Project Details
Projekt
Acceleration of clonal hematopoiesis mediated by the bone marrow niche in heart failure (Project B3)
Subject Area
Hematology, Oncology
Cardiology, Angiology
Cardiology, Angiology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515629962
Clonal hematopoiesis (CH) is a common age-related condition, which is defined by the outgrowth of a hematopoietic clone with acquired mutations in leukemia-associated driver genes. It occurs in 10-20% of elderly individuals, in which a significant proportion of produced blood cells derive from such a mutated clone. A prerequisite of the emergence of CH is the occurrence of DNA mutations in hematopoietic stem cells (HSCs). Inflammatory mechanisms are an important contributor to both, DNA damage and increased proliferation in HSCs and an acute inflammatory response is a hallmark feature of acute myocardial infarction (AMI) as well as heart failure. Here, inflammatory signals are produced by the damaged myocardium and reach HSCs directly via the bloodstream or act on different cell types of the bone marrow (BM) niche, where HSCs reside. The BM microenvironment is a highly complex tissue that consists of stromal cells, osteolineage cells, endothelial cells, resident macrophages and cells of the sympathetic nervous system. The overarching hypothesis of this grant application is that AMI induced acute inflammatory responses increase inflammation in the BM niche. This cascade results in higher mutation rates in HSCs and accelerated clonal outgrowth of leukocytes with CH mutations. Dynamics of CH emergence in murine models and patients with heart failure will be studied and the effect of AMI on the 3D organization of the BM microenvironment and on DNA damage responses of HSCs will be analyzed at single-cell, protein level and tissue-wide scale after MI using quantitative multiplex BM imaging. DNA damage signatures will be linked to special anatomical compartments and inflammatory hotspots will be identified in situ with imaging-based molecular biosensors, followed by gene expression profiling with spatial transcriptomics. We will test whether myocardial ischemia and post-MI heart failure lead to increased DNA damage and accelerate mutation rate in HSPCs with histology, flow based and DNA sequencing assays. Finally, we will test whether cell-type deletion of key inflammatory drivers from the BM niche after AMI reduces ROS levels and DNA- damage in HSCs and subsequently decreases outgrowth of CH clones in murine models of heart failure. Taken together, this application will investigate the connection between myocardial ischemia and post-MI heart failure with hematopoietic cells and their BM microenvironment and provide a framework of CH progression in patients with ischemic heart disease, and define targets to block acceleration of CH and its detrimental sequelae.
DFG Programme
Research Units
