Nfia-mediated troponin C activation enhances pluripotent stem cell-derived cardiomyocyte function and improves cardiac remodeling after myocardial infarction
- 1Department of Cardiology, Affiliated Hospital of Yangzhou University, Yangzhou University, Institute of Cardiovascular Disease, Yangzhou, China
Abstract
Background: Myocardial infarction (MI) causes irreversible cardiomyocyte loss and adverse ventricular remodeling because of the limited regenerative capacity of adult cardiomyocytes. Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) represent a promising strategy for myocardial repair, but their therapeutic efficacy is limited by incomplete maturation and insufficient functional integration. This study investigated whether nuclear factor I A (Nfia) enhances PSC-CM-mediated cardiac repair and explored its downstream mechanism.
Methods: Public single-cell RNA sequencing (scRNA-seq) data from male post-MI mouse hearts and a mouse PSC-CM differentiation dataset were analyzed to characterize post-infarction remodeling and screen candidate transcriptional regulators. Mouse PSCs/PSC-CMs were modified by lentiviral Nfia overexpression and troponin C (TnC) silencing and evaluated by quantitative reverse transcription polymerase chain reaction (RT-qPCR), Western blotting, immunofluorescence, calcium transient analysis, dual-luciferase reporter assays, and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR). Engineered PSCs were transplanted into 10-week-old male C57BL/6N mice after MI induction by left anterior descending coronary artery ligation. Sham, MI, control PSC, Nfia-overexpressing PSC, and TnC-silenced rescue groups were used to assess cardiac function, fibrosis, cardiomyocyte hypertrophy, and lineage marker expression.
Results: Post-MI cardiac tissue exhibited sustained cellular remodeling, fibrotic activation, and impaired endogenous cardiomyocyte recovery, supporting the need for PSC-CM-based repair. Nfia was identified as a candidate regulator during PSC-CM differentiation. Nfia overexpression enhanced cardiomyogenic marker expression, sarcomere organization, and calcium-handling capacity in PSC-CMs. Mechanistically, Nfia directly bound to the TnC promoter and activated TnC transcription. In vivo, transplantation of Nfia-overexpressing PSCs improved left ventricular function and attenuated adverse remodeling after MI, whereas TnC silencing weakened these reparative effects.
Conclusions: Nfia enhances the maturation and reparative capacity of PSC-CMs, at least in part by activating TnC transcription. The Nfia-TnC regulatory axis may provide a potential strategy to improve stem cell-based myocardial repair after MI.
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BibTeX
@article{wang2026nfiamediated,
title = {{Nfia-mediated troponin C activation enhances pluripotent stem cell-derived cardiomyocyte function and improves cardiac remodeling after myocardial infarction}},
author = {Chan Wang and Jiarui Shen and Hui Shen and Xiaochen Yuan},
journal = {Cardiovascular Diagnosis and Therapy},
year = {2026},
month = sep,
doi = {10.21037/cdt-2026-0162},
url = {https://doi.org/10.21037/cdt-2026-0162},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Nfia-mediated troponin C activation enhances pluripotent stem cell-derived cardiomyocyte function and improves cardiac remodeling after myocardial infarction
AU - Chan Wang
AU - Jiarui Shen
AU - Hui Shen
AU - Xiaochen Yuan
PY - 2026
DA - 2026/09/29
JO - Cardiovascular Diagnosis and Therapy
DO - 10.21037/cdt-2026-0162
UR - https://doi.org/10.21037/cdt-2026-0162
AB - Background: Myocardial infarction (MI) causes irreversible cardiomyocyte loss and adverse ventricular remodeling because of the limited regenerative capacity of adult cardiomyocytes. Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) represent a promising strategy for myocardial repair, but their therapeutic efficacy is limited by incomplete maturation and insufficient functional integration. This study investigated whether nuclear factor I A (Nfia) enhances PSC-CM-mediated cardiac repair and explored its downstream mechanism. Methods: Public single-cell RNA sequencing (scRNA-seq) data from male post-MI mouse hearts and a mouse PSC-CM differentiation dataset were analyzed to characterize post-infarction remodeling and screen candidate transcriptional regulators. Mouse PSCs/PSC-CMs were modified by lentiviral Nfia overexpression and troponin C (TnC) silencing and evaluated by quantitative reverse transcription polymerase chain reaction (RT-qPCR), Western blotting, immunofluorescence, calcium transient analysis, dual-luciferase reporter assays, and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR). Engineered PSCs were transplanted into 10-week-old male C57BL/6N mice after MI induction by left anterior descending coronary artery ligation. Sham, MI, control PSC, Nfia-overexpressing PSC, and TnC-silenced rescue groups were used to assess cardiac function, fibrosis, cardiomyocyte hypertrophy, and lineage marker expression. Results: Post-MI cardiac tissue exhibited sustained cellular remodeling, fibrotic activation, and impaired endogenous cardiomyocyte recovery, supporting the need for PSC-CM-based repair. Nfia was identified as a candidate regulator during PSC-CM differentiation. Nfia overexpression enhanced cardiomyogenic marker expression, sarcomere organization, and calcium-handling capacity in PSC-CMs. Mechanistically, Nfia directly bound to the TnC promoter and activated TnC transcription. In vivo, transplantation of Nfia-overexpressing PSCs improved left ventricular function and attenuated adverse remodeling after MI, whereas TnC silencing weakened these reparative effects. Conclusions: Nfia enhances the maturation and reparative capacity of PSC-CMs, at least in part by activating TnC transcription. The Nfia-TnC regulatory axis may provide a potential strategy to improve stem cell-based myocardial repair after MI.
SN - 2223-3652
SN - 2223-3660
ER -