Impact of macrophages on cardiac maturation

Background

There are resident macrophages in the heart and they are one of the most populous cell types present after endothelial cells, cardiomyocytes and fibroblasts. Recently, high profile publications have shown that macrophages play an important role in regulation of pacemaker activity and conduction. Additionally, during disease processes they have been shown to induce a fibrotic response in resident fibroblasts. However, little is know about their role in cardiac development and maturation where there are profound changes in the phenotype and gene expression of resident macrophages. Furthermore, in human cardiac organoid models in vitro, the top differential expression difference compared with the adult heart is a signature from the resident macrophage population and signalling components.

Aim

To determine the impact of incorporating human macrophages on the biology and function of human cardiac organoids.

Approach

Human monocytes (commercially available) will be added to our human cardiac organoids. We will use different analysis techniques to determine their impact on biology (single cell RNA sequencing and single organoid proteomics) and function (force of contraction analyses, impaling electrode electrophysiological measurements and response to adrenaline). Using these approaches we hope to identify key regulators of macrophage-cardiac interactions under both resting and activated macrophage phenotypes.

Outcome

Elucidating the impact of macrophages on human cardiac organoid biology and function is important for deciphering the cell-cell crosstalk in the regulation of the maturation process to advance our in vitro organoid models. Additionally, it has the potential to unlock new therapeutic targets for treatment of cardiovascular disease.