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American Heart Association

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Final ID: MP2716

Sarcoplasmic Reticulum Ca2+ Leak Drives Arrhythmogenesis During In Vivo Maturation of Stem Cell-Derived Cardiomyocytes

Abstract Body (Do not enter title and authors here): Heart regeneration via transplantation of human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CMs) holds significant clinical potential. However, a transient, yet severe, period of ventricular arrhythmia, termed engraftment arrhythmia (EA), has limited bench-to-bedside translation. EA begins ~1-week post-transplant and persists for ~1-month, coinciding with the period when transplanted cells form intercellular connections to host myocardium but have not fully matured. Immature hiPSC-CMs display automaticity similar to sinoatrial nodal cells where pacemaker activity is regulated by sarcolemmal ion channel currents and spontaneous sarcoplasmic reticulum (SR) calcium (Ca2+) leak. In this study, we hypothesize that dysfunctional excitation-contraction (EC) coupling and aberrant SR Ca2+ leak are mechanistic drivers of EA. To test this, WTC-11 hiPSC-CMs were generated that stably express the cytosolic Ca2+ sensor jGCaMP8f and a membrane targeted RFP. hiPSC-CMs were transplanted into a rat acute myocardial infarction model to mature in-vivo. Cells were re-isolated for experiments after 1 week, coinciding with arrhythmia onset, and after 4 weeks, when arrhythmias terminate. We found hiPSC-CMs remain morphologically immature even after 4-weeks in-vivo. Surprisingly, compared to cells in-vitro, the cells re-isolated at 1-week showed significantly impaired Ca2+ dynamics including ~3-fold reduction in Ca2+ transient amplitude and slower kinetics which recovered by 4-weeks. And only ~20% of the non-transplanted or 1-week re-isolated cells adhered to 1 Hz pacing at room temperature compared to ~80% of the 4-week ex-vivo cells, suggesting more mature electrophysiology. High-spatiotemporal resolution Ca2+ imaging revealed the 1-week ex-vivo hiPSC-CMs have a significant ~2-fold surge in Ca2+ spark rate with a greater number of slowly terminating Ca2+ sparks than in the non-transplanted or 4-week re-isolated cells. Single-cell resolution spatial transcriptomics revealed heterogeneity within grafts, with progressive maturation over time. These data suggest excess SR Ca2+ leak and inefficient EC coupling promote EA early after cardiac cell therapy which improves as cells mature. Therapeutic strategies aimed at reducing SR Ca2+ leak or promoting further maturation of hiPSC-CMs could potentially reduce arrhythmogenicity.
  • Wescott, Andrew  ( University of Washington , Seattle , Washington , United States )
  • Karbassi, Elaheh  ( University of Washington , Seattle , Washington , United States )
  • Marchiano, Silvia  ( University of Washington , Seattle , Washington , United States )
  • Nimmagadda, Likitha  ( University of Washington , Seattle , Washington , United States )
  • Perrault, Nora  ( University of Washington , Seattle , Washington , United States )
  • Blakely, Leslie  ( University of Washington , Seattle , Washington , United States )
  • Maclellan, Robb  ( University of Washington , Seattle , Washington , United States )
  • Davis, Jennifer  ( University of Washington , Seattle , Washington , United States )
  • Murry, Chuck  ( University of Southern California , Los Angeles , California , United States )
  • Author Disclosures:
    Andrew Wescott: DO NOT have relevant financial relationships | Elaheh Karbassi: DO NOT have relevant financial relationships | Silvia Marchiano: DO NOT have relevant financial relationships | Likitha Nimmagadda: DO NOT have relevant financial relationships | Nora Perrault: DO NOT have relevant financial relationships | Leslie Blakely: No Answer | Robb Maclellan: No Answer | Jennifer Davis: DO NOT have relevant financial relationships
Meeting Info:

Scientific Sessions 2025

2025

New Orleans, Louisiana

Session Info:

Molecular Mechanisms in Cardiac Regeneration

Monday, 11/10/2025 , 10:45AM - 11:55AM

Moderated Digital Poster Session

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