Abstract 222: Single Cell Analysis of the Emergency Hematopoietic Response to Myocardial Infarction

Abstract

Myocardial infarction (MI) is the initiating event in ischemic heart disease, the most common cause of death in the world. Although MI-induced injury is sterile, it nevertheless elicits a vigorous emergency hematopoietic response in the bone marrow that supplies abundant myeloid cells to the heart, which remove dying cell debris and orchestrate healing, repair, and fibrosis. Ensemble methods such as flow sorting of immunostained cells and qPCR have provided some insights into infarct leukocyte phenotypes using candidate markers/genes, but the full diversity remains unknown. Here, we used single cell RNA-Seq to perform genome-wide transcriptomic profiling of >50,000 single cells from the hearts, blood, and bone marrow of infarcted and non-infarcted mice on days 1-4 after MI. We defined the diversification of myeloid cells, from their granulocytic and monocytic origins in the bone marrow, through the blood, and into the infarcted heart. This allowed construction of an atlas of MI-induced myeloid diversification and trafficking. Among the many observations enabled by this data were the origins of the type I interferon response. We recently discovered that MI induces a type I interferon response that can be targeted genetically or pharmacologically for therapeutic benefit. Our single cell data now reveal that interferon induced cells (IFNICs) derive from both neutrophilic and monocytic origins as early as 24 hours after MI. These cells are not only found within the heart, but can also be identified in the post-MI blood and bone marrow. Ongoing studies are investigating whether IFNICs can be detected in human blood after MI. Our results have clinical importance for understanding and modulating the immune response to myocardial injury. We show, using single cell transcriptomics, that post-MI treatment with anti-interferon alpha receptor antibody (IFNAR Ab) (the murine equivalent of a therapeutic antibody currently in Phase 3 clinical trials for lupus), completely abolishes MI-induced interferon signaling and shifts the intracardiac macrophage program towards a reparative posture. Our comprehensive atlas of the emergency hematopoietic response to MI can serve as a resource for others studying the inflammation in ischemic heart disease.