 Research Fellow. “The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off. So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”
This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, the study showed. Mutations that inactivate Tet2 are an early step in the formation of leukemia. CRI scientists showed that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of leukemia.
These findings have implications for older patients with a common precancerous condition known as clonal hematopoiesis. This condition puts patients at a higher risk of developing leukemia and other diseases, but it is not well understood why certain patients with the condition develop leukemia and others do not. The findings in this study might offer an explanation.
“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of Tet2. Our results suggest patients with clonal hematopoiesis and a Tet2 mutation should be particularly careful to get 100 percent of their daily vitamin C requirement,” Dr. Morrison said. “Because these patients only have one good copy of Tet2 left, they need to maximize the residual Tet2 tumor-suppressor activity to protect themselves from cancer.”
Researchers in the Hamon Laboratory for Stem Cell and Cancer Biology, in which Dr. Morrison is also appointed, intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.
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What a difference 15 years make. They’re barely a crease on the face of time, but within their span we’ve seen movies go from DVD to the Cloud, telephones from utilities to virtual appendages, and coenzyme Q10 (CoQ10) from “niche” nutrient to veritable household name.
And Scott Steinford, executive director of the CoQ10 Association (Salt Lake City), has been around to witness it all. By the Association’s reckoning, CoQ10 is currently the fourth most consumed specialty supplement in North America, and the expectations, he says, are “for continued growth as education and awareness of its benefits are demonstrated.”
Indeed, CoQ10’s compound annual growth rate (CAGR) has held above 20% for more than the past decade and a half. And where the number of brands identified with the compound stood at 18 in 2001, the tally reached a full 123 by 2016. As for the size of the North American market, “skyrocketed” may be too dramatic a term, but there’s no denying that its ascent from an estimated 3.7 million consumers in 2001 to 16.5 million in 2016 is impressive.
As it happens, one factor that’s driven those consumers to CoQ10 is another inescapable force of change these past 15 years: the Internet. As Steinford says, “The Internet is affording consumers a lot of opportunity for education.” Recalling his own “discovery” of CoQ10 back in the era of hard-copy journals, he notes that the opportunities for diving into research then were limited to all but those with access to major libraries. But now, he says, the Internet unlocks “in a matter of moments literally thousands of studies that support CoQ10. And that’s driving demand because consumers are generating their own interest and knowledge.”
Knowledge Is Power
What knowledge are they generating? For starters, they’re becoming reacquainted with the electron transport chain they first encountered in high school biology, and with CoQ10’s role as a crucial electron carrier in it. In that capacity, CoQ10 helps cells generate ATP (adenosine triphosphate), which, as the body’s fundamental energy-transfer currency, is the stuff of life itself.
No wonder, then, that this ubiquitous compound—not coincidentally known as ubiquinone—resides in nearly every cell of the body, primarily in the mitochondria where electron transport occurs. But CoQ10 does more than carry electrons. As a natural antioxidant, it shields lipids and proteins from oxidation, and as one of the most investigated ingredients in the health space—with 3,000-plus studies referenced on PubMed, Steinford says—CoQ10 is emerging as a compound with the potential to improve everything from heart health and cognitive function to oral health, sports performance, and more.
Research has shown that long-term high doses may slow symptom progressions in early-stage Parkinson’s patients. In patients with heart failure, CoQ10 decreases hospitalizations, reduces labored breathing and edema, and increases overall quality of life, per other studies. Steinford even notes that the Q-SYMBIO Trial found that long-term CoQ10 treatment in patients with chronic heart failure safely attenuated symptoms and reduced major adverse cardiovascular events. “As more clinical studies are completed,” he says, “the ingredient will continue to be one of the most important options in the supplement market.”
The Cardiologist Connection
One sure sign of that importance is the buy-in CoQ10 gets from heart doctors. As Steinford notes, “Cardiologists are getting onboard with CoQ10 at a fairly significant rate. With more studies supporting its strength, these thought leaders are recommending it.”
A 2015 online study fielded by Research Now and commissioned by the CoQ10 Association found that 45% of cardiologists, without prompting, say they recommend CoQ10 to their patients, and that almost one in four—especially younger doctors—are eager to learn more about its efficacy and therapeutic use, Steinford says.
To no small extent, CoQ10’s future lies in these professionals’ hands—and in those of the scientific community tasked with researching it. Yet knowledge about its benefits “is still at its infancy,” Steinford maintains.
Perhaps not for long. “I recognized when I first encountered CoQ10,” he says, “that the more educated you become about it, the more it impresses you.”
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