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Updated: Sep 20, 2025
Isolation, Culture and Transduction of Adult Mouse Cardiomyocytes
Published on: August 28, 2016
Stimulation of Cardiomyocyte Proliferation Is Dependent on Species and Level of Maturation
Dogacan Yücel1,2, Bayardo I Garay1,3,4, Rita C R Perlingeiro1,2,3,5
1Department of Medicine, Lillehei Heart Institute, Cardiovascular Division, University of Minnesota, Minneapolis, MN, United States.
Abstract:
The heart is one of the least regenerative organs. This is in large part due to the inability of adult mammalian cardiomyocytes to proliferate and divide. In recent years, a number of small molecules and molecular targets have been identified to stimulate cardiomyocyte proliferation, including p38 inhibition, YAP-Tead activation, fibroblast growth factor 1 and Neuregulin 1. Despite these exciting initial findings, a therapeutic approach to enhance cardiomyocyte proliferation in vivo is still lacking. We hypothesized that a more comprehensive in vitro validation using live-cell imaging and assessment of the proliferative effects on various cardiomyocyte sources might identify the most potent proliferative stimuli. Here, we used previously published stimuli to determine their proliferative effect on cardiomyocytes from different species and isolated from different developmental timepoints. Although all stimuli enhanced DNA synthesis and Histone H3 phosphorylation in neonatal rat ventricular cardiomyocytes to similar degrees, these effects varied substantially in mouse cardiomyocytes and human iPSC-derived cardiomyocytes. Our results highlight p21 inhibition and Yap-Tead activation as potent proliferative strategies to induce cultured cardiomyocyte cell cycle activity across mouse, rat and human cardiomyocytes.
Insights
Identifying effective strategies for heart regeneration, this study found that p21 inhibition and Yap-Tead activation significantly promote cardiomyocyte cell cycle activity in rat, mouse, and human cultures.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Cellular Biology
Background:
- The mammalian heart exhibits limited regenerative capacity, primarily due to the inability of adult cardiomyocytes to proliferate.
- Previous research identified several molecular targets (e.g., p38 inhibition, YAP-Tead activation) that can stimulate cardiomyocyte proliferation.
- A clinically viable therapeutic strategy for enhancing cardiomyocyte proliferation in vivo remains elusive.
Purpose of the Study:
- To comprehensively validate previously identified cardiomyocyte proliferative stimuli in vitro.
- To assess the proliferative effects of these stimuli on cardiomyocytes from various species and developmental stages.
- To identify the most potent stimuli for inducing cardiomyocyte cell cycle activity.
Main Methods:
- Utilized live-cell imaging techniques for in vitro validation of cardiomyocyte proliferation.
- Assessed the proliferative effects of published stimuli (p38 inhibition, YAP-Tead activation, FGF1, Nrg1) on different cardiomyocyte sources.
- Evaluated DNA synthesis and Histone H3 phosphorylation as markers of proliferation.
Main Results:
- All tested stimuli enhanced DNA synthesis and Histone H3 phosphorylation in neonatal rat ventricular cardiomyocytes.
- The proliferative effects of these stimuli varied significantly in mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes.
- p21 inhibition and Yap-Tead activation demonstrated potent proliferative effects across rat, mouse, and human cardiomyocyte cultures.
Conclusions:
- p21 inhibition and Yap-Tead activation represent promising strategies for inducing cardiomyocyte cell cycle activity.
- These findings provide a foundation for developing therapeutic approaches to enhance heart regeneration.
- Species and developmental stage-specific responses highlight the complexity of cardiomyocyte proliferation.
