Apr. 1, 2003 DALLAS, April 1 – Vitamin C helped convert mouse embryonic stem cells growing in the laboratory to heart muscle cells, researchers report today's rapid track publication of Circulation: Journal of the American Heart Association.
Rapid track articles are released online early because they have major clinical impact or represent important basic science discoveries. This basic-research discovery could lead to future research on ways to treat people suffering from damaged heart muscle.
"Although the findings of this study are very preliminary with respect to their impact on human lives, this line of research has enormous implications for the future care of thousands of patients who develop heart failure each year," says Robert O. Bonow, M.D., president of the American Heart Association. "Identifying mechanisms to transform stem cells into differentiated heart muscle cells is an important step toward clinical reality."
Richard T. Lee, M.D., senior author of the study, says: "We have been taught for decades that when your heart cells are dead, they are dead and there is nothing we can do about it. We are excited about anything suggesting that we can grow more heart cells."
Lee and his colleagues tested 880 bioactive substances – including drugs and vitamins – approved by the U.S. Food and Drug Administration (FDA) to see if they stimulated the mouse stem cells to become heart muscle cells. The cells were genetically altered to give off a fluorescent bright green color when viewed under a microscrope if they had become heart muscle cells.
"We only got 1 out of the 880 to light up, and that was from ascorbic acid, the chemical commonly known as vitamin C," says Lee, an associate professor of medicine at Harvard Medical School and Brigham and Women's Hospital in Boston, and a lecturer in biological engineering at the Massachusetts Institute of Technology in Cambridge, Mass.
He stresses, however, that the finding is preliminary and it should not encourage people to take vitamin C hoping to strengthen or protect their hearts. "There is no clinical evidence that it would help," he says. The ability to grow or implant new heart muscle could save or improve the quality of life of countless people suffering from heart failure – the inability of a weakened heart to pump enough blood to supply the body. About 550,000 new cases and more than 51,500 heart-failure deaths occur each year in the United States as the result of a damaging heart attack, genetic disease, or other causes.
Embryonic stem cells are derived from the very early stages of fetal development and can become any type of cell in the body through a process called differentiation. Efforts to stimulate the differentiation of stem cells to specific types of cells have drawn growing research attention in recent years.
Working with a well-established line of mouse embryonic cells grown by first author Tomosaburo Takahashi, M.D., Ph.D., they placed about 2,000 stem cells each in tiny "wells" and treated each well with a different one of the FDA-approved compounds.
The stem cells had a gene inserted that would fluoresce bright green if the cell converted into the heart-muscle cell.
Beyond finding the green glow of the vitamin C-treated cells, the researchers detected several other important pieces of evidence that the stem cells had converted to heart muscle.
For example, they found that both cardiac myosin and actin (proteins involved in relaxing and contracting muscle) were present in the cells. They also detected three other heart-muscle genes that activated in proper sequence. The differentiated cells also beat spontaneously and rhythmically.
Vitamin C's beneficial activity has been attributed to its ability to neutralize oxidants, which are damaging substances produced naturally by the body. However, other antioxidant compounds tested, including vitamin E, did not trigger the development of heart cells.
"This suggests that the effect of vitamin C on cardiac differentiation is independent of its antioxidant effect," Lee says.
He and his colleagues repeated their experiment many times, always with the same results. "The real significance of the study is that it indicates that we will be able to find other ways to generate heart cells from stem cells more efficiently," Lee says. "It also raises interesting questions about the role of vitamin C in the development of the embryo's heart."
The team is investigating other so-called "chemical libraries" that contain far larger numbers of compounds than the group initially tested.
"A really big issue is going to be whether we can encourage the heart to fix itself, or whether we will need to implant cells of some sort," Lee says. "That is an important and unresolved question for this century, given the prevalence of heart failure."
Co-authors are P. Christian Schulze, M.D.; Bernadette Lord, B.S.; Ryan M. Fryer, Ph.D.; Satinder S. Sarang, Ph.D.; and Steven R. Gullans, Ph.D.
This research was partly funded by the National Heart, Lung, and Blood Institute.
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