Defining cellular mechanisms of chronic graft failure in transplanted hearts with single cell multi-omics

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Project Summary/Abstract Heart transplantation is a definitive treatment option for patients with end-stage heart failure. While short-term survival has made substantial improvements, long-term outcomes are limited by chronic graft failure. Cardiac allograft hypertrophy (CAH) is a clinical phenomenon referring to the gradual increase of left ventricular mass and wall thickness of cardiac grafts. CAH onset can occur as early as 2 months after transplantation, which often lead to progressive changes in cellular environment including cardiomyocytes hypertrophy and fibrosis and accumulate to graft failure in long term. The complete landscape of cellular system in transplant patients represents a major gap in knowledge. Single cell RNA sequencing (scRNA-seq) has emerged as powerful tool to analyze diverse cell types and cell states as well as pseudo-time topologies of single cells in complex organs, which however lacks the power to infer cell lineages that is important for identify the origins of pathogenic cells. In this project, we will develop a novel single cell multi-omics sequencing technology and several computational tools, which will enable simultaneous detection of cell lineage markers (i.e. DNAs) and cell fate markers (i.e. RNAs) from same cells. We will also distinguish donor and host identities for all cells to study their distinct roles in CAH that are largely unknown. We hypothesized that CAH is initiated by specific immune cell subtypes and driven by endothelial to mesenchymal transition that is fueled by enlarged cardiomyocytes. In aim 1, we will develop novel technology to define a unifying cell lineage and cell fate roadmap for cardiac cells. Aim 2 will dissect temporal changes of cellular components in transplanted hearts during CAH early onset. Aim 3 is to trace cell lineages during CAH progression with time-series single cell multi-omics. Successful completion of this project will lead to the identification of donor and host originated cell populations as novel therapeutic targets to extend the life of transplant patients.