Anna Stepanova, PhD
Weill Cornell Medicine
Mapping the Transcriptional Landscape of Cardiac Fibrosis in a Mouse Model of Friedreich's Ataxia Cardiomyopathy
Friedreich's Ataxia (FA) is an inherited disease caused by loss of frataxin (FXN), a mitochondrial protein essential for iron-sulfur cluster biogenesis. The leading cause of death in FA is cardiomyopathy, characterized by extensive fibrosis. Yet, the multicellular programs driving FA cardiac fibrosis remain unknown. Using a cardiomyocyte-specific FXN knockout mouse model that develops cardiac fibrosis, we applied single-nucleus RNA sequencing at postnatal day 45 (before the onset of fibrosis) and day 70 (after the onset of fibrosis). We profiled gene expression in the major cardiac cell populations, including cardiomyocytes, fibroblasts, endothelial cells, pericytes, and immune cells, across both sexes and compared knockout and control groups. We focus on how these cell populations and their communication evolve with disease progression. This dataset reveals, for the first time, the intercellular signals by which cardiomyocyte FXN loss initiates and sustains cardiac fibrotic remodeling. The results provide unique insights into the cell types and molecular pathways involved in FA cardiac fibrosis, as well as potential therapeutic targets to prevent or treat this condition.
Friedreich's Ataxia (FA) is an inherited disease caused by loss of frataxin (FXN), a mitochondrial protein essential for iron-sulfur cluster biogenesis. The leading cause of death in FA is cardiomyopathy, characterized by extensive fibrosis. Yet, the multicellular programs driving FA cardiac fibrosis remain unknown. Using a cardiomyocyte-specific FXN knockout mouse model that develops cardiac fibrosis, we applied single-nucleus RNA sequencing at postnatal day 45 (before the onset of fibrosis) and day 70 (after the onset of fibrosis). We profiled gene expression in the major cardiac cell populations, including cardiomyocytes, fibroblasts, endothelial cells, pericytes, and immune cells, across both sexes and compared knockout and control groups. We focus on how these cell populations and their communication evolve with disease progression. This dataset reveals, for the first time, the intercellular signals by which cardiomyocyte FXN loss initiates and sustains cardiac fibrotic remodeling. The results provide unique insights into the cell types and molecular pathways involved in FA cardiac fibrosis, as well as potential therapeutic targets to prevent or treat this condition.
