Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Dick, Sarah A.; Macklin, Jillian; Nejat, Sara; Momen, Abdul; Clemente-Casares, Xavier; Althagafi, Marwan G.; Chen, Jinmiao; Kantores, Crystal; Hosseinzadeh, Siyavash; Aronoff, Laura; Wong, Anthony; Zaman, Rysa; Barbu, Iulia; Besla, Rickvinder; Lavine, Kory J.; Razani, Babak; Ginhoux, Florent; Husain, Mansoor; Cybulsky, Myron I.; Robbins, Clinton S.; Epelman, Slava

doi:10.1038/s41590-018-0272-2

Cited by 653 publications

(839 citation statements)

References 56 publications

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“…We also observed fast (gut and dermis) versus slow (kidney, spleen and peritoneum) RTM replacement. Others have shown that even within the same tissue, macrophage subpopulations with different phenotypes exhibit different turnover rates, including in the gut (De Schepper et al, 2018;Shaw et al, 2018), heart (Dick et al, 2019) and skin (Tamoutounour et al, 2013). Here, we confirmed that in the dermis, MHCII + macrophages are replaced at a faster rate than MHCIImacrophages (Tamoutounour et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Although Tim-4 can be used for early time points, it is not suitable for later time points, again highlighting that murine tissues are often analyzed prematurely, when macrophage equilibrium is not reached, leading to inaccurate conclusions. Rather, Tim-4 should be considered as a marker of long-term macrophage residency in tissues(Dick et al, 2019). In a sterileScott et al, 2016).…”

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confidence: 99%

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Fate mapping via Ms4a3 expression history traces monocyte-derived cells

Liu

Chakarov

et al. 2019

Preprint

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Most tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone-marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes and their functions compared to embryonic RTM remains unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation and disease is highly debated. Here, we identified Ms4a3 as a specific marker expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3 TdT reporter and Ms4a3 Cre -Rosa TdT fate mapper models to follow monocytes and their progenies. Our Ms4a3 Cre -Rosa TdT model traced efficiently blood monocytes (97%) and granulocytes (100%), but no lymphocytes or tissue dendritic cells. Using this model, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Fate mapping via Ms4a3 expression history traces monocyte-derived cells

Liu

Chakarov

et al. 2019

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132

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“…It is therefore of utmost importance to establish a precise baseline during 25 homeostasis as provided here by our new consensus map, to allow for a better understanding of any deviations of the myeloid cell compartment during stress, pathophysiological conditions and diseases. Furthermore, the dynamic processes of myelopoiesis during homeostasis but even more so during inflammatory conditions requires precise mapping of cellular identities as a prerequisite to identify targets for precise therapeutic intervention (Dick et al, 2019;Schultze, 2019;Schultze et al, 2019). Furthermore, the necessity to continuously iterate the process of 5 improving the consensus maps is nicely illustrated by the accompanying manuscript by Dutertre et al (Dutertre et al, 2019), further defining the cellular relationship of DC2/3 and monocytes.…”

Section: Discussionmentioning

confidence: 99%

A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space

Günther

Cirovic

Baßler

et al. 2019

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Highlights  Defining a consensus of the human myeloid cell compartment in peripheral blood  3 monocytes subsets, pDC, cDC1, DC2, DC3 and precursor DC make up the compartment  Distinguish myeloid cell compartment from other cell spaces, e.g. the NK cell space 5  Providing a generalizable method for building consensus maps for the life sciences 4 Abstract Single-cell genomic techniques are opening new avenues to understand the basic units of life.Large international efforts, such as those to derive a Human Cell Atlas, are driving progress in this area; here, cellular map generation is key. To expedite the inevitable iterations of these underlying maps, we have developed a rule-based data-informed approach to build next 5 generation cellular consensus maps. Using the human dendritic-cell and monocyte compartment in peripheral blood as an example, we performed computational integration of previous, partially overlapping maps using an approach we termed 'backmapping', combined with multi-color flowcytometry and index sorting-based single-cell RNA-sequencing. Our general strategy can be applied to any atlas generation for humans and other species. 10

