Transplanted human stem cells restore heart function in primates after infarction
Key Takeaways
Researchers at UW Medicine in Seattle, WA, restored heart function in monkeys with heart failure by successfully transplanting human stem cells, paving the way for studies of this technique in human patients. They published their results in Nature Biotechnology.
“Our findings show that human embryonic stem cell-derived cardiomyocytes can re-muscularize infarcts in macaque monkey hearts and, in doing so, reduce scar size and restore a significant amount of heart function. This should give hope to people with heart disease,” said Dr. Charles “Chuck” Murry, professor of pathology, medicine, and bioengineering; University of Washington School of Medicine. He is also the director of the UW Medicine Institute for Stem Cell and Regenerative Medicine and the senior leader of this research project.
“The cells form new muscle that integrates into heart so that it pumps vigorously again. In some animals, the cells returned the hearts’ functioning to better than 90% of normal,” he added.
Dr. Murry and colleagues studied the effects of transplanting human cardiomyocytes derived from human embryonic stem cell-derived cardiomyocytes (hESC-CMs), and whether these cardiomyocytes could restore contractile function in macaque monkeys, which have evolutionary proximity and a cardiovascular system similar to humans.
They induced large infarcts in nine macaques by occluding the mid-left anterior descending coronary artery for 3 hours, followed by reperfusion, which induced transmural infarcts and reduced ejection fraction to approximately 40% at 2 weeks. Approximately 750 million hESC-CMs were injected intramuscularly into the infarcted region and bordering zones approximately 14 days after infarction.
Using magnetic resonance imaging scans performed 1 day before transplantation and approximately 27 days after, Dr. Murry and colleagues assessed the effects of hESC-CM transplantation on left ventricular structure and function.
Baseline left ventricular ejection fraction (LVEF) was 69.8% in the control group, and 68.8% in the hESC-CM group, and after infarction, 38.0% and 39.4%, respectively. Four weeks after transplantation, LVEF was significantly improved in macaques receiving hESC-CM compared with controls (50.0% vs 40.5%, respectively; P < 0.05). Improvement was also seen in comparisons of LVEF pre-transplantation and on day 27 post-transplantation (10.6% improvement vs 2.5%, respectively; P=0.001).
Systolic wall thickening was measured to assess contractile function in the infarct zone. Researchers found that wall thickening in the infarct improved to 22% of the left ventricular wall in macaques after cardiomyocyte transplantation, but it was not statistically significantly different than in the control group. Left ventricular end-diastolic volume was not significantly affected by transplantation.
Left ventricular systolic function in infarcted primate hearts may be improved by the formation of human myocardium. In these animals, the human heart cells had formed new muscle tissue in the damaged region, which had replaced 10% to 29% of the scar tissue, integrated with the surrounding healthy tissue, and developed into mature heart cells.
Durability of benefit was assessed in three monkeys 3 months after engraftment in one control and two treated animals. In the hESC-CM—treated animals, LVEF improved from 51.1% and 51.0% at day 27 in both animals, to 66.0% and 61.0% at 3 months. In the single control animal, LVEF decreased from 43.9% to 40.4%.
“The 20% absolute improvement in LVEF seen in the two hESC-CM hearts studied at 3 months was striking and shows that substantial mechanical improvement can occur between 1 and 3 months,” wrote the authors.
Dr. Murry added: “What we hope to do is create a ‘one-and-done’ treatment with frozen ‘off-the-shelf’ cells that, like O-negative blood, can go into any recipient with only moderate immune suppression.”
His UW Medicine team plans to begin clinical trials of this approach in 2020.
This study was supported by the National Institutes of Health, the Fondation Leducq Transatlantic Network of Excellence, the UW Medicine Heart Regeneration Program, the Washington Research Foundation, a gift from Mike and Lynn Garvey, and the Cell Analysis Facility Flow Cytometry and Imaging Core in the Department of Immunology at the University of Washington.