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Peer-reviewedCC BY 4.0Cells

Live-Cell Monitoring and Transcriptomic Profiling Identify Distinct Temporal Patterns of Cell-Cycle Activity and Maturation in Human iPSC-Derived Cardiomyocytes

  • Shiqiao Ye1,2
  • Rabina Shrestha1,2
  • Yang Yu1,2
  • Matthew Alonzo1,2
  • Cankun Wang3,4
  • Qin Ma3,4
  • Ming-Tao Zhao1,2,5,6
6 affiliations
  1. 1Center for Cardiovascular Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
  2. 2The Heart Center, Nationwide Children’s Hospital, Columbus, OH 43205, USA
  3. 3Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
  4. 4Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
  5. 5Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
  6. 6Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show decreasing cell-cycle activity during prolonged culture. However, it remains unclear whether changes in cell-cycle activity occur before, after, or concurrently with transcriptional changes in cell-cycle and maturation-associated programs. Here, we combined a TNNT2-FUCCI reporter, Ki67 immunostaining, and bulk RNA sequencing to define how cell-cycle activity changes during prolonged human iPSC-cardiomyocyte culture. FUCCI and Ki67 analyses showed similar levels of cell-cycle activity at days 20 and 30 of cardiomyocyte differentiation but declined more clearly by day 40. In contrast, transcriptomic profiling revealed that canonical cell-cycle and DNA-replication programs were already reduced by day 30. The subsequent day-30-to-day-40 interval was characterized by increased expression of sarcomeric, contractile, and calcium-handling gene programs rather than a further broad loss of mitotic pathways. These findings support a staged model of human iPSC-cardiomyocyte maturation-associated transcriptional remodeling in which a reduction in cell-cycle-associated transcription is detectable before the subsequent decline in cardiomyocyte cell-cycle activity, thereby identifying distinct temporal patterns of cell-cycle and maturation-associated changes during prolonged hiPSC-CM culture.

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Cite

BibTeXRIS
BibTeX
@article{ye2026livecell,
  title = {{Live-Cell Monitoring and Transcriptomic Profiling Identify Distinct Temporal Patterns of Cell-Cycle Activity and Maturation in Human iPSC-Derived Cardiomyocytes}},
  author = {Shiqiao Ye and Rabina Shrestha and Yang Yu and Matthew Alonzo and Cankun Wang and Qin Ma and Ming-Tao Zhao},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15211936},
  url = {https://www.mdpi.com/2073-4409/15/21/1936},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Live-Cell Monitoring and Transcriptomic Profiling Identify Distinct Temporal Patterns of Cell-Cycle Activity and Maturation in Human iPSC-Derived Cardiomyocytes
AU  - Shiqiao Ye
AU  - Rabina Shrestha
AU  - Yang Yu
AU  - Matthew Alonzo
AU  - Cankun Wang
AU  - Qin Ma
AU  - Ming-Tao Zhao
PY  - 2026
DA  - 2026/10/24
JO  - Cells
DO  - 10.3390/cells15211936
UR  - https://www.mdpi.com/2073-4409/15/21/1936
AB  - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show decreasing cell-cycle activity during prolonged culture. However, it remains unclear whether changes in cell-cycle activity occur before, after, or concurrently with transcriptional changes in cell-cycle and maturation-associated programs. Here, we combined a TNNT2-FUCCI reporter, Ki67 immunostaining, and bulk RNA sequencing to define how cell-cycle activity changes during prolonged human iPSC-cardiomyocyte culture. FUCCI and Ki67 analyses showed similar levels of cell-cycle activity at days 20 and 30 of cardiomyocyte differentiation but declined more clearly by day 40. In contrast, transcriptomic profiling revealed that canonical cell-cycle and DNA-replication programs were already reduced by day 30. The subsequent day-30-to-day-40 interval was characterized by increased expression of sarcomeric, contractile, and calcium-handling gene programs rather than a further broad loss of mitotic pathways. These findings support a staged model of human iPSC-cardiomyocyte maturation-associated transcriptional remodeling in which a reduction in cell-cycle-associated transcription is detectable before the subsequent decline in cardiomyocyte cell-cycle activity, thereby identifying distinct temporal patterns of cell-cycle and maturation-associated changes during prolonged hiPSC-CM culture.
SN  - 2073-4409
ER  -