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  1. Article ; Online: Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy.

    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 / Potter, Jennifer C / 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

    Cell stem cell

    2023  Volume 30, Issue 4, Page(s) 396–414.e9

    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. ...

    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.
    MeSH term(s) Humans ; Animals ; Swine ; Myocytes, Cardiac/metabolism ; Gene Editing ; Cell Line ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/therapy ; Arrhythmias, Cardiac/metabolism ; Cell- and Tissue-Based Therapy ; Cell Differentiation/genetics
    Language English
    Publishing date 2023-04-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2023.03.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy.

    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 / Potter, Jennifer C / 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

    Cell stem cell

    2023  Volume 30, Issue 5, Page(s) 741

    Language English
    Publishing date 2023-04-25
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2023.04.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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  3. Article ; Online: Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes.

    Nakamura, Kenta / Neidig, Lauren E / Yang, Xiulan / Weber, Gerhard J / El-Nachef, Danny / Tsuchida, Hiroshi / Dupras, Sarah / Kalucki, Faith A / Jayabalu, Anu / Futakuchi-Tsuchida, Akiko / Nakamura, Daisy S / Marchianò, Silvia / Bertero, Alessandro / Robinson, Melissa R / Cain, Kevin / Whittington, Dale / Tian, Rong / Reinecke, Hans / Pabon, Lil /
    Knollmann, Björn C / Kattman, Steven / Thies, R Scott / MacLellan, W Robb / Murry, Charles E

    Stem cell reports

    2021  Volume 16, Issue 10, Page(s) 2473–2487

    Abstract: Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore ... ...

    Abstract Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythmia (EA). Although transient, the risk posed by EA presents a barrier to clinical translation. We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. This study uses a porcine model to provide proof-of-concept evidence that a combination of amiodarone and ivabradine can effectively suppress EA. None of the nine treated subjects experienced the primary endpoint of cardiac death, unstable EA, or heart failure compared with five out of eight (62.5%) in the control cohort (hazard ratio = 0.00; 95% confidence interval: 0-0.297; p = 0.002). Pharmacologic treatment of EA may be a viable strategy to improve safety and allow further clinical development of cardiac remuscularization therapy.
    MeSH term(s) Amiodarone/therapeutic use ; Animals ; Anti-Arrhythmia Agents/therapeutic use ; Arrhythmias, Cardiac/drug therapy ; Cell Line ; Cell- and Tissue-Based Therapy/adverse effects ; Disease Models, Animal ; Drug Combinations ; Humans ; Ivabradine/therapeutic use ; Male ; Myocardial Infarction/drug therapy ; Myocytes, Cardiac/transplantation ; Pluripotent Stem Cells/transplantation ; Stem Cell Transplantation/adverse effects ; Swine ; Tachycardia/drug therapy
    Chemical Substances Anti-Arrhythmia Agents ; Drug Combinations ; Ivabradine (3H48L0LPZQ) ; Amiodarone (N3RQ532IUT)
    Language English
    Publishing date 2021-09-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2021.08.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Erratum: Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates.

    Liu, Yen-Wen / Chen, Billy / Yang, Xiulan / Fugate, James A / Kalucki, Faith A / Futakuchi-Tsuchida, Akiko / Couture, Larry / Vogel, Keith W / Astley, Clifford A / Baldessari, Audrey / Ogle, Jason / Don, Creighton W / Steinberg, Zachary L / Seslar, Stephen P / Tuck, Stephanie A / Tsuchida, Hiroshi / Naumova, Anna V / Dupras, Sarah K / Lyu, Milly S /
    Lee, James / Hailey, Dale W / Reinecke, Hans / Pabon, Lil / Fryer, Benjamin H / MacLellan, W Robb / Thies, R Scott / Murry, Charles E

    Nature biotechnology

    2018  Volume 36, Issue 9, Page(s) 899

    Language English
    Publishing date 2018-08-15
    Publishing country United States
    Document type Journal Article ; Published Erratum
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/nbt0918-899a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates.

    Liu, Yen-Wen / Chen, Billy / Yang, Xiulan / Fugate, James A / Kalucki, Faith A / Futakuchi-Tsuchida, Akiko / Couture, Larry / Vogel, Keith W / Astley, Clifford A / Baldessari, Audrey / Ogle, Jason / Don, Creighton W / Steinberg, Zachary L / Seslar, Stephen P / Tuck, Stephanie A / Tsuchida, Hiroshi / Naumova, Anna V / Dupras, Sarah K / Lyu, Milly S /
    Lee, James / Hailey, Dale W / Reinecke, Hans / Pabon, Lil / Fryer, Benjamin H / MacLellan, W Robb / Thies, R Scott / Murry, Charles E

    Nature biotechnology

    2018  Volume 36, Issue 7, Page(s) 597–605

    Abstract: Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can ... ...

    Abstract Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ∼750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 ± 0.9% vs. 2.5 ± 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.
    MeSH term(s) Animals ; Cell Differentiation/genetics ; Cryopreservation ; Disease Models, Animal ; Human Embryonic Stem Cells/transplantation ; Humans ; Macaca ; Myocardial Infarction/pathology ; Myocardial Infarction/therapy ; Myocardium/pathology ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/transplantation ; Pluripotent Stem Cells/transplantation ; Primates
    Language English
    Publishing date 2018-07-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/nbt.4162
    Database MEDical Literature Analysis and Retrieval System OnLINE

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