Tissue from the hearts of mice morphed into muscle cells with the ability to beat and form electrical connections, in an experiment that may lead to new therapy for more than 5 million Americans with heart failure.
Connective-tissue cells called fibroblasts make up about half the cells in the heart. Researchers led by Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease in San Francisco, said they used a trial-and-error process to identify three genes able to turn fibroblasts into heart muscle.
The technique may enter clinical trials in as little as five years to test whether damaged areas of patients’ hearts can regenerate, Srivastava said. Heart failure has no cure and will cost the U.S. health-care system $39 billion this year, according to the American Heart Association, based in Dallas.
“It points to a whole new way of potentially doing therapy,” said Chad Cowan, an assistant professor in the department of stem cell and regenerative biology at Harvard University in Cambridge, Massachusetts. “This gives you the idea that you can take those fibroblasts, re-educate them to become heart muscle and thereby repair someone’s heart.”
The research, published today in the journal Cell, follows work by Shinya Yamanaka, of Kyoto University in Japan, who in 2007 identified genes that transformed skin cells into the equivalent of embryonic stem cells.
After a heart attack, the blood supply to the organ is cut off, leaving sections without the oxygen they need. Cells in the oxygen-starved areas die, form scar tissue and no longer contract properly, impairing the heart’s pumping. Patients with this kind of damage, known as heart failure, can become exhausted by walking or climbing stairs.
Damaged parts of the heart can’t regenerate because they have no ability to make new muscle cells, Srivastava said in a telephone interview on Aug. 3. Researchers have hoped that stem cells might regrow heart muscle.
Efforts to transplant adult stem cells into patients’ hearts have led to modest improvements at best because the stem cells failed to form new heart muscle, Srivastava said. His technique may provide an alternative to stem-cell transplants by tapping into and converting a supply of cells already in the heart.
“The ability to take cells that are already in the organ and harness them to generate new muscle has the potential for regeneration from within,” he said. “People living with heart failure would have a chance to lead better lives. People who can’t walk up a flight of stairs might be able to do that with ease.”
Srivastava’s research is the most advanced example so far of a new approach to altering the function and destiny of cells, a process known as directed differentiation. Instead of getting cells to revert back to an immature stem-cell state, then converting them to a particular cell type, scientists try to turn one kind of mature cell directly into another.
Transplanting heart cells made from embryonic stem cells carries the risk that immature cells able to form tumors also may be transferred, said Kenneth Chien, director of the Cardiovascular Research Center at Massachusetts General Hospital in Boston. An advantage of Srivastava’s technique is that it eliminates the risk from the immature cells, Chien said.
While Srivastava’s work is an “important scientific advance,” there are questions, Chien said.
“Will this work in human cells?” he said. “Will this work ‘in vivo,’” inside an animal or person?
Srivastava’s team began by identifying 14 genes that are especially active in heart muscle cells, and used a virus to insert them into fibroblasts. If the corresponding genes in the fibroblasts were turned on, the cells would glow green. Then they removed each gene one at a time until they found three that could convert the fibroblasts on their own.
In a second experiment, one day after inserting the three genes into fibroblasts, they injected the fibroblasts into the hearts of mice. Within two weeks, the fibroblasts turned into heart muscle cells that formed connections with other heart cells and transmitted electrical signals.
Yamanaka’s technique worked with mouse and human cells and Srivastava said is method may do so as well. A next step for both techniques will be to find chemicals that can perform the same function as the genes he used to transform the cells, cutting the risk of cancer that genes and viruses carry.
Since researchers have made progress finding chemicals to replace the genes used by Yamanaka, Srivastava said he is confident they can be found for his method too.
If chemicals that perform this function can be found, they may be used in stents, tiny wire-mesh devices that are inserted into arteries to prop them open. The stents would release the chemical into the heart, prompting the cells to transform, Srivastava said.