Regenerative cross talk between cardiac cells and macrophages.

Aside from the first week postnatal, murine heart regeneration is restricted and responses to damage follow classic fibrotic remodeling. Recent transcriptomic analyses have suggested that significant cross talk with the sterile immune response could maintain a more embryonic-like signaling network that promotes acute, transient responses. However, with age, this response-likely mediated by neonatal yolk sac macrophages-then transitions to classical macrophage-mediated, cardiac fibroblast (CF)-based remodeling of the extracellular matrix (ECM) after myocardial infarction (MI). The molecular mechanisms that govern the change with age and drive fibrosis via inflammation are poorly understood. Using multiple ribonucleic acid sequencing (RNA-Seq) datasets, we attempt to resolve the relative contributions of CFs and macrophages in the bulk-healing response of regenerative () and nonregenerative hearts (+). We performed an analysis of bulk RNA-Seq datasets from myocardium and cardiac fibroblasts as well as a single-cell RNA-Seq dataset from cardiac macrophages. MI-specific pathway differences revealed that nonregenerative hearts generated more ECM and had larger matricellular responses correlating with inflammation, produced greater chemotactic gradients to recruit macrophages, and expressed receptors for danger-associated molecular patterns at higher levels than neonates. These changes could result in elevated stress-response pathways compared with neonates, converging at NF-κB and activator protein-1 (AP-1) signaling. Profibrotic gene programs, which greatly diverge on post MI, lay the foundation for chronic fibrosis, and thus postnatal hearts older than 7 days typically exhibit significantly less regeneration. Our analyses suggest that the macrophage ontogenetic shift in the heart postnatally could result in detrimental stress signaling that suppresses regeneration. Immediately postnatal mammalian hearts are able to regenerate after infarction, but the cells, pathways, and molecules that regulate this behavior are unclear. By comparing RNA-Seq datasets from regenerative mouse hearts and older, nonregenerative hearts, we are able to identify biological processes that are hallmarks of regeneration. We find that sterile inflammatory processes are upregulated in nonregenerative hearts, initiating profibrotic gene programs 3 days after myocardial infarction that can cause myocardial disease.