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Volume 20, Issue 3
  • ISSN: 1574-888X
  • E-ISSN: 2212-3946

Abstract

Background

Clinical application of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is a promising approach for the treatment of heart diseases. However, the tumorigenicity of hiPSC-CMs remains a concern for their clinical applications and the composition of the hiPSC-CM subtypes need to be clearly identified.

Methods

In the present study, hiPSC-CMs were induced from hiPSCs modulation of Wnt signaling followed by glucose deprivation purification. The structure, function, subpopulation composition, and tumorigenic risk of hiPSC-CMs were evaluated by single-cell RNA sequencing (scRNAseq), whole exome sequencing (WES), and integrated molecular biology, cell biology, electrophysiology, and/or animal experiments.

Results

The high purity of hiPSC-CMs, determined by flow cytometry analysis, was generated. ScRNAseq analysis of differentiation day (D) 25 hiPSC-CMs did not identify the transcripts representative of undifferentiated hiPSCs. WES analysis showed a few newly acquired confidently identified mutations and no mutations in tumor susceptibility genes. Further, no tumor formation was observed after transplanting hiPSC-CMs into NOD-SCID mice for 3 months. Moreover, D25 hiPSC-CMs were composed of subtypes of ventricular-like cells (23.19%) and atrial-like cells (66.45%) in different cell cycle stages or mature levels, based on the scRNAseq analysis. Furthermore, a subpopulation of more mature ventricular cells (3.21%) was identified, which displayed significantly up-regulated signaling pathways related to myocardial contraction and action potentials. Additionally, a subpopulation of cardiomyocytes in an early differentiation stage (3.44%) experiencing nutrient stress-induced injury and heading toward apoptosis was observed.

Conclusions

This study confirmed the biological safety of hiPSC-CMs and described the composition and expression profile of cardiac subtypes in hiPSC-CMs which provide standards for quality control and theoretical supports for the translational applications of hiPSC-CMs.

© 2025 Bentham Science Publishers
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2025-05-05

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The Low Tumorigenic Risk and Subtypes of Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells
Curr Stem Cell Res Ther 20, 317 (2025); https://doi.org/10.2174/011574888X318139240621051224
/content/journals/cscr/10.2174/011574888X318139240621051224
/content/journals/cscr/10.2174/011574888X318139240621051224
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Fig. () Characterization of the three established hiPSC lines at passage 15; Fig. (). The analysis of the residual of Sendai virus vectors and the short tandem repeats assay of the 3 established hiPSC lines; Fig. () Flow cytometry analysis and immunofluorescence staining for ANB_D25 and AOF_D25 hiPSC-CMs; Fig. () Violin plot of the expression of gene in all the six samples; Fig. () scRNA-seq analysis on D25 hiPSC-CMs; Fig. () Feature plot of the expression of fibroblast marker genes; Table : Primers for qPCR; Table : Action potential items of D50 hiPSC-CMs; Table : The numbers of and cells in 6 samples. Table : The detailed cell numbers and frequencies of the 7 cardiac subtypes. Supplementary material is available on the publisher's website along with the published article.

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  • Article Type:     Research Article
Keyword(s): cardiac subtypes; cardiomyocytes; hiPSC; single-cell RNA sequence; tumorigenicity; whole exome sequence

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