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Beat that! – Human ESC-derived Cardiomyocytes Restore Cardiac Function in Monkeys

Review of “Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates” from Nature Biotechnology by Stuart P. Atkinson

A recent study by researchers led by Charles E. Murry (University of Washington, Seattle, Washington, USA) demonstrated that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) engrafted well into infarcted hearts of macaque monkeys, raising the hope of the translation of this therapeutic strategy to human patients [1]. However, this study and another related study employing monkey induced pluripotent stem cell (iPSC)-CMs [2] reported the onset of ventricular arrhythmias (disrupted heart rate or rhythm), an unwanted side effect that could inhibit clinical translation.

The team now returns with a new Nature Biotechnology study in which they aimed to discover if hESC-CMs can return lost contractile activity to macaque monkey hearts and to investigate the cause of the ventricular arrhythmias [3]. Encouragingly, Liu et al. now establishes hESC-CM transplantation as a potentially effective means to restore lost cardiac function - beat that!

Following the induction of large myocardial infarcts in macaque monkey hearts by occluding the mid-left anterior descending coronary artery for three hours, the authors transplanted around 750 million cryopreserved hESC-CMs by direct injection and followed the consequences. The resultant grafts comprised around 12% of infarct size and formed electromechanical junctions with the host heart allowing a significant improvement in global left ventricular systolic function at one month (as measured by cardiac magnetic resonance imaging) when compared to the uninjected control animals. Encouragingly, observations at three months, a time point at which grafts comprised almost entirely ventricular myocytes, uncovered further improvements in heart function and established the durability of hESC-CM therapy.

While the authors did not observe any signs of teratoma formation, the study still observed the troublesome graft-associated ventricular arrhythmias; however, detailed electrical mapping analysis suggested that the arrhythmias arose from a disorder of impulse generation rather than due to an electrical feedback loop (reentry), an insight that may aid the development of arrhythmia-limiting interventions in the future.

While the study does note several limitations to their study (related to the use of monkeys, such as small group size and a lack of data on human immune response to allogeneic cardiomyocytes), they believe that the robust functional recovery noted will help to push hESC-CM therapy towards human clinical translation.

For more on hESC-CM therapy and other stem cell approaches to treat the infarcted heart, stay tuned to the Stem Cells Portal!

References

  1. Chong JJH, Yang X, Don CW, et al., Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 2014;510:273.
  2. Shiba Y, Gomibuchi T, Seto T, et al., Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 2016;538:388.
  3. Liu Y-W, Chen B, Yang X, et al., Human embryonic stem cell–derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nature Biotechnology 2018;36:597.