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“…Discussion Innate immunity and cardiac inflammation have recently been linked to heart failure (Sager et al, 2016;Bajpai et al, 2018;Dick et al, 2019), a connection that may contribute to the dismal survival rate of patients with recurrent MI (Thune et al, 2011). There were no available systems for modeling inflammatory circuits in recurrent MI.…”

Section: !mentioning

confidence: 99%

A mouse model of recurrent myocardial infarction reports diminished emergency hematopoiesis and cardiac inflammation

Cremer

Vinegoni

et al. 2019

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Recurrent MI is common in patients with coronary artery disease and associates with high mortality. Here we developed a surgical mouse model in which two subsequent MIs affect different left ventricular regions in the same mouse. Recurrent MI was induced by ligating the left circumflex followed by the left anterior descending branch of the coronary artery. We characterized the resulting ischemia by whole-heart fluorescent coronary angiography after optical organ clearing and by cardiac MRI. We report that a first MI induces bone marrow "memory" via a circulating signal, thereby affecting hematopoietic factor expression in bone marrow macrophages. This altered the organism's reaction to subsequent events. Inspite at least similar extent of injury reported by blood troponin, recurrent MI caused reduced emergency hematopoiesis and less leukocytosis than a first MI. Consequently, fewer leukocytes migrated to the ischemic myocardium. The hematopoietic response to lipopolysaccharide was also mitigated after a previous MI. Our data suggest that hematopoietic and innate immune responses are shaped by a preceding MI. ! 2 ! 3 ! 4 S. Cremer and M.J. Schloss developed and validated the mouse model of recurrent MI. C. Vinegoni developed fluorescent coronary angiography. S. Cremer, M.J. Schloss, S. Zhang, D. Rohde and C.Vinegoni performed experiments and collected, analyzed and discussed data. G. Wojtkiewicz and S. Schmitt performed imaging experiments and collected data. S. Cremer, F. Swirski and M. Nahrendorf conceived experiments and discussed results and strategy. M. Nahrendorf conceived, designed and directed the study. S. Cremer and M. Nahrendorf wrote the manuscript, which was revised and approved by all authors. ! 13 ! 28 Supplementary Figure 2. HSPC numbers 10 days after MI. (A) Experimental outline. Mice had LAD MI 10 days before bone marrow analysis. (B) Dot plots and (C) quantification of HSPC in bone marrow of mice with MI compared to naive mice. (D) Numbers of mature leukocytes in bone marrow. *p<0.05, n=5 Student's t-test. Data are mean ± s.e.m.. ! 29 Supplementary Figure 3. Troponin after a first versus recurrent MI. (A) Experimental design. (B) Troponin levels after LAD ligation as the first compared to recurrent MI. n=5-9. ! 30 Supplementary Figure 4. Macrophage gating. (A) Gating strategy for bone marrow macrophages with antibody directed against F4/80 and (B) isotype control. (C) Histograms in red depicting the expression of MHCII, Cx3cr1, CD169 and Vcam1 in Gr1 hi monocytes and bone marrow macrophages. Isotype controls are shown in blue. ! 31 Supplementary Video 1: MRI short axis cine loop of LCX infarct. Delayed enhancement MRI short axis views of a mouse with LCX MI demonstrating injury of posterolateral left ventricular wall. Supplementary Video 2: MRI short axis cine loop after recurrent MI (LCX followed by LAD ligation). Delayed enhancement MRI short axis views of the same mouse as in supplementary video 1, now also showing injury of the anterior left ventricular wall.! 32

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Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Cited by 653 publications

References 56 publications

Fate mapping via Ms4a3 expression history traces monocyte-derived cells

Fate mapping via Ms4a3 expression history traces monocyte-derived cells

A rule-based data-informed cellular consensus map of the human mononuclear phagocyte cell space

A mouse model of recurrent myocardial infarction reports diminished emergency hematopoiesis and cardiac inflammation

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