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 and increased cardiac mass are essential to withstand hypertensive stress; however, whether immune cells are involved in this compensatory 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 states, directly correlating with increased cardiomyocyte growth. During hypertension, inducible ablation of RMs or selective deletion of RM-derived Igf1 prevented adaptive cardiomyocyte growth, and cardiac mass failed to increase, which led to cardiac dysfunction. 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. [Display omitted] •Cardiac resident macrophage (RM) subsets respond differentially to hypertension•Cardiac RM-derived IGF-1 drives compensatory cardiac muscle growth to hypertension•Loss of cardiac RM-derived IGF-1 during hypertension leads to heart failure•An IGF1-expressing cardiac macrophage subset is conserved in human heart failure Hypertensive stress requires cardiac muscle growth to maintain organ function. Zaman et al. reveal that the ability of the heart to adapt to hypertension through cardiomyocyte growth is entirely dependent on local IGF-1 produced by resident cardiac macrophages.