Hormonal contraints limiting mammalian cardiomyocyte cell division

The National Institute of General Medical Sciences awarded San Jose State University Research Foundation $146,500 on August 15, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate hormonal constraints limiting mammalian cardiomyocyte cell division and heart regenerative capacity.

The research examines how thyroid hormone restricts cardiomyocyte proliferative potential after birth, limiting the heart's regenerative capacity in adult mammals. The project uses cell cycle marker analysis, FUCCI time-lapse imaging, digital holography, and molecular characterization to define how thyroid hormone interferes with cell cycle activity and to test whether postnatal thyroid hormone depletion enhances proliferative responses. The work may establish thyroid hormone status as a modifiable endocrine switch to enhance mammalian heart regenerative capacity. Performance occurs at San Jose, California through April 30, 2030. Over the four-year award period, approximately 40 undergraduates and 4 master's-level graduate students will receive training through the project.

Abstract

Heart failure is a leading cause of death worldwide because adult human hearts cannot regenerate lost cardiomyocytes (CMS) after injury. In contrast, neonatal mammals briefly regenerate their hearts through CM proliferation, but this capacity is rapidly lost after birth as CMS exit the cell cycle, binucleate, and become polyploid. Our long-term goal is to define the endocrine and cellular mechanisms that restrict CM proliferative potential after birth and limit mammalian heart regenerative capacity. Our preliminary studies suggest that thyroid hormone (TH) is a critical endocrine signal enforcing CM cell cycle arrest. We find that TH suppresses GSK3 inhibitor-induced proliferation in vitro and decreases the frequency of complete CM divisions. We also observed that early postnatal binucleated CMS can divide to generate mononucleated daughters, suggesting that binucleation may be reversible. Based on these findings, we hypothesize that the postnatal rise in TH blocks cell cycle progression and stabilizes the polyploid state, thus restricting CM proliferative potential. Aim 1 will define how TH interferes with GSK3 inhibitor-induced cell cycle activity, using cell cycle marker analysis, fucci time- lapse imaging, digital holography, and molecular characterization of cell cycle regulators. Aim 2 will test whether postnatal TH depletion enhances CM proliferative responses to GSK3 inhibition, focusing on cell cycle activity, cell size dynamics, binucleated CM division, and ploidy reversal. The expected outcome is new mechanistic insight into how TH enforces postnatal CM cell cycle arrest and loss of regenerative capacity. If successful, this work may establish TH status as a modifiable endocrine switch to enhance mammalian heart regenerative capacity. Over the 4-year award, approximately 40 undergraduates (about 10 per year) and 4 master's-level graduate students will receive training. This sure award will provide these students with hands-on experience in microscopy, molecular biology, primary culture, and animal models. The project will strengthen the research environment at a primarily undergraduate institution while providing transformative training experiences that prepare trainees for advanced careers in biomedical research.