Study Offers Fundamental Insights for Repairing the Heart and Other Organs

In keeping with their tradition of groundbreaking, fundamental discoveries, researchers at The Texas Heart Institute (THI) and Baylor College of Medicine (BCM) have made exciting new advancements in understanding the mechanisms behind mammalian cell cycle arrest, specifically in adult heart muscle cells, or cardiomyocytes. Their groundbreaking study, recently published in the journal Circulation, provides new insights into the molecular processes behind cell cycle arrest—or quiescence—in these specialized cells. These discoveries may hold promise not only for heart regeneration but also for understanding similar mechanisms in other mammalian organs.

Adult mammalian cardiomyocytes are known for their limited ability to divide and form new cells, with an estimated renewal rate of only 1% per year. This limitation significantly impairs the heart’s capacity to repair itself following injuries such as a myocardial infarction (heart attack) or during ongoing disease. However, the research team at THI’s Cardiomyocyte Renewal Laboratory, led by James F. Martin, MD, PhD, professor and vice chairman of molecular physiology and biophysics at Baylor, has long been at the forefront of exploring how these cells behave and how the heart might be encouraged to regenerate itself.

Dr. Martin’s lab made a critical discovery with the identification of the Hippo “stop-growth” molecular pathway, which keeps cardiomyocytes in a non-dividing, quiescent state. In previous studies, the lab demonstrated that suppressing the Hippo pathway allowed for heart tissue regeneration, forming the foundation for a promising heart-regeneration treatment. In the latest study, titled “YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division,” the researchers present an in-depth look into how removing these molecular barriers may trigger cardiomyocyte division.

The collaboration between THI and BCM researchers, including first author Yuka Morikawa, PhD, and fellow researchers Jong H. Kim, PhD, Rich Gang Li, PhD, Shijie Liu, PhD, Vaibhav Deshmukh, PhD, and Dr. Martin, used innovative tools, such as a Confetti mouse model and scRNA-Seq, to explore the process of adult cardiomyocyte division. The team found that YAP, a protein regulated by the Hippo pathway, plays a critical role in initiating the cell cycle in cardiomyocytes. An active form of YAP, known as YAP5SA, enabled these previously non-dividing cells to re-enter the cell cycle and progress from the G1/S phase transition through the S and G2 phases.

Dr. Morikawa, commenting on the broader implications of the study, stated, “Our findings offer a deeper understanding of the molecular processes that prevent adult cardiomyocytes from dividing. This research not only sheds light on heart regeneration but could have far-reaching implications for other specialized cells in the mammalian body, opening up new avenues for therapies in various organs.”

The study also uncovered that while YAP5SA prompted cardiomyocytes to initiate the division process, it alone was not sufficient to drive the cells through mitosis. By inhibiting P21, a protein that acts as a checkpoint to halt the cell cycle in response to DNA damage, the researchers were able to increase the number of cardiomyocytes that successfully completed division.

Dr. Martin added, “These findings have profound potential therapeutic implications. By deepening our understanding of the regulatory mechanisms that control cell division in the heart, we are even closer to developing new, more targeted treatments that could enhance the heart’s ability to regenerate itself after injury. This could be a transformative breakthrough for patients suffering from heart disease.”

The study’s results offer significant insights into cell cycle regulation in cardiomyocytes and provide an expanded set of molecular targets for the development of additional novel therapies aimed at repairing the adult heart. As the research continues, the hope is that these breakthroughs will lead to clinical interventions that harness the regenerative capacity of the heart, improving patient outcomes for those with heart disease.

Read the Spotlight on YAP: Unlocking New Insights to Overcome the Barriers to Heart Regeneration at Circulation, here.