Diet, exercise, stress and sleep are receiving attention as important environmental modifiers of chronic inflammatory diseases. Accumulating evidence indicates that psychosocial stress and a diet high in fat and cholesterol aggravate, whereas regular physical activity and healthy sleeping habits help to prevent atherosclerosis. We hypothesize that clinically relevant environmental inputs affect specific biological immune pathways that can be targeted to reverse the atherosclerosis disease trajectory. Hematopoiesis, the process by which monocytes and their descendant macrophages develop from multipotent progenitors, is essential to disease development and progression. Hematopoiesis adjusts to environmental stimuli, its configuration aligning with disease severity. As atherosclerosis worsens, control of cell production in the bone marrow deteriorates. Through mechanisms we do not fully understand, protective medullary niches expel hematopoietic progenitors, which then seed secondary lymphoid organs where they give rise to inflammatory cells through extramedullary hematopoiesis. At advanced stages of disease, even mature, fully-differentiated leukocytes undergo limited hematopoiesis in the vessel wall. Here, we will test the hypothesis that real-life modifiers of disease, such as diet, exercise, stress and sleep, influence the leukocyte supply chain. We will test, using mouse models, how lifestyle changes hematopoiesis' molecular and cellular machinery during atherosclerosis. We propose that negative modification (high fat diet, lack of exercise, chronic stress, and sleep deprivation) rearranges hematopoietic geography, diverting production from the bone marrow to the periphery, thus propagating a quantitative and qualitative drift of the macrophage supply chain. We will examine the microenvironment that governs macrophage production, including growth factors, cytokines and adhesion molecules that regulate hematopoiesis (proliferation, retention, migration patterns of progenitors from bone marrow to spleen). Apoe-/- and Ldlr-/- mice will be exposed to various lifestyle changes and microenvironmental factors will be studied using double knock out mice and functional genomics approaches which rely on nanoparticle-enabled in vivo RNAi. We will further study how lifestyle alters cell-intrinsic factors that influence proliferation, migraton and phenotype of macrophages and their progenitors. Specifically, we will target transcription factors which give rise to myeloid biased hematopoietic stem cells. Our motivation is to understand how lifestyle transforms hematopoiesis and how these transformations influence the course of disease. In conjunction with improvements in public health policy, future therapeutics may involve nudging the hematopoietic tree towards reversal of risk. The work will substantially improve understanding of how leukocytes are (over)supplied in the setting of cardiovascular disease. These new insights into how the hematopoietic system is perturbed after exposure to real-life risk factors will provide a foundation for new therapeutic strategies aiming at reduction of inflammation in blood vessels, in the heart and in the brain.

Public Health Relevance

While we know that leukocytosis correlates with cardiovascular mortality, it is largely unknown how inflammatory leukocyte production is regulated in atherosclerosis. We will study how the hematopoietic system, plaque macrophage supply and phenotype is perturbed as a function of real-life lifestyle factors such as stress, diet sleep and exercise.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hanspal, Manjit
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Fayad, Zahi A; Swirski, Filip K; Calcagno, Claudia et al. (2018) Monocyte and Macrophage Dynamics in the Cardiovascular System: JACC Macrophage in CVD Series (Part 3). J Am Coll Cardiol 72:2198-2212
Honold, Lisa; Nahrendorf, Matthias (2018) Resident and Monocyte-Derived Macrophages in Cardiovascular Disease. Circ Res 122:113-127
Hulsmans, Maarten; Aguirre, Aaron D; Bonner, Matthew D et al. (2018) A Miniaturized, Programmable Pacemaker for Long-Term Studies in the Mouse. Circ Res 123:1208-1219
Vandoorne, Katrien; Rohde, David; Kim, Hye-Yeong et al. (2018) Imaging the Vascular Bone Marrow Niche During Inflammatory Stress. Circ Res 123:415-427
Nahrendorf, M (2018) Myeloid cells in cardiovascular organs. J Intern Med :
Herisson, Fanny; Frodermann, Vanessa; Courties, Gabriel et al. (2018) Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci 21:1209-1217
Tawakol, Ahmed; Ishai, Amorina; Takx, Richard Ap et al. (2017) Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet 389:834-845
Anzai, Atsushi; Choi, Jennifer L; He, Shun et al. (2017) The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes. J Exp Med 214:3293-3310
Vandoorne, Katrien; Nahrendorf, Matthias (2017) Multiparametric Imaging of Organ System Interfaces. Circ Cardiovasc Imaging 10:
Hulsmans, Maarten; Clauss, Sebastian; Xiao, Ling et al. (2017) Macrophages Facilitate Electrical Conduction in the Heart. Cell 169:510-522.e20

Showing the most recent 10 out of 24 publications