Language
English
Publication Date
1-7-2025
Journal
Circulation
DOI
10.1161/CIRCULATIONAHA.123.066004
PMID
39392007
PMCID
PMC11671297
PubMedCentral® Posted Date
1-7-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Background: Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP.
Methods: We performed clonal analyses to determine the cell cycle kinetics of YAP5SA cardiomyocytes. We also performed single-cell RNA sequencing, marker gene analysis, and functional studies to examine how YAP5SA cardiomyocytes progress through the cell cycle.
Results: We discovered that YAP5SA-expressing cardiomyocytes divided efficiently, with >20% of YAP5SA cardiomyocyte clones containing ≥2 cardiomyocytes. YAP5SA cardiomyocytes re-entered cell cycle at the G1/S transition and had an S phase lasting ≈48 hours. Sarcomere disassembly is required for cardiomyocyte progression from S to G2 phase and the induction of mitotic rounding. Although oscillatory Cdk expression was induced in YAP5SA cardiomyocytes, these cells inefficiently progressed through G2 phase. This is improved by inhibiting P21 function, implicating checkpoint activity as an additional barrier to YAP5SA-induced cardiomyocyte division.
Conclusions: Our data reveal that YAP5SA overcomes the mechanically constrained myocardial microenvironment to induce mitotic rounding with cardiomyocyte division, thus providing new insights into the in vivo mechanisms that maintain cell cycle quiescence in adult mammals.
Keywords
Myocytes, Cardiac, Animals, YAP-Signaling Proteins, Mitosis, Adaptor Proteins, Signal Transducing, Mice, Cell Cycle Proteins, Sarcomeres, Cells, Cultured, Signal Transduction, Transcription Factors, Cell Division, myocyte proliferation, YAP, Hippo pathway, cell cycle, sarcomere disassembly, mitotic rounding, P21
Published Open-Access
yes
Recommended Citation
Morikawa, Yuka; Kim, Jong H; Li, Rich Gang; et al., "YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division" (2025). Faculty, Staff and Students Publications. 6402.
https://digitalcommons.library.tmc.edu/baylor_docs/6402