Article Impact Level: HIGH Data Quality: STRONG Summary of NPJ Regenerative Medicine, 10(1), 1–19. https://doi.org/10.1038/s41536-025-00389-z Dr. Lynn A. C. Devilée et al.
Points
- The study explores how calcium signaling influences cardiomyocyte (CM) proliferation, focusing on its potential for cardiac regeneration after ischemic injury.
- Screening human cardiac organoids (hCOs) for calcium cycling inhibitors revealed that LTCC inhibition uniquely induced CM cell cycle activity, making it a promising therapeutic target.
- Further research identified the calcineurin pathway as a crucial mediator of CM proliferation following LTCC inhibition, with pharmacological (nifedipine) and genetic inhibition (RRAD overexpression) stimulating cell cycle activity.
- Combining RRAD, an endogenous LTCC inhibitor, with cell cycle regulators CDK4 and CCND further improved CM proliferation and cardiac function in post-myocardial infarction models.
- This study targets LTCC and calcium signaling pathways and presents a novel strategy for heart tissue regeneration, offering hope for future heart failure treatments.
Summary
This study investigates the role of calcium signaling in cardiomyocyte (CM) proliferation, a critical process for cardiac regeneration after ischemic injury. The research, led by Dr. Riham Abouleisa and collaborators from Baylor College of Medicine, explores the potential of L-Type Calcium Channel (LTCC) inhibition as a therapeutic strategy. Using human embryonic stem cell-derived cardiac organoids (hCOs), the team performed a drug screen targeting proteins involved in calcium cycling. The results revealed that inhibiting LTCC was the only approach that induced CM cell cycle activity, offering a promising avenue for promoting cardiac regeneration.
Further mechanistic studies identified the calcineurin pathway as a key modulator of CM proliferation when LTCC was inhibited. Notably, pharmacological (nifedipine) and genetic inhibition of LTCC, including the overexpression of Ras-related associated with Diabetes (RRAD), stimulated CM proliferation. RRAD, an endogenous inhibitor of LTCC, induced CM cell cycle activity in vitro, in human cardiac slices, and in vivo. These findings were corroborated by experiments that showed enhanced cell cycle activity following LTCC inhibition in diverse models. The team also demonstrated that combining RRAD with cell cycle regulators, CDK4 and CCND, further enhanced CM proliferation and improved cardiac function post-myocardial infarction, suggesting a potential therapeutic approach for heart failure patients.
This research represents a significant step forward in cardiac regeneration. By targeting calcium signaling pathways, particularly LTCC, the study provides a novel strategy for enhancing CM proliferation. The results hold promise for future therapies aimed at heart failure and ischemic injury, as they offer a way to regenerate heart tissue that could transform the treatment landscape for heart failure patients.
Link to the article: https://www.nature.com/articles/s41536-025-00389-z
References Devilée, L. A. C., Salama, A. bakr M., Miller, J. M., Reid, J. D., Ou, Q., Baraka, N. M., Abou Farraj, K., Jamal, M., Nong, Y., Rosengart, T. K., Andres, D., Satin, J., Mohamed, T. M. A., Hudson, J. E., & Abouleisa, R. R. E. (2025). Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity. Npj Regenerative Medicine, 10(1), 1–19. https://doi.org/10.1038/s41536-025-00389-z
