Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory ventricular arrhythmias, termed engraftment arrhythmias (EAs), hampers clinical applications. We hypothesized that EA results from pacemaker-like activity of hPSC-CMs associated with their developmental immaturity. We characterized ion channel expression patterns during maturation of transplanted hPSC-CMs and used pharmacology and genome editing to identify those responsible for automaticity in vitro. Multiple engineered cell lines were then transplanted in vivo into uninjured porcine hearts. Abolishing depolarization-associated genes HCN4, CACNA1H, and SLC8A1, along with overexpressing hyperpolarization-associated KCNJ2, creates hPSC-CMs that lack automaticity but contract when externally stimulated. When transplanted in vivo, these cells engrafted and coupled electromechanically with host cardiomyocytes without causing sustained EAs. This study supports the hypothesis that the immature electrophysiological prolife of hPSC-CMs mechanistically underlies EA. Thus, targeting automaticity should improve the safety profile of hPSC-CMs for cardiac remuscularization.

Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy

Bertero, Alessandro
Co-last
;
2023-01-01

Abstract

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory ventricular arrhythmias, termed engraftment arrhythmias (EAs), hampers clinical applications. We hypothesized that EA results from pacemaker-like activity of hPSC-CMs associated with their developmental immaturity. We characterized ion channel expression patterns during maturation of transplanted hPSC-CMs and used pharmacology and genome editing to identify those responsible for automaticity in vitro. Multiple engineered cell lines were then transplanted in vivo into uninjured porcine hearts. Abolishing depolarization-associated genes HCN4, CACNA1H, and SLC8A1, along with overexpressing hyperpolarization-associated KCNJ2, creates hPSC-CMs that lack automaticity but contract when externally stimulated. When transplanted in vivo, these cells engrafted and coupled electromechanically with host cardiomyocytes without causing sustained EAs. This study supports the hypothesis that the immature electrophysiological prolife of hPSC-CMs mechanistically underlies EA. Thus, targeting automaticity should improve the safety profile of hPSC-CMs for cardiac remuscularization.
2023
30
4
396
414
arrhythmia; automaticity; cardiac remuscularization; cell therapy; engraftment arrhythmia; hPSC-CM maturation; heart regeneration; human pluripotent stem cell-derived cardiomyocytes; myocardial infarction; pacemaker
Marchiano, Silvia; Nakamura, Kenta; Reinecke, Hans; Neidig, Lauren; Lai, Michael; Kadota, Shin; Perbellini, Filippo; Yang, Xiulan; Klaiman, Jordan M; Blakely, Leslie P; Karbassi, Elaheh; Fields, Paul A; Fenix, Aidan M; Beussman, Kevin M; Jayabalu, Anu; Kalucki, Faith A; Futakuchi-Tsuchida, Akiko; Weber, Gerhard J; Dupras, Sarah; Tsuchida, Hiroshi; Pabon, Lil; Wang, Lili; Knollmann, Björn C; Kattman, Steven; Thies, R Scott; Sniadecki, Nathan; MacLellan, W Robb; Bertero, Alessandro; Murry, Charles E
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1898772
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