Cardio-Immunologist, Macrophages. Associate Prof, Univ of Toronto. UHN. Research Director Peter Munk Cardiac Center. Loretta Rogers Chair. #Cardioimmunology
Toronto, Ontario
Based in Canada
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Great few days at #Cardioimmunology 2026. Excellent science, great discussions, and even better to catch up with friends @lavinelab, @xcc, @CardioOncology, Ricky Baylis and Burkhard Ludewig. Thanks to @PilarAlcaidePhD and @PilarMartinFern for organizing such a great meeting!
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Excited to share our review @CircRes with my former office mate @LavineLab doi.org/10.1161/circresaha.1…. Tracking cardiac macrophage heterogeneity from 🐭to human, including imaging tools! Written by talented students Megan Holt, Julia Lin, Markus Cicka & @AnthonyWongUofT
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Congrats @Homaira_H for your well received talk @WeinsteinConf #WeinsteinCVD2024 on improving engineered heart tissue function using macrophages!
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Search for genes & proteins of interest
See searchable datasets on our website (epelmanlab.com/resources)
For example, want to see if a protein increases in mini-hearts with hESC-MFs? svohra.shinyapps.io/Proteomi…
More data sets as well!
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hESC-MFs induce compartment specific effects (Cytosol vs mito)
I found this interesting. Krebs cycle proteins – those in mitochondria are reduce by MFs, those isoforms in cytosol are increased
But, only the mito effect is efferocytosis dependent. Needs more work!
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hESC-MFs reduce mitochondrial proteins & mitochondria
MFs reduce total mito proteins in mini-hearts while ATP stores are increased
MFs reduce mitochondria with CMs (as described by @NicolasAvilaJA @AndrsHidalgo16) & FBs
Reduced mito content inhibited when MFs cannot eat
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hESC-MFs efferocytosis of stressed cardiomyocytes drives beneficial effects
In❤️tissue, MFs upregulate efferocytic programs
MF eat labeled cardiomyocytes via phosphatidyl serine (can block with annexin)
Efferocytosis blockade reduces MF benefit to ❤️ function
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hESC-MFs metabolically reprogram cardiomyocytes to in vivo like fate
MFs decreased mito pathways (AT5PA, CPT1A, CS) & increased glycolysis (MCT1, GLUT1). CM1➡️CM2 with MFs
Mito pathways are down in early fetal CMs. hESC-CM educated by MFs became more early "fetal like"🧑🎓
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hESC-MFs reduce mitochondrial debris & improve micro-environment
36 Marker CyTOF revealed a massive reduction in mitochondrial protein (ATP5A) containing debris in mini-hearts integrated with MFs
MFs reduce mt-DNA release & cardiomyocyte apoptosis
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hESC-MFs induce sarcomeric protein production & maturation
With the help of @A_Gramolini & team, proteomics (LC-MS) on individual mini-hearts revealed widespread changes in contractile proteins & sarcomeric maturation (⬆️MYH7/6 and MYL2/7)
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hESC-Macrophages improve mini-heart function
1) Integrating hESC-MFs makes mini-hearts more compact & dense (physical remodeling)
2) Integrating MFs improved both the force of contraction and speed of relaxation.
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hESC-Macrophage (MF) Education
MFs are imprinted in tissues, but little known about human MF education.
MFs integrated in 3D mini-hearts transcriptionally reprogrammed to yolk sac & fetal cardiac MFs in utero. Cardiomyocytes (CM) & fibroblasts (FB) required for full education
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Our latest study, led by @Homaira_H. Hard to study #macrophages (MFs) in early human heart development (no tissue). Homaira integrated human ES-derived-MFs into beating cardiac microtissues & improved🫀function. rdcu.be/dHbj0. #cardioimmunology #regeneration.
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Interested in #cancer #immunotherapy & #myocarditis?
Great study @Nature by @MargaretAxelrod @CardioOncology & @BalkoLab, et al. nature.com/articles/s41586-0…
@AnthonyWongUofT and I are fortunate to provide a perspective on their work @NatureCVR rdcu.be/c0SJ5
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Cardiac macrophages can exert key functions directly, or act through surrogates via paracrine mediators. Moreover, cardiac macrophages are active both before & after birth, so if you are using constitutive knockouts, don't skip embryonic development!
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@rysa_zaman and I are happy to share our latest review on resident #cardiac #macrophages in health and disease @ImmunityCP. authors.elsevier.com/a/1fl5c… . We focus on key biological traits that influence macrophage functions (new and old).
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Bittersweet day as we say good bye to wonderfully talented @SarahADick. She is starting her own group at @queensu, and we are all excited to see her begin the next chapter! Great things to come!
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Thanks Javid! We tried to be complete, but in a table - some nuances about each population is lost. We did not include subsets of each lineage (i.e. different macrophage subset - our favorite, or different subsets of CD4+ T cells). But some of these details are found in text.
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What about publicly available tools? Why not start with @ImmGen_ to see express of your gene. Download publicly available data sets (which we list), and searchable websites for where your gene is expressed (also listed), including our own epelmanlab.com/resources.
