Selective loss of resident macrophage derived insulin-like growth factor-1 abolishes adaptive cardiac growth to stress

Hypertension affects one-third of the world's population, leading to cardiac dysfunction that is modulated by resident and recruited immune cells. Cardiomyocyte growth is essential to withstand hypertensive stress, however whether immune cells are involved in this cardioprotective process is unclear. In normotensive animals, single-cell transcriptomics of fate-mapped self-renewing cardiac resident macrophages (RMs) revealed transcriptionally diverse cell states with a core repertoire of reparative gene programs, including high expression of Insulin-like Growth Factor-1 (Igf1). Hypertension drove selective in situ proliferation and transcriptional activation of some cardiac RM subsets, directly correlating with increased cardiomyocyte size and cardiac mass. Inducible ablation of RMs, or selective deletion of RM-derived Igf1 caused complete absence of adaptive cardiomyocyte growth and development of cardiac dysfunction without adaptive organ growth. Single cell transcriptomics identified a conserved IGF1-expressing macrophage subpopulation in human cardiomyopathy. Here, we defined the absolute requirement of RM-produced IGF-1 in cardiac adaptation to hypertension. Overall design: Single cell RNA sequencing of resident cardiac macrophages at steady state and during acute and chronic hypertensive stress in mice.