Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair

Cardiac macrophages/monocytes participate in maintaining homeostasis and orchestrating cardiac responses upon injury. However, the function of specific macrophage/monocyte subtypes and the related cell fate commitment mechanisms remain elusive in regenerative and nonregenerative hearts due to their cellular heterogeneities. Using spatiotemporal single-cell epigenomic analysis of cardiac macrophages/monocytes in regenerative (P1) and nonregenerative (P10) mouse hearts post injury, we found that P1 hearts accumulate reparative Arg1+ macrophages, while proinflammatory S100a9+Ly6c+ monocytes are uniquely abundant during nonregenerative remodeling. Moreover, blocking chemokine CXCR2 to inhibit the specification of the S100a9+Ly6c+-biased inflammatory fate in P10 hearts resulted in elevated wound repair responses and marked improvements in cardiac function after injury. Single-cell RNA-seq further confirmed an increased Arg1+ macrophage subpopulation after CXCR2 blockade, which was accomplished by increased expression of wound repair-related genes and reduced expression of proinflammatory genes. Collectively, our findings provide instructive insights into the molecular mechanisms underlying the function and fate specification of heterogeneous macrophages/monocytes during cardiac repair and identify potential therapeutic targets for myocardial infarction.