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

Publisher: Springer Country of Publication: Switzerland NLM ID: 9705402 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-9071 (Electronic) Linking ISSN: 1420682X NLM ISO Abbreviation: Cell Mol Life Sci Subsets: MEDLINE

Publication: Basel : Springer
Original Publication: Basel ; Boston : Birkhauser, c1997-

Myocytes, Cardiac* ; Induced Pluripotent Stem Cells*; Humans ; Myofibroblasts ; Connexin 43/genetics ; Interleukin-6/genetics ; Arrhythmias, Cardiac/genetics ; Cardiotonic Agents

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.
(© 2023. The Author(s).)

Erratum in: Cell Mol Life Sci. 2024 Dec 27;82(1):20. doi: 10.1007/s00018-024-05492-w. (PMID: 39725787)

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FS/PHD/20/29053 United Kingdom BHF_ British Heart Foundation; PG/22/11172 United Kingdom BHF_ British Heart Foundation; FS/17/33/32931 United Kingdom BHF_ British Heart Foundation

Keywords: Cardiac cell therapy; Connexin-43; Crosstalk; Fibroblasts; Heterocellular communication; Interleukin-6; Myocardial infarction; Paracrine

0 (Connexin 43)
0 (Interleukin-6)
0 (Cardiotonic Agents)

Date Created: 20230905 Date Completed: 20230906 Latest Revision: 20241226

20241227

PMC10480244

10.1007/s00018-023-04924-3

37668685