Human myofibroblasts increase the arrhythmogenic potential of human induced pluripotent stem cell-derived cardiomyocytes

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 Ca2+ handling using optical mapping of advanced human cell coculture systems mimicking cell-cell interaction modalities. Human myofibroblasts altered the electrophysiology and Ca2+ handling of hiPSC-CMs and downregulated mRNAs encoding voltage channels (KV4.3, KV11.1 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.

Automated summary

Human myofibroblasts alter the electrophysiology and Ca2+ handling of hiPSC-CMs, downregulating mRNAs encoding voltage channels and SERCA2a calcium pump. Interleukin-6 is elevated in the presence of myofibroblasts and can recapitulate their paracrine effects on hiPSC-CMs when directly stimulated. Blocking interleukin-6 reduces the effects of myofibroblasts in the absence of physical contact, while myofibroblast-specific connexin43 knockdown reduces functional changes in contact cocultures when combined with interleukin-6 blockade. This study provides valuable insights into understanding how human myofibroblasts modulate hiPSC-CMs and highlights potential targets for reducing arrhythmic risk in cardiac cell therapy.