Data from the latest animal studies support the notion that it may one day be possible to use human embryonic stem cell-derived cardiomyocytes (hESC-CMs) to directly help repair damaged heart muscle. Studies in rats and mice have already provided initial indication that transplanted hESC-CMs can improve the function of heart muscle damaged by an infarction. However, what hasn’t been clear to date is whether such stem cell-derived cells might increase the likelihood of arrhythmias. Nor has it been demonstrated whether the increased contractile function evident after transplantation of hESC-CMs is actually due to the cells integrating with the heart’s own cells and contributing directly to force generation, or whether it relates to an alternative, perhaps paracrine mechanism.
To address these questions researchers at the University of Washington’s Institute for Stem Cell and Regenerative Medicine turned to studies in immunosuppressed guinea pigs, which have a lower natural heart rate than rats or mice, and so represent a more easily analyzed model for studying hESC-CM transplantation. The team, led by Michael A. Laflamme, Ph.D., initially confirmed that transplanting hESC-CMs into hearts with damaged left ventricles resulted in a significant amount of remuscularization, and far fewer episodes of ventricular tachycardia compared with the control heart-damaged animals. In fact, the control animals demonstrated 785% more ventricular tachycardic episodes than those implanted with the hESC-CMs.
To further investigate the electrical stability of hearts receiving hESC-CM transplants, the researchers devised a programmed electrical stimulation (PES) protocol that wasn’t strong enough to affect undamaged hearts, but was enough to induce ventricular tachycardia in about 40% of untreated animals with ventricular damage. When they applied this PES to the hearts of hESC-CM transplant recipients, only 6.7% suffered ventricular tachycardia, indicating that the transplantation therapy significantly improved the electrical stability of recipient heart muscle.
What the studies still hadn’t confirmed was whether the transplanted hESC-CMs actually couple to and beat in synchrony with the recipient’s myocardium. To investigate this the University of Washington team created ESC-CMS that effectively fluoresced each time they contracted. Encouragingly, results from imaging studies of grafted hearts showed that the hESC-CM transplants were indeed capable of contracting completely in synchrony with the animals’ own heart muscle, indicating true host-graft coupling.
“These intravital imaging studies are, to our knowledge, the first direct demonstration that human cardiomyocytes can integrate and contract synchronously with host myocardium,” the researchers write in their published paper in Nature. “Although additional paracrine mechanisms cannot be excluded, the demonstration of electromechanically coupled grafts in injured hearts supports the idea that hESC-CMs can improve mechanical function by creating new force-generating units, a sine qua non for heart regeneration.”
Dr. Laflamme et al admit that graft coupling to injured heart muscle wasn’t 100% efficient, and was less likely to occur in the most scarred areas of the ventricle. Nevertheless, they state, the guinea pig model will represent a useful platform for testing strategies that might improve host-graft integration.
“Our study also provides reassurance about the arrhythmogenic risk of cardiac repair with immature stem-cell-derived cardiomyocytes,” the investigators stress. “Consistent with prior transplantation studies with primary fetal mouse cardiomyocytes, we observed an arrhythmia-suppressive effect that was unique to cardiomyocyte grafts and occurred despite incomplete host-graft coupling.”
The studies are described in a paper titled “Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts.”