Michigan State University scientists have used human stem cells to create what might be the world’s first miniature heart model for the study of congenital heart defects and cardiovascular disease.
The tiny hearts, each about the size of a pinhead, are fully functional, with all the primary cell types, vascular structure, chambers and organization of a real fetal human heart, the scientists say.
The team’s work was published on the pre-print server bioRxiv in June, while still awaiting peer review.
“This is a first step to actually grow larger, more sophisticated hearts,” said Aitor Aguirre, an assistant professor of biomedical engineering who leads the project at MSU’s Institute for Quantitative Health Science and Engineering.
“One of things we’re trying to do right now is connect them to an artificial vasculatory system so that we can pump nutrients through them — this will allow them to grow larger,” Aguirre said.
Aguirre’s team replicated developmental conditions like those found in the early human embryo on a laboratory plate, triggering pluripotent stem cells — cells with the capacity to self-renew by dividing and developing into all three basic body layers — to grow and assemble into a heart just as an embryo would do in the mother’s uterus. The cells used are induced pluripotent stem cells obtained from consenting adults, so there are no ethical concerns about the process, the scientists say.
“We are very excited about the work that Dr. Aguirre is doing,” sid Dr. Joseph C. Wu, immediate past-chair of the American Heart Association Council on Basic Cardiovascular Sciences, of the project, which is partially funded by the heart association.
The director of the Stanford Cardiovascular Institute and a professor of medicine and radiology at Stanford University School of Medicine in California, Wu said the work at MSU builds on a body of research involving induced pluripotent stem cells that has broad implications for the study of heart disease, as well as for future drug testing, and developments in precision and regenerative medicine.
“This technology is really revolutionary,” he said.
Where drugs currently are tested mostly on mice or hamsters before going to human trials, potential treatments could be tested on thousands of mini-hearts that genetically reflect the diversity of the population, Wu believes.
Hearts created from an individual patient’s stem cells could be used to develop a precise medical treatment for that person, he said. And one day, it might be possible to grow genetically identical heart tissue to replace what was lost from an individual during a heart attack.
The MSU team already is working with the Congenital Heart Center at Helen DeVos Children’s Hospital in Grand Rapids to develop a solution to extend the lives of children born with only a single functioning heart ventricle. One of the two ventricles is underdeveloped, so the other has to do all of the work.
Such infants undergo several operations, including what’s called a Fontan Procedure, where the surgeon reroutes the circulation to reduce the workload for the functioning ventricle.
While the procedure is life-saving, the blood flows to the lungs directly without a pumping ventricle. This causes high pressure in the vein, which eventually backs up to the kidneys, liver and other organs.
“Slowly, the circulation starts failing as the children grow older,” said Dr. Joseph Vettukattil, director of pediatric cardiology at DeVos. “The blood flow to the organs stagnates, and organs start failing.”
Vettukattil’s team hopes to create, with the MSU scientists, a small pumping chamber out of the patient’s own stem cells to improve blood flow to the lungs.
“It’s a small chamber that we’re trying to create, just to augment the blood flow to the lung,” he said. “This research at MSU is very important because that will produce the heart cells for us to harvest on to a tissue 3D printed model.
“Almost one in a hundred children are born with a congenital heart defect. So it’s a huge magnitude. If we can either reduce those or help in managing or repairing them, it’s going to make a huge difference in the future.”
At Aguirre’s laboratory, the pulsing of 96 tiny hearts assembled on a small plate is just visible to the naked eye. Their beating is readily apparent when viewed under a microscope, as are what appear to be chambers and other features of a human heart.
The small plate includes 96 wells, each containing a heart. They’re about the size of the heart of a one- to three-month-old embryo, Aguirre said. The 600 created at the lab so far are kept in a kind of incubator warmed to body temperature to replicate womb-like conditions.
“We replicate those conditions in vitro, and when you give the cells the right instructions they know what to do — and they will make a heart,” Aguirre said. “It’s all based on chemical and micro-environment manipulation around the cells, basically telling them the right instructions.”
Until now, most of what’s known about congenital heart defects has been learned from studying the hearts of infants born with defective hearts, or from mouse studies, Aguirre said.
It wouldn’t be practical or ethical to conduct research on the hearts of fetuses developing in the womb, he noted. And information gained from mouse studies doesn’t always translate to human heart development.
That’s a serious problem. According to the federal Centers for Disease Control and Prevention, about 1% of babies in the U.S. are born with congenital heart defects, or about 40,000 babies annually. About 2.4 million people in the U.S. were estimated to be living with such a defect in 2010, including 1 million younger than age 18.
With funding from the National Institutes of Health, National Heart, Lung and Blood Institute and the American Heart Association, the team is already conducting research using the human heart models.
One study is exploring the effects of nutrition, specifically Omega-3 fatty acids, on fetal heart development. About 60% of congenital heart defects are thought to be caused by environmental factors, such as nutrition, Aguirre said.
The team is also looking to find out how maternal diabetes can result in congenital heart defects in infants. And the effects of diabetes on the developing heart were clearly visible during a recent visit to the laboratory at MSU.
Yoni Israeli, a graduate student in biomedical engineering and first author of the report published on the bioRxiv website, held up a plate where half of the hearts were immersed in a medium made to replicate conditions in the womb of a mother with diabetes. The other half floated in a concoction that resembles the environment of a non-diabetic mother.
While the hearts in the non-diabetic environment were clearly pink, the hearts in the diabetic “womb” were a dingy yellow color.
“Because they’re all in individual wells, you can treat them with different treatments, or different conditions,” said Israeli, noting someday production of the hearts could be sped up to produce thousands with automation.
“You can actually see there’s a huge difference between this half and this half,” he said, pointing to the healthy and diabetic hearts.
“These are diabetic, so they eat up the (medium) faster,” he said of the yellowish hearts. “They are bigger, so they beat faster and they use up more glucose — the yellow means that media is getting depleted faster.”
Experimentation is key
It will take years, perhaps decades, to develop a heart large enough to transplant to an infant or adult, but that isn’t the team’s goal, Aguirre said.
Having many small hearts, rather than a few larger ones, provides more opportunity for experimentation that could lead to breakthroughs in the understanding and treatment of congenital heart disease, he said.
“If we can study the causes of heart disease and cardiovascular disease or congenital heart defects at the origin of the disease, we might be able to actually treat them much better,” Aguirre said.
“If I had the opportunity to choose whether I’m going to make a transplant on this child, or I’m going to try to prevent or treat its cardiac disease, I would (choose) the cardiac treatment or the prevention.
“The transplant is a good option when there are no other options, but when you can actually treat congenital disease, if we can find something (using) our system that we can stop it before it develops into full-fledged congenital heart disease — that child might never need a transplant.
“That is our goal, that we don’t need transplants. But I think it is possible to make transplants in the future with this technology, like decades in the future.”