In the quest to develop safe cell therapy for heart diseases, the translation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) into clinical application for heart regeneration has been hindered by transient Engraftment Arrhythmia (EA).
The group of CE. Murry provides new insights into the mechanisms for EA. They demonstrated that EA results from pacemaker-like activity of the immature hESC-CM. The authors demonstrated that remodelling the cell's ions channel following their transplantation in rat hearts may explain EA. In particular, the authors identified a quadruple gene combination (HCN4, CACNA1H, and SLC8A1, KCNJ) related to hESC-CM automaticity
The authors' groundbreaking discovery relies on the generation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) lacking these genes, these cells named MEDUSA remain pacemaker activity free. Although quiescent, MEDUSA cells remain excitable upon external stimulation.
When MEDUSA hESC-CMs were transplanted into uninjured pig hearts, they exhibited stable engraftment for three months, synchronous beating with the host myocardium, and, most importantly, a marked reduction in ventricular arrhythmias. While these cells represent an advance toward safely revascularizing of the injured heart, further studies are needed to determine if MEDUSA hESC-CMs can engraft in a fibrotic environment and restore systolic function.
This study represents a major breakthrough in the development of safe cell therapies for heart regeneration and progress towards translating this therapy into clinical practice.
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