Lastly, you wish to specifically delete gene X in an immune cell subset. What genetic tools are available, what factors should you consider when selecting a strain? Constitutive or inducible Cre? Have a read! We always welcome your feedback.
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If immune cell #/functions are altered in gene X-/- mice post injury, what can you learn from BM chimera studies? Cell intrinsic vs extrinsic functions, but also how changing micro-environments can confound interpretations. Great place for 50:50, and 10:90 competitive BM groups
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We highlight major issues that should be addressed. For example, have you properly taken into account known heterogeneity of the cell types altered in your study? Take for example resident & recruited macrophages, and how differing cell ratios can alter results.
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Fortunate to be part of a great @WUSTL study (labs of A. Diwan and J.M Lee), showing monocyte-derived macrophages target amyloid plaque in brains of mice with Alzheimer's Disease, splenectomy reduces their number and increases plaque burden. #Alzheimers jci.org/articles/view/152565
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7.Interesting details
-Why do fetal Kidney TLF+ MFs disappear after birth?
-Why do iWAT MFs have more monocyte replacement than eWAT/BAT MFs?
-Labeling CCR2+ cells at E14/E16 labels 40-70% of adult alveolar MFs. Much higher than any other subset, why this big difference?
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6b. Need for CCR2-post-natal
- Using CCR2 in gating is critical and helps define the 3rd subset of interstitial MFs (recently / continually recruited), mouse and human.
- Particularly helpful after birth, when MHC-II is being upregulated and dynamic compositional changes occur.
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6a. Need for CCR2-development
- CCR2 expression in early fetal tissue MFs reveals interesting developmental patterns
- large number of CCR2+ monocyte-derived MFs in the early brain (where do they go?)
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4b.Development
-labeling murine monocytes (~E14) or yolk-sac derived MFs (E8.5), both labeled TLF+ MFs after birth
-using amazing human fetal atlas @Muzz_Haniffa, MFs in early human yolk-sac are TLF+ MFs
-2 pathways for human TLF+ MF development (liver below), similar mouse
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4a. Development - murine
- all 3 MF subsets present in fetal growth
- change in composition over time that is tissue specific
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3b. Replacement Plateau
- MF replacement by monocytes 6&10 months post parabiosis
- When replacement occurred, it reached an upper max, did not appear progressive in most tissues
- Important to differentiate between slow gradual replacement vs. what may be predefined capacity
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3a. Lifecycle
-Used fate mapping (Cx3cr1-ERT2; retention of labeled MFs) and parabiosis (% replaced)
-TLF+ MFs: Least likely to be replaced by monocytes
-CCR2+ MFs: highly replaced by monocytes
-MHC-II+ MFs: More replacement than TLF+ MFs, less that CCR2+ MFs
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2. Transcriptional Similarity Between tissue MFs
- TLF+ MFs were the most similar across organs, followed by CCR2+ and lastly MHC-II+ MFs
- TLF+ MFs were most conserved between human and mouse
- Tissue origin drove the majority of transcriptional changes
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Key takeaways?
1. ScRNA-seq (5 organs) identified a small number of conserved genes that predicted three populations (random-forest modeling)
A. TLF+ MFs (standing for 'T'IMD4, 'L'YVE1 and/or 'F'OLR2)
B. CCR2+ MFs (lack TLF genes)
C. MHC-II+ MFs (lack TLF genes and CCR2)
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Our latest team effort @SciImmunology; doi.org/10.1126/sciimmunol.a…. What is a good starting point to study tissue macrophages (MFs)? We examined 17 murine tissues (5 in detail) & human correlates, fetal & adult. We found 3 interstitial MF subsets in all tissues. Cover @Ella_Maru 1/n
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Excited to share our latest work @immunity, led by @rysa_zaman. doi.org/10.1016/j.immuni.202…. 1/3 of the world has high blood pressure. The heart grows in size (cardiomyocytes grow) to adapt. We asked, are resident cardiac macrophages (MFs) involved in adaptation?
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Congrats to the Razani Lab @WUSTLmed rdcu.be/b0Gld in @NatMetabolism showing high protein #Diet, increased blood amino acids, promote atherosclerosis. What other inflammatory conditions could high protein diets contribute to? Great news&views rdcu.be/b0Glk
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Great timing today, with the start #EMDS2019 and our review on monocyte heterogeneity in cardiovascular disease in @FrontImmunol. doi.org/10.3389/fimmu.2019.0…
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Importantly, congrats to the brilliant women who were the co-first authors @SarahADick @MacklinJill #Sara_Nejat, the great collaborators, and the wonderful commentary by @LabSchultze - see nature.com/articles/s41590-0…. Original article link rdcu.be/bdbZD
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Happy to share our latest work on macrophage heterogeneity within ischemic heart tissue using #singlecell RNA-seq and fate mapping. nature.com/ni/volumes/20/iss… . #NatImmunol #macrophage #cardiac #UHN #PMunkCardiacCnt #TRogersResearch
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