Scientists find master heart cell
Harvard discovery gives new tools for drug development
Harvard University scientists said yesterday they discovered a master human heart cell that gives rise to three major types of heart tissue, providing new tools for drug development and an important advance toward the ultimate goal of repairing damaged hearts.
Using human embryonic stem cells, the researchers have unraveled part of the process by which the human heart is built during development - insight they hope could be used to understand congenital heart disease and create new therapies for cardiovascular disease, the top cause of death in the United States.
“Since these [cells] are entirely human, you can use this system now to study the role of specific genes in human heart disease, and as ways to screen drugs for cardiotoxicity and for therapeutic effect,’’ said Dr. Kenneth R. Chien, director of the Cardiovascular Research Center at Massachusetts General Hospital and principal faculty member at the Harvard Stem Cell Institute. He is senior author of the paper, published in Nature yesterday.
The work points to new applications for regenerative medicine. For years, attempts to repair damaged heart tissue using different types of cells have come back with “ambiguous, disappointing, marginal, and, in certain cases, negative’’ results, Chien said. For example, Genzyme Corp. of Cambridge stopped enrolling patients in a clinical trial for a heart cell therapy three years ago because it was deemed to have little chance of success.
Because the new work reveals progenitor cells that naturally create specific types of heart tissue during development, Chien thinks they might have a better chance of repairing damaged hearts.
But the greatest near-term promise of the work might be in routine drug development. It could now be possible, for example, to create large numbers of heart muscle cells to test drugs.
“Add one drug, two drugs, or all combinations of drugs a heart patient would take’’ to test how effective or toxic compounds are in actual human heart cells, said Christine Mummery, a professor of developmental biology at Leiden University Medical Center who was not involved with the work. “It’s really a kind of tool to bring us a step further.’’
Drug companies are especially interested in such applications. Using the actual human cells affected by a disease, instead of mice, dogs, or other stand-ins, could potentially speed up drug development by giving com panies a more accurate template for screening potential drugs. Animal cells and other types of assays have been invaluable for testing and screening drugs, but the new cells could give scientists a chance to see how the human cells they are interested in react to drugs.
Such cells could also prevent companies from spending too much time on a drug that ultimately fails. One big concern at pharmaceutical companies is that drugs might have a side effect on the heart that only emerges late in the drug development process, said John D. McNeish, executive director of Pfizer Regenerative Medicine. Testing the drug on human heart cells might alert scientists to side effects before they begin administering the drug to patients in clinical trials.
“I think this is in many ways a groundbreaking work,’’ McNeish said, because of both its short- and long-term implications. “It is fair to say in the future, stem cell technology could develop highly predictive cell-based assays for cardiotoxicity that could one day replace’’ the current models, such as using cells from cadavers or animals.
GlaxoSmithKline, the pharmaceutical company that made a $25 million investment in the Harvard Stem Cell Institute last year, is interested in using stem cells as drug discovery tools.
“Stem cells would allow pharmaceutical researchers to see the effects of new compounds on human cells, and so ultimately replace current testing on non-human cells, and help improve the accuracy of screening to improve therapeutic efficacy and reduce risks to patients,’’ Aaron Chuang, scientific manager for stem cell research at GSK, wrote in an e-mail.
Chien and his colleagues began their work by searching in fetal human hearts for master cells, grandfather cells that give rise to three major types of tissue.
His team confirmed the presence of master cells in fetal hearts, but found that they decrease in number as the heart develops. They turned to human embryonic stem cells to better understand the cells and their potential applications.
Using stem cells, which are capable of turning into any cell in the human body, they created the master stem cells. Then, they tagged those cells, and confirmed that the master cells gave rise to three types of cells. They also identified a family of “intermediate’’ cells, each of which is a mother to a single kind of tissue - giving rise to heart muscle tissue, smooth muscle tissue that contracts to regulate blood flow, or endothelial cells that line blood vessel walls.
Chien is already pushing the work forward. Plans include turning back the clock of adult cells to create embryonic-like stem cells that could create cardiac master cells. A major question is whether such cells would be equivalent to the ones made from embryonic stem cells. If it works, that could offer the possibility of creating patient-specific cells to model different diseases. Chien is also interested in understanding the role progenitor cells play in congenital heart disease.
But ultimately, he wants to use the basic understanding of the cell to treat heart disease.
“My interest,’’ Chien said, “is taking the disease out.’’
Carolyn Y. Johnson can be reached at firstname.lastname@example.org.