Niche-dependent programming of macrophage function in the regenerating heart

The damage caused by a heart attack leads to a permanent loss of cardiac tissue in adult mammals.

In contrast, zebrafish have the remarkable ability to regenerate their hearts after injury, even in the presence of scarring.

Macrophages are integral to both repair by scar formation and tissue regeneration; however, the local environmental cues and cell-cell interactions controlling distinct macrophage functions across the injured heart, which allow zebrafish to precisely adjust the balance between a pro-fibrotic versus a pro-regenerative state, remain elusive.

What is clear is that the zebrafish post-cardiac injury environment is unique compared to mammals and, therefore, key in elucidating how the interplay between the cardiac niche and macrophages can dictate a successful regenerative response.

Here I propose to dissect the dynamic cellular crosstalk and spatial relationships occurring between macrophages and the regenerating cardiac niche.

I will combine single-cell (epi)genomics, spatial-transcriptomics and proteomics, imaging, and genome-editing approaches to dissect the spatiotemporal dynamics of cellular microenvironments, identify extracellular and intercellular signalling networks and decipher how these converge to define macrophage identity, plasticity and function.

Ultimately, this knowledge may contribute to the development of therapeutic strategies aimed at harnessing pro-regenerative intercellular communications within the injured non-regenerative mammalian heart.