Cell therapies are thought to have great promise as a way to help repair damaged tissue that will not normally regenerate to any great degree. When it comes to the heart, and following nearly two decades of stem cell and other therapies tested in trials and via medical tourism, the research community is still in search of a reliable, highly effective methodology. Work in the laboratory continues, and researchers have recently reported improvement in heart function following heart attack in Southern pig-tailed macaques.
The approach used here involves generating a sizable cell population of cardiomyocytes, heart muscle cells, from embryonic stem cells. Those cells are then introduced into the heart directly, where a large enough proportion of them survive to produce long term reconstruction and some gain in function - not yet a path back to normal, but better than the alternative. The survival of the transplanted cells is the key to effective regenerative therapies: approaches using patches of lab-grown heart tissue in which there is sizable survival of cells following transplantation have also shown promise in heart repair. First generation stem cell therapies are less effective and reliable when it comes to tissue regrowth precisely because near all the cells die, and the benefits produced are mediated by signaling effects on native cells.
The heart is an organ in which the fine structure matters. Its muscle cells participate in an electrical communication network, ensuring that all beat in unison. If that network is disrupted by haphazard growth, then failure of function can result. Unfortunately, there are the first signs of that in this study. The challenge for heart regeneration is perhaps less that it is naturally one of the least regenerative organs, and more that regeneration must be achieved carefully. Other organs are less of a problem on this front, particularly those that are essentially chemical factories or cell nurseries, and their structure and even location isn't anywhere near as important as is the case for the heart or the brain.
Injecting human cardiac muscle cells into monkeys that suffered heart attacks helped the animals' damaged hearts pump blood better, researchers report. The treatment is based on the reprogramming of human embryonic stem cells, and the results move the therapy a step closer to clinical trials. "We're talking about the number one cause of death in the world for humans. And at the moment all of our treatments are dancing around the root problem, which is that you don't have enough muscle cells."
When a heart attack goes untreated, blood is blocked from flowing to the heart, which leads to the death of heart muscle cells. There can also be scarring and heart failure - when the heart cannot pump enough blood to the body. In the study, after 9 monkeys were made to have heart attacks, their heart-pumping capacity dropped by more than 30 percent. Injecting 750 million cardiac muscle cells, derived from human embryonic stem cells, into the monkeys' hearts led to the growth of new heart muscle tissue. After four weeks, most monkeys' hearts showed improved pumping capacity, up to a third better than right after the heart attacks, and two monkeys had two-thirds of the lost capacity restored after 12 weeks.
However, some of the monkeys had irregular heartbeats after the cardiac cell transfusion. "That is a very important observation because now you can perhaps begin to design a strategy to get at what is happening. How can we prevent this from happening? That, to me, is the story of this paper."
Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ∼750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions.
One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 vs. 2.5 in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.