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Hulsmans, Maarten

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Hulsmans

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Maarten

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Hulsmans, Maarten
Author's Publications: search.filters.isAuthorOfPublication.35416203-2fda-4dd5-9db1-184f04015992

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    Myocardial Infarction Activates CCR2+ Hematopoietic Stem and Progenitor Cells
    (Elsevier BV, 2015) Dutta, Partha; Sager, Hendrik B; Stengel, Kristy R.; Nahrendorf, Kamila; Courties, Gabriel; Saez, Borja; Silberstein, Lev; Heidt, Timo; Sebas, Matthew; Sun, Yuan; Wojtkiewicz, Gregory; Feruglio, Paolo Fumene; King, Kevin Robert; Baker, Joshua N.; van der Laan, Anja M.; Borodovsky, Anna; Fitzgerald, Kevin; Hulsmans, Maarten; Hoyer, Friedrich; Iwamoto, Yoshiko; Vinegoni, Claudio; Brown, Dennis; Di Carli, Marcelo; Libby, Peter; Hiebert, Scott W.; Scadden, David; Swirski, Filip; Weissleder, Ralph; Nahrendorf, Matthias
    Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2+CD150+CD48− LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2−CD150+CD48− LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2+ HSPC emergence. Mtg16−/− mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.
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    Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction
    (Ovid Technologies (Wolters Kluwer Health), 2015) Sager, Hendrik B.; Heidt, Timo; Hulsmans, Maarten; Dutta, Partha; Courties, Gabriel; Sebas, Matthew; Wojtkiewicz, Gregory R.; Tricot, Benoit; Iwamoto, Yoshiko; Sun, Yuan; Weissleder, Ralph; Libby, Peter; Swirski, Filip; Nahrendorf, Matthias
    Background—Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood. Methods and Results—With the use of parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1β, increase bone marrow hematopoietic stem cell proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that interleukin-1β enhances hematopoietic stem cell proliferation by both direct actions on hematopoietic cells and through modulation of the bone marrow’s hematopoietic microenvironment. An antibody that neutralizes interleukin-1β suppresses these effects. Anti-interleukin-1β treatment dampens the post-MI increase in hematopoietic stem cell proliferation. Consequently, decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE–/– mice with atherosclerosis. Conclusions—The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart.
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    Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure
    (Ovid Technologies (Wolters Kluwer Health), 2016) Sager, Hendrik B.; Hulsmans, Maarten; Lavine, Kory J.; Moreira, Marina B.; Heidt, Timo; Courties, Gabriel; Sun, Yuan; Iwamoto, Yoshiko; Tricot, Benoit; Khan, Omar F.; Dahlman, James E.; Borodovsky, Anna; Fitzgerald, Kevin; Anderson, Daniel; Weissleder, Ralph; Libby, Peter; Swirski, Filip; Nahrendorf, Matthias
    Rationale: Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear. Objective: This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation. Methods and Results: Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6Chigh monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2−/− mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05). Conclusions: Myocardial failure is influenced by an altered myeloid cell repertoire.
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    Recruited macrophages elicit atrial fibrillation
    Hulsmans, Maarten; Schloss, Maximilian J.; Lee, I-Hsiu; Bapat, Aneesh; Iwamoto, Yoshiko; Vinegoni, Claudio; Paccalet, Alexandre; Yamazoe, Masahiro; Grune, Jana; Pabel, Steffen; Momin, Noor; Seung, Hana; Kumowski, Nina; Pulous, Fadi; Keller, Daniel; Bening, Constanze; Green, Ursula; Lennerz, Jochen K.; Mitchell, Richard N.; Lewis, Andrew; Casadei, Barbara; Iborra-Egea, Oriol; Bayes-Genis, Antoni; Sossalla, Samuel; Ong, Chin Siang; Pierson, Richard N.; Aster, Jon C.; Rohde, David; Wojtkiewicz, Gregory R.; Weissleder, Ralph; Swirski, Filip K.; Tellides, George; Tolis, George; Melnitchouk, Serguei; Milan, David J.; Ellinor, Patrick T.; Naxerova, Kamila; Nahrendorf, Matthias
    Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We here decipher how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2−∕− HOMER mice. Cell–cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through crosstalk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1+ macrophages as targets for immunotherapy in atrial fibrillation.