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 compen...

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Veröffentlicht in:Immunity (Cambridge, Mass.) Mass.), 2021-09, Vol.54 (9), p.2057-2071.e6
Hauptverfasser: Zaman, Rysa, Hamidzada, Homaira, Kantores, Crystal, Wong, Anthony, Dick, Sarah A., Wang, Yiming, Momen, Abdul, Aronoff, Laura, Lin, Julia, Razani, Babak, Mital, Seema, Billia, Filio, Lavine, Kory J., Nejat, Sara, Epelman, Slava
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container_end_page 2071.e6
container_issue 9
container_start_page 2057
container_title Immunity (Cambridge, Mass.)
container_volume 54
creator Zaman, Rysa
Hamidzada, Homaira
Kantores, Crystal
Wong, Anthony
Dick, Sarah A.
Wang, Yiming
Momen, Abdul
Aronoff, Laura
Lin, Julia
Razani, Babak
Mital, Seema
Billia, Filio
Lavine, Kory J.
Nejat, Sara
Epelman, Slava
description 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.
doi_str_mv 10.1016/j.immuni.2021.07.006
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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. 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subjects Adaptation, Physiological - physiology
Animals
cardiac
cardiomyocyte hypertrophy
fate mapping
heart failure
Heart Failure - etiology
Heart Failure - metabolism
Heart Failure - pathology
Humans
hypertension
Hypertension - complications
Hypertension - immunology
Hypertension - metabolism
IGF-1
Infant
Insulin-Like Growth Factor I - metabolism
macrophages
Macrophages - metabolism
Male
Mice
Middle Aged
Myocardium - immunology
Myocardium - metabolism
Myocardium - pathology
organ growth
resident macrophages
scRNA-seq
Ventricular Remodeling - physiology
title Selective loss of resident macrophage-derived insulin-like growth factor-1 abolishes adaptive cardiac growth to stress
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