Contractility governs cardiomyocyte cell cycle activity

Shehata, N.; Srikantharajah, R.; Baier, E.; Manthey, C.; Stuedemann, T.; Nehring, M.; Covic, A.; Mueller, C.; Siebels, B.; Nissen, P.; Witten, A.; Castellano, M. Z.; Rodriguez, Y.; Gomez, L. Z.; Janssen, I.; Rodriguez, J.; Enriquez, A. G.; Romero, M. A. G.; Di Mattia, R.; Dendorfer, A.; Moretti, A.; Poch, C. M.; Eschenhagen, T.; Weinberger, F.

doi:10.1101/2025.08.19.671096

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bioRxiv · 10.1101/2025.08.19.671096

Contractility governs cardiomyocyte cell cycle activity

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Abstract

The hearts rhythmic contractions keep blood flowing to deliver the oxygen and nutrients that sustain life, but this very strength may also explain why the heart has so little capacity to regenerate. Whereas embryonic and neonatal hearts can repair themselves, this ability is rapidly lost after birth as heart muscle cells (cardiomyocytes) exit the cell cycle. We tested whether the force-generating machinery of the heart acts as a barrier to regeneration. Across human cardiomyocytes, engineered heart tissue, and myocardial slices, we found that active force generation suppresses proliferation, whereas its inhibition, through chemogenetic or pharmacological modulation, enabled cell cycle re-entry. These findings identify contractility as a central regulator of regenerative potential, highlighting new directions for strategies to restore repair in the diseased heart.

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Shehata, N., Srikantharajah, R., Baier, E., Manthey, C., Stuedemann, T., Nehring, M., Covic, A., Mueller, C., Siebels, B., Nissen, P., Witten, A., Castellano, M. Z., Rodriguez, Y., Gomez, L. Z., Janssen, I., Rodriguez, J., Enriquez, A. G., Romero, M. A. G., Di Mattia, R., Dendorfer, A., Moretti, A., Poch, C. M., Eschenhagen, T., Weinberger, F.. 2025-08-20. Contractility governs cardiomyocyte cell cycle activity. https://doi.org/10.1101/2025.08.19.671096

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