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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.
Affiliation
  • Marchiano S; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Nakamura K; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Division of Cardiology, Department of Medicine, University of Wa
  • Reinecke H; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Neidig L; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Comparative Medicine, University of Washington, Se
  • Lai M; Sana Biotechnology, Seattle, WA 98102, USA.
  • Kadota S; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Perbellini F; Sana Biotechnology, Seattle, WA 98102, USA.
  • Yang X; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Klaiman JM; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Blakely LP; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Karbassi E; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Fields PA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Fenix AM; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Beussman KM; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Mechanical Engineering, University of Washington,
  • Jayabalu A; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Kalucki FA; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Potter JC; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Futakuchi-Tsuchida A; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Weber GJ; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Division of Cardiology, Department of Medicine, University of Wa
  • Dupras S; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Tsuchida H; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Pabon L; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Wang L; Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Knollmann BC; Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Kattman S; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Thies RS; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Sniadecki N; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • MacLellan WR; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Division of Cardiology, Department of Medicine, University of Wa
  • Bertero A; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
  • Murry CE; Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine & Pathology, University of
Cell Stem Cell ; 30(4): 396-414.e9, 2023 04 06.
Article in En | MEDLINE | ID: mdl-37028405
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Myocytes, Cardiac / Gene Editing Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Cell Stem Cell Year: 2023 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Myocytes, Cardiac / Gene Editing Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Cell Stem Cell Year: 2023 Document type: Article