“Transcriptional Profiling of Pediatric Cardiac Stem Cells”
This grant is being funded by The Lauren Elise Memorial Foundation
Children with congenital heart disease and heart failure from cardiomyopathy represent some of our most fragile patients, yet many therapeutic and diagnostic challenges remain. While our clinical understanding of these disorders is robust, we have relatively little insight into the underlying molecular, cellular, and genetic events contributing to their disease. Resident stem cells have been identified in the hearts of both adult and pediatric patients, and to a limited extent, these cells support tissue homeostasis and repair. Strategies to promote cardiac regeneration remain at the research frontier for children with cardiomyopathy.
Our established research program has investigated the potential for pediatric heart-derived stem cells to repair cardiac injury. Previous work has demonstrated that these cells are capable of improving heart function in an animal model following ischemic injury, mimicking a heart attack. Two key observations were made during these studies; that the number of cardiac stem cells and their regenerative capacity declined sharply with age. Therefore, we propose to examine the associated genetic changes in these resident cardiac stem cells across the pediatric age spectrum in patients with congenital heart disease.
When children undergo heart surgery, a small piece of the heart is removed and discarded to permit the connection to the heart-lung bypass machine. These specimens can be collected for study and isolation of cardiac stem cells. We will collect specimens from three age groups, <1 month, between 1 month and 2 years, and over 2 years. In the first part of our study, we will collect two types of RNA from these stem cells, the “regular” mRNA, representing the complete set of genes that the cell has turned on, and a special set of tiny RNAs call microRNA (miRNA), which modify the function of other genes. We will profile these sequences against each other to identify the mRNA and miRNA that are differentially regulated during aging in pediatric patients. In the second part of our study, occurring at the same time, we will obtain samples from patients undergoing heart transplantation for heart failure. The stress of heart failure should activate the stem cells to stimulate repair, and we propose that they will be reprogrammed to resemble younger cells. We will examine these cells for evidence of replication, and compare their RNA profile to the RNA profile obtained from children of different ages in the first part of our study.
We hope to harness the ability of cardiac stem cells to regenerate damaged tissue by understanding their biology. New insight into the age-related decline in function may reveal novel approaches to increase their potential for repair in patients with congenital heart disease and heart failure.