IRX3 depletion promotes early cardiac commitment of hiPSC-Derived Cardiomyocytes.
A, R.K., ND, F., CM, S., I, C.V., I, P.d.S., ERM, B., VM, L., LT, T., ABRA, B., & MH, F.A. (2026). IRX3 depletion promotes early cardiac commitment of hiPSC-Derived Cardiomyocytes.. PloS one. https://doi.org/10.1371/journal.pone.0351704
A RK, ND F, CM S, I CV, I PdS, ERM B, et al. IRX3 depletion promotes early cardiac commitment of hiPSC-Derived Cardiomyocytes.. PloS one. 2026; doi: 10.1371/journal.pone.0351704
A RK, ND F, CM S, et al. IRX3 depletion promotes early cardiac commitment of hiPSC-Derived Cardiomyocytes.[J]. PloS one. 2026. DOI: 10.1371/journal.pone.0351704.
@article{a2026,
author = {Ribeiro Kalthof A and Ferreira ND and Silva CM and Cordeiro Valadão I and Pinheiro de Sousa I and Bertoldi ERM and Lima VM and Turaca LT and Barbosa ABRA and Fonseca-Alaniz MH},
title = {IRX3 depletion promotes early cardiac commitment of hiPSC-Derived Cardiomyocytes.},
journal = {PloS one},
year = {2026},
doi = {10.1371/journal.pone.0351704},
note = {PMID: 42302071},
}
TY - JOUR AU - Ribeiro Kalthof A AU - Ferreira ND AU - Silva CM AU - Cordeiro Valadão I AU - Pinheiro de Sousa I AU - Bertoldi ERM AU - Lima VM AU - Turaca LT AU - Barbosa ABRA AU - Fonseca-Alaniz MH TI - IRX3 depletion promotes early cardiac commitment of hiPSC-Derived Cardiomyocytes. T2 - PloS one PY - 2026 DO - 10.1371/journal.pone.0351704 AN - PMID:42302071 ER -
Generating mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) remains a major obstacle to accurate disease modeling and cardiac repair. As the transcription factor Irx3 is a key determinant of ventricular conduction system fate in mice, we hypothesized that suppressing IRX3 expression accelerates human working cardiomyocyte differentiation. Here, we demonstrate that depleting IRX3 enhances hiPSC-CM differentiation. IRX3-knockout (KO) hiPSCs generated a greater number of cardiomyocytes with elevated expression of TNNI1 and CX43. Notably, IRX3-KO cardiomyocytes exhibited improved electrophysiological properties, more uniform mitochondrial distribution, better sarcomere organization, and enhanced intercellular connectivity. We observed that IRX3 expression peaks during the early stages of cardiomyocyte differentiation, whereas IRX3-KO cardiac progenitors have increased expression of GATA4, NKX2-5, and TBX5, as well as enhanced cell proliferation. These integrative analyses indicate that IRX3 influences cardiomyocyte differentiation by modulating the gene regulatory networks driven by GATA4, NKX2-5, and TBX5, providing functional evidence linking gene regulatory networks to the structural and electrophysiological development of cardiomyocytes. Collectively, these findings identify IRX3 as a key regulator of early cardiac commitment and highlight the potential of IRX3 suppression to enhance the molecular and functional phenotype of hiPSC-derived cardiomyocytes.