Human myofibroblasts reduced the pacing rate needed to induce loss of 1:1 action potential capture in hiPSC-CMs from 2.56 Hz to 1.84 Hz in contact coculture, increasing arrhythmogenic potential.
Human myofibroblasts increase the arrhythmogenic potential of hiPSC-CMs via interleukin-6 and connexin43, identifying these as potential targets to improve the safety of cardiac cell therapy.
Absolute Event Rate: 1.84% vs 2.56%
p-value: p=<0.0001
Abstract Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have the potential to remuscularize infarcted hearts but their arrhythmogenicity remains an obstacle to safe transplantation. Myofibroblasts are the predominant cell-type in the infarcted myocardium but their impact on transplanted hiPSC-CMs remains poorly defined. Here, we investigate the effect of myofibroblasts on hiPSC-CMs electrophysiology and Ca 2+ handling using optical mapping of advanced human cell coculture systems mimicking cell–cell interaction modalities. Human myofibroblasts altered the electrophysiology and Ca 2+ handling of hiPSC-CMs and downregulated mRNAs encoding voltage channels (K V 4.3, K V 11.1 and Kir6.2) and SERCA2a calcium pump. Interleukin-6 was elevated in the presence of myofibroblasts and direct stimulation of hiPSC-CMs with exogenous interleukin-6 recapitulated the paracrine effects of myofibroblasts. Blocking interleukin-6 reduced the effects of myofibroblasts only in the absence of physical contact between cell-types. Myofibroblast-specific connexin43 knockdown reduced functional changes in contact cocultures only when combined with interleukin-6 blockade. This provides the first in-depth investigation into how human myofibroblasts modulate hiPSC-CMs function, identifying interleukin-6 and connexin43 as paracrine- and contact-mediators respectively, and highlighting their potential as targets for reducing arrhythmic risk in cardiac cell therapy.
Johnson et al. (Fri,) conducted a other in Arrhythmia in cardiac cell therapy. Human myofibroblasts (contact coculture) vs. hiPSC-CMs cultured with hiPSC-CM-conditioned medium was evaluated on Pacing rate needed to induce loss of 1:1 action potential capture (p=<0.0001). Human myofibroblasts reduced the pacing rate needed to induce loss of 1:1 action potential capture in hiPSC-CMs from 2.56 Hz to 1.84 Hz in contact coculture, increasing arrhythmogenic potential.