Damaged hearts may be healed by their own stem cells

Thanks to stem cells, each of us develops from a single-celled embryo into a fetus with hundreds of different cell types. Stem cells multiply and specialize until they become heart muscle, bone, nerves, etc. Tissues like skin keep pools of stem cells on hand into adulthood, activating them as needed to replace worn out cells in a constant turnover.

But not the heart. Cardiologists believed for a long time that you get one set of heart cells for life. If you lost a bunch in the wake of heart attack, you had to live with whatever was left. In recent years, however, researches have revised that view. There is cell turnover in the heart, albeit as a much slower pace than that seen in other tissues.

The existence of such replenishing mechanisms suggested that it may be possible to coax them into action to regenerate heart muscle damaged by disease. Results of early human trials have been positive, although there is still work to do before such treatments become part of clinical practice.

It may be no surprise then stem cell-based therapies were a focus of the recently held UAB Comprehensive Cardiovascular Center’s Annual Symposium. We sat down with Sumant Prabhu, M.D., director of the center and symposium organizer to talk about the promise of regenerative medicine.



1:32 Dr. Prabhu said he organized the symposium with this theme at this time because his team wanted to focus on the next wave of science and therapeutics in cardiology. He believes that stem cell-based, genetic and tissue regeneration therapies will dominate the field in the coming years, just as drugs and devices did in during eras past. The symposium was designed to foster new collaborations in these areas among leading researchers.

3:19 Several symposium presentations were dedicated to stem cells that are present in the heart, and on attempts to manipulate them such that the become needed replacement cells in damaged hearts. Over the last ten years, clinical trials have examined the value of stem cells taken from the bone marrow or blood to repair damaged hearts, but a more recent thrust is the use of stem cells in the heart itself.

4:37 Joshua Hare, M.D., from the University of Miami, described in his presentation the use of mesenchymal stem cells, which can become bone, cartilage or fat cells, and how they showed "incredible promise" in clinical trials.  The studies looked at whether they could repair heart tissue after heart attack, and heart failure, the loss of pumping efficiency, seen in the wake of heart attacks. While these studies are promising, the field still has a long way to go before stem cell treatments become part of standard medical practice.

5:35 Harvard's Piero Anversa, M.D., delivered the keynote lecture for the symposium on the topic of stem cells in the heart, their discovery, their use in animal studies to repair hearts damaged by heart attack. In particular he described strong, early results in the Phase I human Scipio trial. In this trial, researchers removed stem cells from the hearts of patients as they underwent coronary bypass surgery. The research team then reinfused each patient's stem cells into their hearts after the surgery, where they proved to be safe, to improve pumping function and to lessen the amount of dead tissue in the heart.

6:39 Stem cell therapies target tissue that forms scar when damaged by a heart attack. Scar tissue is made of structural cells instead of functional muscle cells, and scars interfere with the hearts ability to pump blood (heart failure). Dr. Prabhu said there are often pockets of live tissue within the scarred area.  The hope is that added stem cells will receive signals from the surviving areas that turn them into the kind of cells that either improve the remaining tissue or build new tissue.

9:04 It was actually the dawn the nuclear era that made possible the discovery of the slow stem-cell led turnover of heart muscle. Heart cells exposed to low level of radiation from power plants, for instance, could the be carbon dated to show cell turnover. There is not much turnover, but over a lifetime it makes hearts more durable. After a heart attack, the process of stem-cell based tissue replacement seems to kick up a notch, said Dr. Prabhu, but obviously not enough to counter the massive damage caused by a heart attack. What if researchers could temporarily pump up this natural response? Would more the presence of more stem cells mean more rebuilding of tissues in of damaged areas?

10:28 Whether injected stem cells themselves bring about cardiac repair or whether they trigger some chain reaction that brings about repair is a matter of debate. How much heart muscle for instance that grows back in damaged hearts after stem cells are infused has varied considerably from study to study. What has been shown in animal studies is that stem-cell driven regeneration can be manipulated to improve cardiac function. Human studies are seeking to confirm that now.

Nobel Prizes recall promise of and obstacles to stem cell medicine

Sir John Gurdon of the University of Cambridge and Shinya Yamanaka of Kyoto University were recently awarded Nobel Prizes for their work with induced pluripotent stem cells.

We used the occasion to ask Tim Townes, Ph.D., chair of UAB’s Department of Biochemistry and Molecular Genetics, for his comment on the state of the iPSC field, its wondrous potential and the remaining obstacles to human treatment.

Gurdon discovered in 1962 that an entire living tadpole could be created from an already mature frog intestine cell using a technique called nuclear transfer. But his technique required the use of an embryo, and led to the controversy over the potential use of human embryonic stem cells. Yamanaka’s work ended the controversy by showing you could turn skin cells into stem cells just using proteins called transcription factors (no embryos needed).

“Proving that a fully differentiated bodily cell could be turned back into a stem cell, and determining all the steps necessary to do so, were absolutely phenomenal accomplishments worthy of a Nobel Prize,” says Townes.

Just after Yamanaka did his Nobel-winning work in 2006, Townes’ team, in collaboration with scientists at the Massachusetts Institute of Technology (MIT), "cured” sickle-cell disease in mice using genetically altered induced pluripotent stem cells. This was the very first demonstration that researchers could not only take a differentiated cell back to a stem cell, but could also fix a genetic problem in iPS cells and transplant them to cure a disease.

In a perfect world, says Townes, you could take a few skin cells from a patient and coax them back along the differentiation pathway to become stem cells, which are capable of becoming many kinds of cells. Then you would program the stem cells to become, say, red blood cells to treat sickle cell anemia, or white blood cells to replace those causing leukemia. You might be able to make stem cells that attack tumors, or even keep them on ice for years to fight a disease you don’t have yet.

The problem is that the field must prove such cells are safe and potentially effective in humans before they are ever given to humans, even in clinical trials. Stem cells in our body rarely move backward from being fully mature differentiated cells to immature stem cells. Some kinds of tumor cells are among the exceptions, so it pays to tread carefully.

The traditional solution is to create a model of the disease in mice — for instance, ones genetically engineered to have a human gene responsible for a disease. But mice and humans have evolved to have considerable differences, and many treatments that work in one do not work in the other. Researchers are currently debating whether or not studies in a larger animal like a pig are needed to better ensure safety. Furthermore, how long do you wait after giving stem cells to an animal before you declare the treatment to be safe? It may be a few years, says Townes.

In the meantime, he and others are studying whether they can make the treatments safer by using more mature stem cells. After a certain point in the process of maturing, stem cells can no longer move backwards along the pathway to become immature (potentially cancerous) again. Treatments based on mature stem cells would not provide a permanent cure for a disease like sickle cell. Patients might need a monthly infusion, but it could potentially still bring considerable relief.

For those interested in learning more about induced pluripotent stem cells, Townes recommends the National Institutes of Health's stem cell website and its research site. Also see Yamanaka’s recent GEN article, which warns against putting stem cell treatments into human patients too soon, or without proper proof in place. Then there is the iPSC content offered by Genetic Engineering & Biotechnology News.