The complexity that underlies the dynamics in the composition and maintenance of the cardiac niche in both normal and pathological conditions has been studied for decades, but it remains as a mystery. Which are the regulators that orchestrate the sequential phases that give rise to the ventricular remodeling process after myocardial infarction? Might it be possible to identify the key master regulators that could allow us to target the resolution of the fibrotic scar? Indeed, the new era of high throughput -omics is significantly contributing with precise description of the cellular landscape of the myocardial wall. However, the molecular mechanisms and the cellular interactions that regulate this dynamic are still poorly understood.

In this context, the paper that we recommend here, published in Nature last December-2024, is, thus far, one of the strongest contributions to decipher/untangle the cardiac niche under pathological conditions. In Amrute et al. (1), Dr. Lavine’s group deeply describes this niche and experimentally demonstrates that targeting the communication between CCR2+ non-resident macrophages and FAP+/POSTN+ activated cardiac fibroblasts, through IL1-β signalling pathway, it is possible to reduce cardiac fibrosis. 

To get these conclusions, Lavine’s group analyzed 45 human samples using a multi-omics approach that allows them to study at the same time transcriptomics, proteomics and epigenomics of all cell types in heart failure. The integration of these -omics and their validation using datasets published by other authors (2), reveals three transcriptional subsets of cardiac fibroblasts. Using Spatial transcriptomic data, they suggest that these subsets can be considered as terminal states, nevertheless FAP+/POSTN+ activated cardiac fibroblasts are highlighted as the potential effector of the fibrotic resolution. Nicely, they validate the role of the transcriptional factors responsible for the transition from quiescent to activated cardiac fibroblast, such as MEOX1 and RUNX1, highlighting the results by other group (3) published in the same issue.

Next, authors described clearly the fibrotic niche and associate these activated cardiac fibroblasts with CCR2+ non-resident macrophages. Besides, they demonstrate their interaction with elegant in vivo functional assays using different transgenic mice models for cardiac fibrosis. Remarkably, authors vindicate the feasibility of animal models for cardiac fibrosis studies over the use of cultured human cardiac fibroblasts, whose limitations reduce their utility in this complex niche.
Altogether, their results clearly open a door to perform faster in vivo assays, bring closer/nearing basic science to the clinic and highlight IL1-β signaling pathway as a potential target for therapeutical and personalized treatments for cardiomyopathies.

In the new era of multi-omics applications, the formulation of a precise biological question, and the adequate experimental validations to clearly respond to it, is sometime missing. If you agree with us, we fervently recommend you read this complete study, even if heart failure is not your field of research