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May 12, 2014
Stem Cell Therapy Rebuilds Heart Muscle in Primates
Scientists used human embryonic stem cells to regenerate damaged primate hearts. The strategy might one day be used to repair human hearts, but challenges still need to be overcome.
Damage to the heart—such as that caused by a heart attack—isn’t easy to mend. The heart’s muscle cells, called cardiomyocytes, don’t readily replenish themselves. After a typical heart attack, an estimated billion cardiomyocytes die. This jeopardizes heart function and can lead to chronic heart failure and possibly death.
Scientists have been searching for innovative ways to replenish damaged heart tissue. Human embryonic stem cells have proven promising in small animal models. These cells have the potential to develop into any cell type in the body. Derivatives of the cells are already being tested in people for retinal diseases and spinal cord injury. However, cardiac repair requires much larger numbers of cells. The approaches developed in small animals also need to be tested in larger, more clinically relevant animals.
A research team led by Dr. Charles Murry at the University of Washington set out to test whether an approach they were developing could be scaled up and used in a large animal model. Their work was funded in part by NIH’s National Heart, Lung, and Blood Institute (NHLBI) and National Institute of General Medical Sciences (NIGMS). Results appeared online on April 30, 2014, in Nature.
The team first created cardiomyocytes from human embryonic stem cells that were genetically engineered to produce a fluorescent calcium indicator. This indicator allowed the researchers to track the calcium waves that mark the electrical activity of a beating heart. Pigtail macaques (Macaca nemestrina) with heart damage were treated to suppress their immune systems. Five days later, the cardiomyocytes were delivered in a surgical procedure to the damaged regions and surrounding border zones.
Over a 3-month period, the grafted cells infiltrated damaged heart muscle, matured, and organized into muscle fibers in all the monkeys who received the treatment. On average, the grafts replaced 40% of damaged tissue. Three-dimensional imaging showed that arteries and veins integrated into the grafts, suggesting the grafts could be long lasting. There was no evidence of graft rejection by the animals’ immune systems.
Calcium activity revealed that the grafts were electrically active and coupled to activity of the host heart. Grafts beat along with host muscle at rates of up to 240 beats per minute, the highest rate tested.
All the macaques that received the grafts showed transient arrhythmias—problems with the rate or rhythm of the heartbeat—that subsided by 4 weeks post-transplantation. The animals remained conscious and in no distress during periods of arrhythmia, but this problem will need to be addressed before the approach could be tested in humans.
“Before this study, it was not known if it is possible to produce sufficient numbers of these cells and successfully use them to remuscularize damaged hearts in a large animal whose heart size and physiology is similar to that of the human heart,” Murry says.
While several obstacles still need to be addressed, these experiments support the idea that human cardiomyocyte transplantation therapy may be feasible.
—by Harrison Wein, Ph.D.
Reference: Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Chong JJ, Yang X, Don CW, Minami E, Liu YW, Weyers JJ, Mahoney WM, Van Biber B, Palpant NJ, Gantz JA, Fugate JA, Muskheli V, Gough GM, Vogel KW, Astley CA, Hotchkiss CE, Baldessari A, Pabon L, Reinecke H, Gill EA, Nelson V, Kiem HP, Laflamme MA, Murry CE. Nature. 2014 Apr 30. doi: 10.1038/nature13233. [Epub ahead of print]. PMID: 24776797.
Funding: NIH’s National Heart, Lung, and Blood Institute (NHLBI), National Institute of General Medical Sciences (NIGMS); Institute of Translational Health Sciences; National Health and Medical Research Council of Australia; Australian-American Fulbright Commission; and American Heart Association.