Human heart muscle cells that are derived from embryonic stem cells and implanted into a rat after a heart attack helped rebuild heart muscle and improve function, according to a new study.
The researchers also developed a new process that greatly improves how stem cells are turned into heart muscle cells and then survive after being implanted in the damaged rat heart.
The findings suggest that stem-cell-based treatments might one day help people suffering from heart disease, the leading cause of death in most of the world, the scientists said.
The study, published in the September issue of Nature Biotechnology, was conducted by researchers at the University of Washington School of Medicine in Seattle and at Geron Corp. in Menlo Park, Calif.
“This is one of the most important publications on hESCs for Geron to date,” said CEO Thomas Okarma. “Our cardiomyocytes are the first human cardiac cells shown to survive after injection into an infarcted ventricle and to produce significant improvement in heart function. hESCs are the only cell type shown definitively to form cardiomyocytes.”
According to the company, about 5.2 million people in the United States suffer from heart failure.
Approximately 865,000 people experience myocardial infarction (heart attack) each year.
Thirty-six percent of these progress to heart failure within five years of a first infarction.
More than one-third of all heart failure patients die within two years of diagnosis.
“We’re developing our cardiomyocyte product, GRNCM1, to address the large unmet need in heart failure,” Okarma said. “We expect GRNCM1 to be our second hESC-derived cell type to enter clinical development.”
Two of the main challenges to treating damaged hearts with stem cells were targeted in the study: creation of cardiac cells from embryonic stem cells, and the survival of those cells when implanted in a damaged heart.
“Past attempts at treating infarcted hearts with stem cells have shown promise, but they have really been hampered by these challenges,” said Dr. Chuck Murry, director of the Center for Cardiovascular Biology in the UW Institute for Stem Cell and Regenerative Medicine, and corresponding author on the study. “This method we developed goes a long way towards solving both of those problems. We got stem cells to differentiate into mostly cardiac muscle cells, and then got those cardiac cells to survive and thrive in the damaged rat heart.”
Embryonic stem cells can differentiate, or turn into, any type of cell found in the body.
But researchers had struggled to get stem cells to differentiate into just cardiomyocytes, or heart muscle cells.
Previous efforts resulted in cell preparations in which only a fraction of one percent of the differentiated cells were cardiac muscle cells.
By treating the stem cells with two growth factors, or growth-encouraging proteins, and then purifying the cells, they were able to transform 90 percent of stem cells into cardiomyocytes.
The researchers dealt with the other big challenge of stem cell death by implanting the cells along with a brew of compounds aimed at helping them grow.
The cocktail included a growth “matrix” and drugs that block processes related to cell death.
A matrix is a tissue scaffolding that cells adhere to as they grow.
When using the pro-growth mixture, the success rate of heart muscle grafts improved significantly: 100 percent of rat hearts showed successful tissue grafts, compared to only 18 percent in grafts without the mixture.
“The problem of cell death is pretty common in stem-cell treatments,” Murry said. “When we try to regenerate with liquid tissues, like blood or bone marrow, we’re pretty good at it, but we haven’t been very successful with solid tissues like skeletal muscle, brain tissue, or heart muscle. This is one of the most successful attempts so far using cells to repair solid tissues. E every one of the treated hearts had a well-developed tissue graft.”
When the researchers followed up on the stem-cell treatment by taking images of the rat hearts, they found that the grafts helped thicken the walls that normally stretch out after a heart attack and cause the heart to weaken.
The thickened walls were also associated with more vigorous contraction.
“We found that the grafts didn’t just survive in the rat hearts, they also helped improve the function of the damaged heart,” said Dr. Michael Laflamme, UW assistant professor of pathology and the lead author of the study. “That’s very important, because one of the major problems for people suffering a myocardial infarction is that the heart is damaged and doesn’t pump blood nearly as well. This sort of treatment could help the heart rebound from an infarction and retain more of its function afterwards.”
The next step in studying stem-cell treatments for the heart is to conduct similar experiments in large animals, like pigs or sheep, while further refining the treatment in rats.
Early human clinical trials could begin in about two years, Murry said.
According to Geron, the study is the first to document the potential clinical utility of regenerating damaged heart muscle by injecting hESC-derived cardiomyocytes directly into the infarct zone of the heart.
The survival cocktail administered with the cells enables their long-term survival in the infarcted muscle.
The injected cells stimulate endogenous blood vessel formation, possibly contributing to both cell survival and improved contractile function.
The scalable production system allows for production runs at sufficient scale for large animal studies (ongoing) as well as for ultimate testing in humans.
Geron is developing human embryonic stem cell-based therapeutics, with its spinal cord injury treatment anticipated to be the first product to enter clinical development.
Contact: http://www.geron.com
Contact: Michael Laflamme, laflamme@u.washington.edu
Contact: Chuck Murry, murry@u.washington.edu
