Advancing understanding of cardiac regeneration through comparative analysis across vertebrates

Project Summary Cardiovascular disease is a leading cause of mortality in the United States. One hallmark of heart failure is the reactivation of a “fetal gene program” involving increased expression of genes related to contractility, calcium handling, and energy metabolism. Despite adopting fetal-like gene expression patterns, the failing adult heart lacks the regenerative potential seen in prenatal mammals or certain species, such as fish and amphibians. The lack of regenerative capacity in the adult heart means that tissue damage leads to maladaptive cardiac remodeling, fibrosis, and eventual organ failure, rather than regrowth of the lost cardiomyocytes. This proposed work aims to understand the loss of regenerative capacity in adult mammalian cardiomyocytes through the lens of evolutionary and developmental biology. My central hypothesis is that there is a core gene expression program enabling heart regenerative capacity that is active in fetal mammals as well as lower vertebrates. In Aim 1, I will compare fetal, healthy adult, and failing human hearts and the single-cell using both transcriptomic and open-chromatin data. This will enable me to identify genes that are not reactivated during heart failure, hindering the return to a proliferative state. My preliminary analyses of multiple single-cell transcriptomics datasets suggest that the differences between healthy and failing hearts are small compared to the differences between fetal and adult hearts, and furthermore, these gene expression differences map onto changes in chromatin accessibility. In Aim 2, I will compare single-cell transcriptomics of fetal and adult human hearts with the adult and embryonic hearts of multiple other vertebrate species. This will enable me to identify gene expression programs active in species capable of cardiac regeneration in adulthood but not in those incapables. Integrating single-cell transcriptomic data across multiple species presents its own unique challenges, but preliminary work indicates that it is feasible to obtain an integration that balances species-mixing and separation of shared cell types. Together, completion of this proposal will result in hypotheses for how the regenerative capacity of hearts is conserved across vertebrates and how it becomes inactivated in adult mammals, bolstering the search for improved therapeutic strategies for heart failure by reactivating regenerative potential.